University of Groningen



-954659-112585500Sterre Koops S2365618, supervisor: prof. dr. J.C. Billeter, may 2016 -95906227199200Faculty of Mathematics & Natural SciencesUniversity of GroningenFOXP2 The language gene?AN ANALYSIS OF THE ROLE THE FOXP2 GENE PLAYS IN THE DEVELOPMENT OF LANGUAGE IN HUMANSB A C H E L O R T H E S I SF O X P 2The language gene?An analysis of the role theFOXP2 gene plays in the developmentof language in humansSterre KoopsS2365618May, 2016Supervisor: Prof. Dr. J.C. BilleterFaculty of Mathematics & Natural SciencesUniversity of GroningenSource front page image: PyMOL, created by Emw, 2009Word count: 6191Table of ContentInhoudsopgaveTOC \o "1-3" \h \z \uTable of Content PAGEREF _Toc456536636 \h 3Abstract PAGEREF _Toc456536637 \h 4Introduction PAGEREF _Toc456536638 \h 5The evolution of mankind PAGEREF _Toc456536639 \h 5The evolution of language PAGEREF _Toc456536640 \h 6The Gossip Theory of Language PAGEREF _Toc456536641 \h 6What is language? PAGEREF _Toc456536642 \h 8Communication versus language PAGEREF _Toc456536643 \h 8The biology of language PAGEREF _Toc456536644 \h 9Grammar & complex syntax PAGEREF _Toc456536645 \h 10FOXP2 PAGEREF _Toc456536646 \h 11Results PAGEREF _Toc456536647 \h 11FOXP2, the gene PAGEREF _Toc456536648 \h 11Evolutionary story of FOXP2 PAGEREF _Toc456536649 \h 12Mechanisms through which FOXP2 affects language PAGEREF _Toc456536650 \h 13Comparison of the above with the biological mechanisms of language PAGEREF _Toc456536651 \h 15Other genes involved in language PAGEREF _Toc456536652 \h 16Childhood Apraxia of Speech (CAS) PAGEREF _Toc456536653 \h 16Stuttering PAGEREF _Toc456536654 \h 17Specific Language Impairment (SLI) and Dyslexia PAGEREF _Toc456536655 \h 17Epilepsy-Aphasia Spectrum Disorders (EAS) PAGEREF _Toc456536656 \h 18Conclusion PAGEREF _Toc456536657 \h 18Acknowledgements PAGEREF _Toc456536658 \h 22Further reading tips PAGEREF _Toc456536659 \h 22Sources PAGEREF _Toc456536660 \h 23AbstractLanguage played a remarkable role in the evolution of humans and our culture, but to what extent does genetics relate to language? A gene, FOXP2, was found to have influence on the development of language and was soon named ‘the language gene’ among the more popular reports about FOXP2. If FOXP2 genuinely affects the development of language, it must play a role in the components that distinguish language from other forms of communication. Those components are grammar and complex syntax. Grammar most probably evolved due to the increase in group size in which humans lived, an idea grasped by the gossip theory of language. The human form of FOXP2, however, evolved before the group sizes were thusly big that grammar was needed. It therefore seems to play a role in communication as a whole, and not specifically to language. After examining the evolutionary story of FOXP2, the mechanisms through which FOXP2 affects language and other genes that seem to be involved in language, we can conclude that the evolution of the human form of FOXP2 was a necessary spark to ignite the origin of language, but there is much, much more to language. FOXP2 is a necessary gene for language, but cannot be presumed more important than certain other – cultural, biological, genetic – factors that contributed to the origin of language.IntroductionAny reader of this paper has a vocabulary of his or her primary language containing around 50 000 words. We have the knowledge to understand the meaning of those words, and possess the ability to combine the words in a correct, understandable sentence. About a fourth of our vocabulary is already in our possession at the age of six. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : ";", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Hurford", "given" : "James R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Oxford University Press", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "title" : "The Origins of Grammar", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hurford, 2011)", "plainTextFormattedCitation" : "(Hurford, 2011)", "previouslyFormattedCitation" : "(Hurford, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hurford, 2011) Language is a remarkable, often presumed uniquely human, quality. It can be viewed as a phenotype, which indicates that there is also a genetic architecture at the base of the quality. Unravelling this genetic architecture would allow us to understand the origin and evolution of language. And rather recently a gene was found that seems to play a role in speech production, opening up our view of that genetic architecture. That gene is FOXP2. This thesis will take a closer look at the genetic architecture and evolution of language in general and at the influence of FOXP2 in particular. To what extent does genetics relate to language? But first, we must define language, what makes it different from other forms of communication and why we consider language uniquely human. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1098/rstb.2000.0723", "ISSN" : "0962-8436", "PMID" : "11127907", "abstract" : "Language is the most important evolutionary invention of the last few million years. It was an adaptation that helped our species to exchange information, make plans, express new ideas and totally change the appearance of the planet. How human language evolved from animal communication is one of the most challenging questions for evolutionary biology The aim of this paper is to outline the major principles that guided language evolution in terms of mathematical models of evolutionary dynamics and game theory. I will discuss how natural selection can lead to the emergence of arbitrary signs, the formation of words and syntactic communication.", "author" : [ { "dropping-particle" : "", "family" : "Nowak", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Philosophical transactions of the Royal Society of London. Series B, Biological sciences", "id" : "ITEM-1", "issue" : "1403", "issued" : { "date-parts" : [ [ "2000", "11", "29" ] ] }, "page" : "1615-22", "title" : "Evolutionary biology of language.", "type" : "article-journal", "volume" : "355" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Nowak, 2000)", "plainTextFormattedCitation" : "(Nowak, 2000)", "previouslyFormattedCitation" : "(Nowak, 2000)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Nowak, 2000) To do so, we will begin by taking a step back and look at how language evolved. After all, the light of evolution is needed to illuminate the context in which language came about, and traits – especially as complex as language – don’t suddenly arise out of nothing. Our closest relatives must have had access to – perhaps other, perhaps similar – forms of language. The evolution of mankind-6184904023995Figure SEQ Figure \* ARABIC 1: An illustration of the trunk on the tree of life that displays the lineage from which homo sapiens arose.Figure SEQ Figure \* ARABIC 1: An illustration of the trunk on the tree of life that displays the lineage from which homo sapiens arose.-48895127444500The species homo diverged from the apes somewhere between 7 to 13 million years ago, and branched into several species, including erectus, habilis, neanderthalensis and sapiens, as displayed in figure 1. But out of all those species, only one appears to have developed the ability to communicate in a very refined way, namely via language as we know it today: Homo sapiens. 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Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971)", "previouslyFormattedCitation" : "(Dunbar, 1996; Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dunbar, 1996; Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971) As Steels (2012) puts it: “Language and language processing is extraordinary complex and as we probe deeper into its origins we find more complexity than anyone ever imagined.” The main problem making the origin of language such a difficult topic, is the lack of direct evidence about its origin. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.plrev.2011.11.003", "ISBN" : "1571-0645", "ISSN" : "15710645", "PMID" : "22119477", "abstract" : "This is a reply to commentaries on a target article in this volume reviewing models for the cultural evolution of language. 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All arguments are based on inferences. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Tallerman", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gibson", "given" : "K.R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Oxford University Press", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011", "11", "17" ] ] }, "title" : "The Oxford Handbook of Language Evolution", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tallerman & Gibson, 2011)", "plainTextFormattedCitation" : "(Tallerman & Gibson, 2011)", "previouslyFormattedCitation" : "(Tallerman & Gibson, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Tallerman & Gibson, 2011) Still, many theories try to unravel the emergence of this unique feature of mankind. 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M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Longmans, Green, and co., London", "id" : "ITEM-8", "issued" : { "date-parts" : [ [ "1885" ] ] }, "title" : "Lectures on the science of language", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dunbar, 1996; W. T. Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971)", "plainTextFormattedCitation" : "(Dunbar, 1996; W. T. Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971)", "previouslyFormattedCitation" : "(Dunbar, 1996; Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dunbar, 1996; Fitch, 2004; Goodall, 1986; Muller, 1885; Paget, 1930; Premack & Premack, 1984; Rappaport, 1999; Trivers, 1971) Out of those theories, there is one which attracted my attention because it combines an evolutionary approach with the fact that humans are amongst the most social of animals. This theory is the gossip theory of language. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Dunbar", "given" : "R.I.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Faber & Faber", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1996" ] ] }, "title" : "Grooming, Gossip and the Evolution of Language", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dunbar, 1996)", "plainTextFormattedCitation" : "(Dunbar, 1996)", "previouslyFormattedCitation" : "(Dunbar, 1996)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dunbar, 1996)The Gossip Theory of LanguageLanguage is used to transfer information, whether this concerns the whereabouts of a predator, or creative ideas. The gossip theory of language argues that the most relevant information to transfer specifically via language is information about other people. This theory states that language evolved as a medium for gossip. Homo sapiens are very social animals and our social abilities helped us survive, thrive and climb up the food chain. Knowledge about other individuals and their social relationships (with yourself and others) is very important for creating a stable, coherent society. As individuals, we will never be stronger than a lion, but as a group, our combined intellect and strength can outsmart any animal. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Dunbar", "given" : "R.I.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Faber & Faber", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1996" ] ] }, "title" : "Grooming, Gossip and the Evolution of Language", "type" : "webpage" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Harari", "given" : "Y.N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Sapiens: A Brief History of Humankind", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dunbar, 1996; Harari, 2012)", "plainTextFormattedCitation" : "(Dunbar, 1996; Harari, 2012)", "previouslyFormattedCitation" : "(Dunbar, 1996; Harari, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dunbar, 1996; Harari, 2012)As shown in figure 2, group size has increased exponentially since the evolution of Homo erectus, a phenomenon that put a tremendous amount of pressure on the coherency of groups of Homo. This rapid increase in group size might have created an evolutionary pressure to develop a more efficient way for social interaction. Up until then, social grooming was probably the way used to bond social groups, but research has found that the maximum amount of time primates spend on this activity is 20% of waking hours. The time spent on social grooming would need to increase to 43% of the day for the group size typical to modern humans (figure 3). 295275000Figure SEQ Figure \* ARABIC 2: How average group size probably increased during the evolution of Homo. AMH = Anatomically Modern Humans.294005161290004108452706370Figure SEQ Figure \* ARABIC 3: The predicted grooming time per Homo species, in percentage per day. The x-axis displays the millions of years ago that the named species lived. AMH = anatomically modern humansFigure SEQ Figure \* ARABIC 3: The predicted grooming time per Homo species, in percentage per day. The x-axis displays the millions of years ago that the named species lived. AMH = anatomically modern humans“In the course of our human evolution, as we’ve been trying to evolve bigger and bigger groups to cope with the challenges that the world has thrown at us, we needed some additional mechanism to allow us to breakthrough what was effectively a glass ceiling”Robin DunbarDunbar is stating here that language probably evolved to bridge that gap in bonding time requirement, because it allowed time to be used more efficiently, because of three key features of language ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Dunbar", "given" : "R.I.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Faber & Faber", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1996" ] ] }, "title" : "Grooming, Gossip and the Evolution of Language", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dunbar, 1996)", "plainTextFormattedCitation" : "(Dunbar, 1996)", "previouslyFormattedCitation" : "(Dunbar, 1996)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dunbar, 1996):Several individuals can be ‘groomed’ at onceIt is possible to timeshare with speech in a way that is not possible with groomingLanguage allows exchanging information about events within our social network that happened during our absence. Sapiens most probably developed the best form of language, compared to their relatives, allowing them to extent their smaller groups the most and develop a closer and more refined collaboration. Because even though Neanderthals possessed the same version of FOXP2 as modern humans, and might have already possessed the physiological requirements for speech, it is likely that it was not at the same level as that of modern humans. Their maximum group size, as shown in figure 2, was still lower than the maximum group size of modern humans. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3389/fpsyg.2013.00397", "ISSN" : "1664-1078", "PMID" : "23847571", "abstract" : "It is usually assumed that modern language is a recent phenomenon, coinciding with the emergence of modern humans themselves. Many assume as well that this is the result of a single, sudden mutation giving rise to the full \"modern package.\" However, we argue here that recognizably modern language is likely an ancient feature of our genus pre-dating at least the common ancestor of modern humans and Neandertals about half a million years ago. To this end, we adduce a broad range of evidence from linguistics, genetics, paleontology, and archaeology clearly suggesting that Neandertals shared with us something like modern speech and language. This reassessment of the antiquity of modern language, from the usually quoted 50,000-100,000 years to half a million years, has profound consequences for our understanding of our own evolution in general and especially for the sciences of speech and language. As such, it argues against a saltationist scenario for the evolution of language, and toward a gradual process of culture-gene co-evolution extending to the present day. Another consequence is that the present-day linguistic diversity might better reflect the properties of the design space for language and not just the vagaries of history, and could also contain traces of the languages spoken by other human forms such as the Neandertals.", "author" : [ { "dropping-particle" : "", "family" : "Dediu", "given" : "Dan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levinson", "given" : "Stephen C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in psychology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "1", "5" ] ] }, "language" : "English", "page" : "397", "publisher" : "Frontiers", "title" : "On the antiquity of language: the reinterpretation of Neandertal linguistic capacities and its consequences.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Harari", "given" : "Y.N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Sapiens: A Brief History of Humankind", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dediu & Levinson, 2013; Harari, 2012)", "plainTextFormattedCitation" : "(Dediu & Levinson, 2013; Harari, 2012)", "previouslyFormattedCitation" : "(Dediu & Levinson, 2013; Harari, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dediu & Levinson, 2013; Harari, 2012)246634040386000What is language?All animals have some sort of communication, and some of them – like bees and ants – are even capable of very refined communication. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Harari", "given" : "Y.N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Sapiens: A Brief History of Humankind", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Harari, 2012)", "plainTextFormattedCitation" : "(Harari, 2012)", "previouslyFormattedCitation" : "(Harari, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Harari, 2012) What is the difference between the language we speak, and the communication forms that other animals use? Communication versus language2465705231775Figure SEQ Figure \* ARABIC 4: The basic design of communication. Most animals only communicate according to the red box, some animals’ communication also fits the description in the orange box, whereas the blue box is only represented in human’s main form of communication: language. (Berwick, 2013)00Figure SEQ Figure \* ARABIC 4: The basic design of communication. Most animals only communicate according to the red box, some animals’ communication also fits the description in the orange box, whereas the blue box is only represented in human’s main form of communication: language. (Berwick, 2013)The grivet, or African green monkey, uses different types of alarm calls to alert the others for a specific type of predator. Grivets know whether they are being warned for lions (they would all hastily climb trees), or for eagles (and they would look fearful to the skies). ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Harari", "given" : "Y.N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Sapiens: A Brief History of Humankind", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Harari, 2012)", "plainTextFormattedCitation" : "(Harari, 2012)", "previouslyFormattedCitation" : "(Harari, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Harari, 2012) But even though grivets can be rather specific concerning the type of predator that is coming, we do not consider that to be language. We consider that to be communication. Language specifies the method of human communication in which words are phrased that are used in a structured and conventional way. It is one of many systems within the spectrum of communication, as shown in figure 4. But what is the key module that represents the beginning of language among this spectrum? A person needs to master several components, before he or she has a proper native tongue. There is the biological aspect, making someone biologically capable of producing and hearing language, and there is the linguistic component, allowing someone to comprehend what the other is saying and producing correct sentences that others can understand. The latter involves components like vocabulary, pronunciation and grammar. The biology of languageSeveral anatomical changes appeared in early Homo, in between the time period of 2.5 to 0.8 million years ago (see figure 1). Changes needed for the biological ability to acquire speech arose since the australopithecines, who developed a more L-shaped vocal tract necessary for speech-like vocalization. Other developments among other Homo-species were a smaller trachea, lowered larynx and finer muscle control of our face, all necessary for many of the sounds that modern humans can produce. The Neanderthal was most likely already anatomically able to speak. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cub.2007.10.008", "ISSN" : "0960-9822", "PMID" : "17949978", "abstract" : "Although many animals communicate vocally, no extant creature rivals modern humans in language ability. Therefore, knowing when and under what evolutionary pressures our capacity for language evolved is of great interest. Here, we find that our closest extinct relatives, the Neandertals, share with modern humans two evolutionary changes in FOXP2, a gene that has been implicated in the development of speech and language. We furthermore find that in Neandertals, these changes lie on the common modern human haplotype, which previously was shown to have been subject to a selective sweep. These results suggest that these genetic changes and the selective sweep predate the common ancestor (which existed about 300,000-400,000 years ago) of modern human and Neandertal populations. This is in contrast to more recent age estimates of the selective sweep based on extant human diversity data. 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Many assume as well that this is the result of a single, sudden mutation giving rise to the full \"modern package.\" However, we argue here that recognizably modern language is likely an ancient feature of our genus pre-dating at least the common ancestor of modern humans and Neandertals about half a million years ago. To this end, we adduce a broad range of evidence from linguistics, genetics, paleontology, and archaeology clearly suggesting that Neandertals shared with us something like modern speech and language. This reassessment of the antiquity of modern language, from the usually quoted 50,000-100,000 years to half a million years, has profound consequences for our understanding of our own evolution in general and especially for the sciences of speech and language. As such, it argues against a saltationist scenario for the evolution of language, and toward a gradual process of culture-gene co-evolution extending to the present day. 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At least two changes were necessary prerequisites for modern human speech abilities: (1) modification of vocal tract morphology, and (2) development of vocal imitative ability. Despite an extensive literature, attempts to pinpoint the timing of these changes using fossil data have proven inconclusive. However, recent comparative data from nonhuman primates have shed light on the ancestral use of formants (a crucial cue in human speech) to identify individuals and gauge body size. Second, comparative analysis of the diverse vertebrates that have evolved vocal imitation (humans, cetaceans, seals and birds) provides several distinct, testable hypotheses about the adaptive function of vocal mimicry. These developments suggest that, for understanding the evolution of speech, comparative analysis of living species provides a viable alternative to fossil data. However, the neural basis for vocal mimicry and for mimesis in general remains unknown.", "author" : [ { "dropping-particle" : "", "family" : "Fitch", "given" : "WT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends in cognitive sciences", "id" : "ITEM-3", "issue" : "7", "issued" : { "date-parts" : [ [ "2000", "7" ] ] }, "page" : "258-267", "title" : "The evolution of speech: a comparative review.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dediu & Levinson, 2013; W. Fitch, 2000; Krause et al., 2007b)", "plainTextFormattedCitation" : "(Dediu & Levinson, 2013; W. Fitch, 2000; Krause et al., 2007b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dediu & Levinson, 2013; Fitch, 2000; Krause et al., 2007b) Even the auditory system of modern humans evolved to create our improved perception of sounds within the 2-4 kHz range, which is the range in which the human voice lies. Besides these anatomical changes, our brain is also refined to deal with the complexity that is language. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Aronoff", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rees-Miller", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Blackwell publishers", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2001" ] ] }, "title" : "The Handbook of Linguistics", "type" : "webpage" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1007/s11065-014-9277-2", "ISSN" : "1573-6660", "PMID" : "25597031", "abstract" : "The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.", "author" : [ { "dropping-particle" : "", "family" : "Graham", "given" : "Sarah A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deriziotis", "given" : "Pelagia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychology review", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "3" ] ] }, "page" : "3-26", "title" : "Insights into the genetic foundations of human communication.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Johansson", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rocky Mountain Modern Language Association", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "2006" ] ] }, "title" : "Origins of Language: Constraints on Hypotheses", "type" : "webpage" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1098/rstb.2000.0723", "ISSN" : "0962-8436", "PMID" : "11127907", "abstract" : "Language is the most important evolutionary invention of the last few million years. It was an adaptation that helped our species to exchange information, make plans, express new ideas and totally change the appearance of the planet. How human language evolved from animal communication is one of the most challenging questions for evolutionary biology The aim of this paper is to outline the major principles that guided language evolution in terms of mathematical models of evolutionary dynamics and game theory. I will discuss how natural selection can lead to the emergence of arbitrary signs, the formation of words and syntactic communication.", "author" : [ { "dropping-particle" : "", "family" : "Nowak", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Philosophical transactions of the Royal Society of London. Series B, Biological sciences", "id" : "ITEM-4", "issue" : "1403", "issued" : { "date-parts" : [ [ "2000", "11", "29" ] ] }, "page" : "1615-22", "title" : "Evolutionary biology of language.", "type" : "article-journal", "volume" : "355" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Aronoff & Rees-Miller, 2001; Graham, Deriziotis, & Fisher, 2015; Johansson, 2006; Nowak, 2000)", "plainTextFormattedCitation" : "(Aronoff & Rees-Miller, 2001; Graham, Deriziotis, & Fisher, 2015; Johansson, 2006; Nowak, 2000)", "previouslyFormattedCitation" : "(Aronoff & Rees-Miller, 2001; Graham, Deriziotis, & Fisher, 2015; Johansson, 2006; Nowak, 2000)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Aronoff & Rees-Miller, 2001; Graham, Deriziotis, & Fisher, 2015; Johansson, 2006; Nowak, 2000)Two brain areas are mostly associated with language, namely Broca’s area and Wernicke’s area (Figure 5). Broca’s area is concerned with the production of speech, while Wernicke’s area is involved with the comprehension of speech, and using the proper words to express our thoughts. Together they allow us to truly communicate with others, because we could not speak without Broca’s area, and we could not understand speech without Wernicke’s area. It is debatable whether these areas are uniquely human. Similar brain structures have been found in other animals, mainly mammals including primates, but since those animals are not capable of producing language, the question remains whether those areas are functional and not only anatomically similar between species, or whether they serve a completely different purpose. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Kean", "given" : "M.L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "UC Irvine", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "title" : "Broca's and Wernicke's Aphasia", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kean, 2016)", "plainTextFormattedCitation" : "(Kean, 2016)", "previouslyFormattedCitation" : "(Kean, 2016)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kean, 2016)Although these biological aspects contribute to our ability to produce speech, this ability is useless if we don’t understand what the other is saying, or if one is misunderstood. This is why grammar is so important for language.18034017462500 Figure SEQ Figure \* ARABIC 5: The location of broca’s area and wernicke’s area in the human brain. both areas are most often located in the left hemisphere. broca’s area is situated in the left inferior frontal gyrus, and wernicke’s area lies in the left posterior superior temporal gyrus. Source: carta., 2016. Grammar & complex syntaxSyntax are the rules needed to construct a proper sentence, while grammar involves syntax among other sets of rules. Grammar is the overall term that involves all sets of rules in any given language. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Unknown", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Literary Devices", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "title" : "Syntax - Examples and Definition of Syntax", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Unknown, 2016)", "plainTextFormattedCitation" : "(Unknown, 2016)", "previouslyFormattedCitation" : "(Unknown, 2016)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Literary devices, 2016) Grammar, and then especially complex syntax, are the most valuable features of language. Without grammar, it does not matter whether we understand the words, because we might not understand the sentence. Grammar is therefore an important feature that separates human language from the broad spectrum of animal communication. 28073352967355Figure SEQ Figure \* ARABIC 6: Assessment of grammatical ability. A person needs to show the picture in which ‘the horse kicks the cow’. source: Carlson, 2014Figure SEQ Figure \* ARABIC 6: Assessment of grammatical ability. A person needs to show the picture in which ‘the horse kicks the cow’. source: Carlson, 201428073355016500Grammar has been essential in the development of coherent, large societies. According to the gossip theory, language evolved to help us live in larger groups. But for gossip to work, it is important that information conveyed through language is truthful. Otherwise, gossip would never help us increase group coherence, because we would still not know who to trust and who not. Dishonest language is not an evolutionary stable strategy and would thus be expected to quickly be selected against, while it would not be beneficial for the increased group sizes in which humans live. Grammar is required for the information to be transferred truthfully. Many false conclusions can be drawn if someone cannot make up from a gossip whom is doing something to or with whom. The significance of grammar can become clear if we look at the assessment of grammatical ability among patients who suffer from Broca’s aphasia. Patients who suffer from Broca’s aphasia experience difficulty with producing fluent speech and also face trouble understanding complex grammatical constructs. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Carlson", "given" : "N.R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pearson Education Limited", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "title" : "Physiology of Behavior", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Carlson, 2014)", "plainTextFormattedCitation" : "(Carlson, 2014)", "previouslyFormattedCitation" : "(Carlson, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Carlson, 2014) When shown the picture in figure 6 and ask which one depicts a horse kicking a cow, patients with Broca’s aphasia often fail to show the picture in which ‘the horse kicks the cow’. 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What has emerged from this research is that the unified nature of human language arises from a shared, species-specific computational ability. This ability has identifiable correlates in the brain and has remained fixed since the origin of language approximately 100 thousand years ago. Although songbirds share with humans a vocal imitation learning ability, with a similar underlying neural organization, language is uniquely human. ?? 2012 Elsevier Ltd.", "author" : [ { "dropping-particle" : "", "family" : "Berwick", "given" : "Robert C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friederici", "given" : "Angela D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chomsky", "given" : "Noam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bolhuis", "given" : "Johan J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends in Cognitive Sciences", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "98", "title" : "Evolution, brain, and the nature of language", "type" : "article", "volume" : "17" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Dunbar", "given" : "R.I.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Faber & Faber", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "1996" ] ] }, "title" : "Grooming, Gossip and the Evolution of Language", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Berwick, Friederici, Chomsky, & Bolhuis, 2013; Carlson, 2014; Dunbar, 1996)", "plainTextFormattedCitation" : "(Berwick, Friederici, Chomsky, & Bolhuis, 2013; Carlson, 2014; Dunbar, 1996)", "previouslyFormattedCitation" : "(Berwick, Friederici, Chomsky, & Bolhuis, 2013; Carlson, 2014; Dunbar, 1996)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Berwick, Friederici, Chomsky, & Bolhuis, 2013; Carlson, 2014; Dunbar, 1996)FOXP2Even though there is still much debate concerning the origin of language, by now it is widely accepted that speech is an innate capacity of the human brain, and this innate capacity allows us to learn a language. Genetic changes may underpin the reason why humans evolved language, but our relatives did not. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Matsuzawa", "given" : "T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Opinion in Neurobiology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "23:443-449", "title" : "Evolution of the brain and social behavior in chimpanzees", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Matsuzawa, 2013)", "plainTextFormattedCitation" : "(Matsuzawa, 2013)", "previouslyFormattedCitation" : "(Matsuzawa, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Matsuzawa, 2013) Despite other apes also being rather social animals, humans seem to be unique in the extent of their social drive, which increased the benefit-to-cost ratio of developing this complex and demanding communication system. A search for the genetic underpinning of language has therefore been of high interest. And in 1998 the genetic basis of this capability was thought to be found. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrn1605", "ISBN" : "1471-003X (Print)\\n1471-003X (Linking)", "ISSN" : "1471-003X", "PMID" : "15685218", "abstract" : "That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech. [ABSTRACT FROM AUTHOR]", "author" : [ { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Copp", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Neuroscience", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "131-138", "title" : "FOXP2 and the neuroanatomy of speech and language", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vargha-Khadem, Gadian, Copp, & Mishkin, 2005)", "plainTextFormattedCitation" : "(Vargha-Khadem, Gadian, Copp, & Mishkin, 2005)", "previouslyFormattedCitation" : "(Vargha-Khadem, Gadian, Copp, & Mishkin, 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vargha-Khadem, Gadian, Copp, & Mishkin, 2005) Half of the KE family suffered from a severe speech disorder, called developmental verbal dyspraxia, indicating that this speech disorder has a genetic basis following a dominant mode of inheritance. Geneticists from the University of Oxford identified the gene responsible for their condition, and named the gene FOXP2. Although we do not yet fully understand how the disruption of one copy of FOXP2 could induce such a severe speech and language disorder, it has become clear that FOXP2 plays a significant role in the most complex mechanical motion that the human body can execute: the fine muscle movements needed to produce speech. Most probably, FOXP2 has influences in our brain’s basic learning circuitry, allowing us to learn these fine muscle movements but exactly how remains an unanswered question. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1414542111", "ISSN" : "1091-6490", "PMID" : "25225386", "abstract" : "The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.", "author" : [ { "dropping-particle" : "", "family" : "Schreiweis", "given" : "Christiane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bornschein", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burgui\u00e8re", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kerimoglu", "given" : "Cemil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schreiter", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dannemann", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goyal", "given" : "Shubhi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rea", "given" : "Ellis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "French", "given" : "Catherine a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puliyadi", "given" : "Rathi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groszer", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mundry", "given" : "Roger", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winter", "given" : "Christine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hevers", "given" : "Wulf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "P\u00e4\u00e4bo", "given" : "Svante", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Enard", "given" : "Wolfgang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Graybiel", "given" : "Ann M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proc. 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A.", "id" : "ITEM-1", "issue" : "39", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "14253-8", "title" : "Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.", "type" : "article-journal", "volume" : "111" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Schreiweis et al., 2014)", "plainTextFormattedCitation" : "(Schreiweis et al., 2014)", "previouslyFormattedCitation" : "(Schreiweis et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Schreiweis et al., 2014)ResultsFOXP2, the geneFoxP2 is located on chromosome 7 (see figure 7) and belongs to a gene family that produces proteins containing forkhead-box domains ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1006/dbio.2002.0780", "ISSN" : "00121606", "author" : [ { "dropping-particle" : "", "family" : "Carlsson", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mahlapuu", "given" : "Margit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Developmental Biology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2002", "10" ] ] }, "page" : "1-23", "title" : "Forkhead Transcription Factors: Key Players in Development and Metabolism", "type" : "article-journal", "volume" : "250" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Carlsson & Mahlapuu, 2002)", "plainTextFormattedCitation" : "(Carlsson & Mahlapuu, 2002)", "previouslyFormattedCitation" : "(Carlsson & Mahlapuu, 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Carlsson & Mahlapuu, 2002), known to have transcription factors function and hence to regulate gene expression. Indeed, FOXP2 controls the expression of target genes resulting in expression of other proteins in a temporally and spatially regulated manner. ‘FOXP2’s therefore function to regulate a cascade (or cascades) of other genes’. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1364-6613(03)00104-9", "ISBN" : "1879-307X", "ISSN" : "13646613", "PMID" : "12804692", "abstract" : "The human capacity for acquiring speech and language must derive, at least in part, from the genome. In 2001, a study described the first case of a gene, FOXP2, which is thought to be implicated in our ability to acquire spoken language. In the present article, we discuss how this gene was discovered, what it might do, how it relates to other genes, and what it could tell us about the nature of speech and language development. We explain how FOXP2 could, without being specific to the brain or to our own species, still provide an invaluable entry-point into understanding the genetic cascades and neural pathways that contribute to our capacity for speech and language.", "author" : [ { "dropping-particle" : "", "family" : "Marcus", "given" : "Gary F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends in Cognitive Sciences", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "257-262", "title" : "FOXP2 in focus: What can genes tell us about speech and language?", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Marcus & Fisher, 2003)", "plainTextFormattedCitation" : "(Marcus & Fisher, 2003)", "previouslyFormattedCitation" : "(Marcus & Fisher, 2003)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Marcus & Fisher, 2003) FOXP2 is not unique to Homo Sapiens. Mice and chimpanzees also have a version of FOXP2. That of mice is 93.5% identical to the human version. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature01025", "ISBN" : "0028-0836 (Print)\\r0028-0836 (Linking)", "ISSN" : "0028-0836", "PMID" : "12192408", "abstract" : "Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution.", "author" : [ { "dropping-particle" : "", "family" : "Enard", "given" : "Wolfgang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon\u00a0E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Przeworski", "given" : "Molly", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lai", "given" : "Cecilia S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wiebe", "given" : "Victor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kitano", "given" : "Takashi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "P\u00e4\u00e4bo", "given" : "Svante", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "6900", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "869-72", "title" : "Molecular evolution of FOXP2, a gene involved in speech and language", "type" : "article-journal", "volume" : "418" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Enard, Fisher, et al., 2002)", "plainTextFormattedCitation" : "(Enard, Fisher, et al., 2002)", "previouslyFormattedCitation" : "(Enard, Fisher, et al., 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Enard, Fisher, et al., 2002) However, a mouse squeaks, and – except maybe Mickey Mouse– no mouse ever spoke in words. So how did FOXP2 evolve to the similar yet significantly different versions between mice, apes and humans? -244602024574500Evolutionary story of FOXP29798052338070Figure SEQ Figure \* ARABIC 7: The red line in the cytogenetic band displays the location of FOXP2, located at 7q31.1. Source: 00Figure SEQ Figure \* ARABIC 7: The red line in the cytogenetic band displays the location of FOXP2, located at 7q31.1. Source: Due to the increasing availability of genome sequences, we can compare the human FOXP2 to versions of the gene found in other vertebrate species, including primates and two extinct hominid species, which are contemporary of early Homo sapiens, namely the Neanderthals and the Denisovans. (Gaya-Vidal and Alba 2014). The mouse lineages diverged from chimpanzee, gorilla and rhesus monkeys 75 million years ago, yet these two lineages have just one altered amino acid in the protein encoded by FOXP2, as seen in figure 8. The human FOXP2 differs in two amino acids from the chimpanzee’s, gorilla’s and rhesus monkey’s. (Enard, Fisher, et al., 2002) Research suggests that FOXP2 was already of significance in the development of the common ancestor of the humans and mice’s brain, probably for the development of certain aspects of motor control. (Krause et al., 2007) 692152637790Figure SEQ Figure \* ARABIC 8: The lighter blue bars represent amino acid changes. One bar euqals one amino acid change. Source: Nature, vol. 418, P.869Figure SEQ Figure \* ARABIC 8: The lighter blue bars represent amino acid changes. One bar euqals one amino acid change. Source: Nature, vol. 418, P.8696921512954000The next step is the two mutations that took place at the time of the divergence of humans and chimpanzees, some 7 million years ago.It is now thought that probably only one of these two changes is evident for speech development, while the second mutation may do nothing. This is evidenced by the observation that other mammals, mainly carnivores such as dogs and wolves, independently evolved this other “human” FOXP2 mutation, yet they do not show the necessary (neuro-)anatomical changes needed to produce speech. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature.2011.9395", "ISSN" : "1744-7933", "author" : [ { "dropping-particle" : "", "family" : "Callaway", "given" : "Ewen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011", "11", "18" ] ] }, "title" : "'Language gene' speeds learning", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Callaway, 2011)", "plainTextFormattedCitation" : "(Callaway, 2011)", "previouslyFormattedCitation" : "(Callaway, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Callaway, 2011)Neanderthals might have been chattier than we initially realised, since both mutations that occurred in Homo sapiens have also been found in Neanderthals, indicating that the mutations arose before both hominid populations diverged, 500,000 years ago. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cub.2007.10.008", "ISSN" : "0960-9822", "PMID" : "17949978", "abstract" : "Although many animals communicate vocally, no extant creature rivals modern humans in language ability. Therefore, knowing when and under what evolutionary pressures our capacity for language evolved is of great interest. Here, we find that our closest extinct relatives, the Neandertals, share with modern humans two evolutionary changes in FOXP2, a gene that has been implicated in the development of speech and language. We furthermore find that in Neandertals, these changes lie on the common modern human haplotype, which previously was shown to have been subject to a selective sweep. These results suggest that these genetic changes and the selective sweep predate the common ancestor (which existed about 300,000-400,000 years ago) of modern human and Neandertal populations. This is in contrast to more recent age estimates of the selective sweep based on extant human diversity data. 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In this report, we have identified and characterized two members of this Fox gene family, Foxp1 and Foxp2, and show that they comprise a new subfamily of Fox genes expressed in the lung. Foxp1 and Foxp2 are expressed at high levels in the lung as early as E12.5 of mouse development with Foxp2 expression restricted to the airway epithelium. In addition, Foxp1 and Foxp2 are expressed at lower levels in neural, intestinal, and cardiovascular tissues during development. Upon differentiation of the airway epithelium along the proximal-distal axis, Foxp2 expression becomes restricted to the distal alveolar epithelium whereas Foxp1 expression is observed in the distal epithelium and mesenchyme. Foxp1 and Foxp2 can regulate epithelial lung gene transcription as was demonstrated by their ability to dramatically repress the mouse CC10 promoter and, to a lesser extent, the human surfactant protein C promoter. 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Although studies of twins consistently indicate that a significant genetic component is involved1, 2, 3, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait4. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval6. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. 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The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech. [ABSTRACT FROM AUTHOR]", "author" : [ { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Copp", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Neuroscience", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "131-138", "title" : "FOXP2 and the neuroanatomy of speech and language", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/S1364-6613(03)00104-9", "ISBN" : "1879-307X", "ISSN" : "13646613", "PMID" : "12804692", "abstract" : "The human capacity for acquiring speech and language must derive, at least in part, from the genome. In 2001, a study described the first case of a gene, FOXP2, which is thought to be implicated in our ability to acquire spoken language. In the present article, we discuss how this gene was discovered, what it might do, how it relates to other genes, and what it could tell us about the nature of speech and language development. We explain how FOXP2 could, without being specific to the brain or to our own species, still provide an invaluable entry-point into understanding the genetic cascades and neural pathways that contribute to our capacity for speech and language.", "author" : [ { "dropping-particle" : "", "family" : "Marcus", "given" : "Gary F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends in Cognitive Sciences", "id" : "ITEM-4", "issue" : "6", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "257-262", "title" : "FOXP2 in focus: What can genes tell us about speech and language?", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lai, Fisher, Hurst, Vargha-Khadem, & Monaco, 2001; Marcus & Fisher, 2003; Shu, Yang, Zhang, Lu, & Morrisey, 2001; Vargha-Khadem et al., 2005)", "plainTextFormattedCitation" : "(Lai, Fisher, Hurst, Vargha-Khadem, & Monaco, 2001; Marcus & Fisher, 2003; Shu, Yang, Zhang, Lu, & Morrisey, 2001; Vargha-Khadem et al., 2005)", "previouslyFormattedCitation" : "(Lai, Fisher, Hurst, Vargha-Khadem, & Monaco, 2001; Marcus & Fisher, 2003; Shu, Yang, Zhang, Lu, & Morrisey, 2001; Vargha-Khadem et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lai, Fisher, Hurst, Vargha-Khadem, & Monaco, 2001; Marcus & Fisher, 2003; Shu, Yang, Zhang, Lu, & Morrisey, 2001; Vargha-Khadem et al., 2005) and several tissues. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/35097076", "ISSN" : "0028-0836", "abstract" : "Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity1. Although studies of twins consistently indicate that a significant genetic component is involved1, 2, 3, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait4. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). 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L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hurst", "given" : "Jane A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "Faraneh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "6855", "issued" : { "date-parts" : [ [ "2001", "10", "4" ] ] }, "page" : "519-523", "title" : "A forkhead-domain gene is mutated in a severe speech and language disorder", "title-short" : "Nature", "type" : "article-journal", "volume" : "413" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lai et al., 2001)", "plainTextFormattedCitation" : "(Lai et al., 2001)", "previouslyFormattedCitation" : "(Lai et al., 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lai et al., 2001) Yet, we will concern ourselves with those parts that are of influence on language. Mechanisms through which FOXP2 affects language The exact role of FOXP2 in regulating certain genes, and thus certain pathways in the brain, remains unknown. Yet, research has been able to identify some genes that are most probably regulated by FOXP2. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pgen.1002145", "ISSN" : "1553-7404", "PMID" : "21765815", "abstract" : "Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP-chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections.", "author" : [ { "dropping-particle" : "", "family" : "Vernes", "given" : "Sonja C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliver", "given" : "Peter L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spiteri", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lockstone", "given" : "Helen E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puliyadi", "given" : "Rathi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Jennifer M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ho", "given" : "Joses", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mombereau", "given" : "Cedric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brewer", "given" : "Ariel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lowy", "given" : "Ernesto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nicod", "given" : "J\u00e9r\u00f4me", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groszer", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baban", "given" : "Dilair", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sahgal", "given" : "Natasha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazier", "given" : "Jean-Baptiste", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ragoussis", "given" : "Jiannis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Kay E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geschwind", "given" : "Daniel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS genetics", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "7", "7" ] ] }, "page" : "e1002145", "publisher" : "Public Library of Science", "title" : "Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vernes et al., 2011)", "plainTextFormattedCitation" : "(Vernes et al., 2011)", "previouslyFormattedCitation" : "(Vernes et al., 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vernes et al., 2011)Vernes (2011) and her team have used genome-wide techniques to identify FOXP2’s major targets. All the target genes have been categorised, as shown in figure 9. Their main finding was that FOXP2 effects mostly genes – directly and indirectly – that are involved with modulating the wiring of neural connections, by altering the length and branching of neuronal projections. Because of this, FOXP2 can be linked to specific pathways within the brain and therefore might take a cardinal place in the language and speech network of the brain. Indeed, FOxP2 seems to regulate the genes that are responsible for the wiring of neural connections between different language-related regions in the brain. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pgen.1002145", "ISSN" : "1553-7404", "PMID" : "21765815", "abstract" : "Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. 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The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections.", "author" : [ { "dropping-particle" : "", "family" : "Vernes", "given" : "Sonja C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliver", "given" : "Peter L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spiteri", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lockstone", "given" : "Helen E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puliyadi", "given" : "Rathi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Jennifer M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ho", "given" : "Joses", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mombereau", "given" : "Cedric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brewer", "given" : "Ariel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lowy", "given" : "Ernesto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nicod", "given" : "J\u00e9r\u00f4me", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groszer", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baban", "given" : "Dilair", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sahgal", "given" : "Natasha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cazier", "given" : "Jean-Baptiste", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ragoussis", "given" : "Jiannis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Kay E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geschwind", "given" : "Daniel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS genetics", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "7", "7" ] ] }, "page" : "e1002145", "publisher" : "Public Library of Science", "title" : "Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vernes et al., 2011)", "plainTextFormattedCitation" : "(Vernes et al., 2011)", "previouslyFormattedCitation" : "(Vernes et al., 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vernes et al., 2011)Figure SEQ Figure \* ARABIC 9: Gene ontology categories in which FOXP2 is most probably involved. Beneath the category is stated how many genes were found per category, and the P-value, respectively.Despite the fact that the exact role of FOXP2 in language development is still unknown, implications have been made for its role in developing and modulating pathways. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/35097076", "ISSN" : "0028-0836", "abstract" : "Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity1. Although studies of twins consistently indicate that a significant genetic component is involved1, 2, 3, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait4. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval6. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.", "author" : [ { "dropping-particle" : "", "family" : "Lai", "given" : "Cecilia S. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hurst", "given" : "Jane A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "Faraneh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "6855", "issued" : { "date-parts" : [ [ "2001", "10", "4" ] ] }, "page" : "519-523", "title" : "A forkhead-domain gene is mutated in a severe speech and language disorder", "title-short" : "Nature", "type" : "article-journal", "volume" : "413" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lai et al., 2001)", "plainTextFormattedCitation" : "(Lai et al., 2001)", "previouslyFormattedCitation" : "(Lai et al., 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lai et al., 2001) A closer look into the differences between affected and unaffected family members of the KE-family helped determine probable neuronal circuits in which FOXP2 almost certainly plays a role. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrn1605", "ISBN" : "1471-003X (Print)\\n1471-003X (Linking)", "ISSN" : "1471-003X", "PMID" : "15685218", "abstract" : "That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech. [ABSTRACT FROM AUTHOR]", "author" : [ { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Copp", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Neuroscience", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "131-138", "title" : "FOXP2 and the neuroanatomy of speech and language", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vargha-Khadem et al., 2005)", "plainTextFormattedCitation" : "(Vargha-Khadem et al., 2005)", "previouslyFormattedCitation" : "(Vargha-Khadem et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vargha-Khadem et al., 2005) A broad voxel-based morphometry (VBM) analyses displayed bilateral abnormalities in several motor-related regions, such as the caudate nucleus, which was reduced in volume. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0006-8950", "PMID" : "11872605", "abstract" : "Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family.", "author" : [ { "dropping-particle" : "", "family" : "Watkins", "given" : "K E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ashburner", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Passingham", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Connelly", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friston", "given" : "K J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frackowiak", "given" : "R S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain : a journal of neurology", "id" : "ITEM-1", "issue" : "Pt 3", "issued" : { "date-parts" : [ [ "2002", "3" ] ] }, "page" : "465-78", "title" : "MRI analysis of an inherited speech and language disorder: structural brain abnormalities.", "type" : "article-journal", "volume" : "125" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0027-8424", "PMID" : "9770548", "abstract" : "Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.", "author" : [ { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watkins", "given" : "K E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "C J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ashburner", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alcock", "given" : "K J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Connelly", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frackowiak", "given" : "R S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friston", "given" : "K J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pembrey", "given" : "M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Passingham", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences of the United States of America", "id" : "ITEM-2", "issue" : "21", "issued" : { "date-parts" : [ [ "1998", "10", "13" ] ] }, "page" : "12695-700", "title" : "Neural basis of an inherited speech and language disorder.", "type" : "article-journal", "volume" : "95" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vargha-Khadem et al., 1998; Watkins et al., 2002)", "plainTextFormattedCitation" : "(Vargha-Khadem et al., 1998; Watkins et al., 2002)", "previouslyFormattedCitation" : "(Vargha-Khadem et al., 1998; Watkins et al., 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vargha-Khadem et al., 1998; Watkins et al., 2002) The results from the analyses implied a relationship between the unusual development of the caudate nucleus and the deterioration of oromotor control and articulation among the affected KE-family members. Abnormally low levels of grey matter in Broca’s area, the precentral gyrus, the temporal pole, the head of the caudate nucleus and the ventral cerebellum were observed, along with a high level of grey matter in Wernicke’s area, the angular gyrus and the putamen. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1065-9471", "PMID" : "11098800", "abstract" : "In this article we describe a new method, using SPM99, that searches explicitly for bilateral structural abnormalities. Children with bilateral pathology have a poorer prognosis than children with unilateral damage. After brain injury or disease in childhood, it is thought that rescue of function is only possible if the neuronal substrates of that function are preserved and operational in at least one hemisphere [Vargha-Khadem and Mishkin, 1997]. If this is the case, the detection of bilateral abnormalities would greatly facilitate more accurate prognosis in children with brain injury or developmental disorders. We have therefore developed a technique to detect bilateral abnormalities that uses conjunction analysis with voxel based morphometry. It is illustrated using a group of patients with bilateral hypoxic-ischaemic damage to the hippocampus. The approach is shown to have enhanced specificity and sensitivity relative to conventional unilateral characterisations.", "author" : [ { "dropping-particle" : "", "family" : "Salmond", "given" : "C H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ashburner", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friston", "given" : "K J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Human brain mapping", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2000", "11" ] ] }, "page" : "223-32", "title" : "Detecting bilateral abnormalities with voxel-based morphometry.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Salmond, Ashburner, Vargha-Khadem, Gadian, & Friston, 2000)", "plainTextFormattedCitation" : "(Salmond, Ashburner, Vargha-Khadem, Gadian, & Friston, 2000)", "previouslyFormattedCitation" : "(Salmond, Ashburner, Vargha-Khadem, Gadian, & Friston, 2000)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Salmond, Ashburner, Vargha-Khadem, Gadian, & Friston, 2000)Functional neuroimaging studies during human speech revealed a typical left-dominant pattern of activation involving Broca’s area and a more bilateral distribution were found in the unaffected KE-family members, whereas the affected family members displayed a more posterior and more extensively bilateral pattern of activation. The affected family members also showed significantly less activation in Broca’s area and in the putamen, compared to unaffected family members. Finally, the affected family members displayed overactivation in regions that normally are not involved in language, such as the postcentral, posterior parietal and occipital regions, implying a possible form of compensation by other neuronal circuits, or extra cognitive effort that was required by the affected family members to perform the tasks. All these findings suggested that a point mutation in the FOXP2 gene affects the development of two main neural circuits, namely the fronto-striatal and fronto-cerebellar circuits, which are shown in figure 10. The fronto-striatal circuit lets the frontal cortex interplay with the accumbens nucleus. The fronto-cerebellar circuit is a one-way lap, beginning and ending in the frontal cortex, and going via the cerebellum and the thalamus. Both networks engage with learning and performing manual and other motor sequences. The language related processes they are evidential for are learning, planning and the execution of orofacial and speech motor sequences. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0270-7306", "PMID" : "14701752", "abstract" : "Foxp1, Foxp2, and Foxp4 are large multidomain transcriptional regulators belonging to the family of winged-helix DNA binding proteins known as the Fox family. Foxp1 and Foxp2 have been shown to act as transcriptional repressors, while regulatory activity of the recently identified Foxp4 has not been determined. Given the importance of this Fox gene subfamily in neural and lung development, we sought to elucidate the mechanisms by which Foxp1, Foxp2, and Foxp4 repress gene transcription. We show that like Foxp1 and Foxp2, Foxp4 represses transcription. Analysis of the N-terminal repression domain in Foxp1, Foxp2, and Foxp4 shows that this region contains two separate and distinct repression subdomains that are highly homologous termed subdomain 1 and subdomain 2. However, subdomain 2 is not functional in Foxp4. Screening for proteins that interact with subdomains 1 and 2 of Foxp2 using yeast two-hybrid analysis revealed that subdomain 2 binds to C-terminal binding protein 1, which can synergistically repress transcription with Foxp1 and Foxp2, but not Foxp4. Subdomain 1 contains a highly conserved leucine zipper similar to that found in N-myc and confers homo- and heterodimerization to the Foxp1/2/4 family members. These interactions are dependent on the conserved leucine zipper motif. Finally, we show that the integrity of this subdomain is essential for DNA binding, making Foxp1, Foxp2, and Foxp4 the first Fox proteins that require dimerization for DNA binding. These data reveal a complex regulatory mechanism underlying Foxp1, Foxp2, and Foxp4 activity, demonstrating that Foxp1, Foxp2, and Foxp4 are the first Fox proteins reported whose activity is regulated by homo- and heterodimerization.", "author" : [ { "dropping-particle" : "", "family" : "Li", "given" : "Shanru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weidenfeld", "given" : "Joel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morrisey", "given" : "Edward E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular and cellular biology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2004", "1" ] ] }, "page" : "809-22", "title" : "Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions.", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1074/jbc.M100636200", "ISSN" : "0021-9258", "PMID" : "11358962", "abstract" : "Epithelial gene expression in the lung is thought to be regulated by the coordinate activity of several different families of transcription factors including the Fox family of winged-helix/forkhead DNA-binding proteins. In this report, we have identified and characterized two members of this Fox gene family, Foxp1 and Foxp2, and show that they comprise a new subfamily of Fox genes expressed in the lung. Foxp1 and Foxp2 are expressed at high levels in the lung as early as E12.5 of mouse development with Foxp2 expression restricted to the airway epithelium. In addition, Foxp1 and Foxp2 are expressed at lower levels in neural, intestinal, and cardiovascular tissues during development. Upon differentiation of the airway epithelium along the proximal-distal axis, Foxp2 expression becomes restricted to the distal alveolar epithelium whereas Foxp1 expression is observed in the distal epithelium and mesenchyme. Foxp1 and Foxp2 can regulate epithelial lung gene transcription as was demonstrated by their ability to dramatically repress the mouse CC10 promoter and, to a lesser extent, the human surfactant protein C promoter. In addition, GAL4 fusion proteins encoding subdomains of Foxp1 and Foxp2 demonstrate that an independent and homologous transcriptional repression domain lies within the N-terminal end of the proteins. Together, these studies suggest that Foxp1 and Foxp2 are important regulators of lung epithelial gene transcription.", "author" : [ { "dropping-particle" : "", "family" : "Shu", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yang", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morrisey", "given" : "E E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of biological chemistry", "id" : "ITEM-2", "issue" : "29", "issued" : { "date-parts" : [ [ "2001", "7", "20" ] ] }, "page" : "27488-97", "title" : "Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors.", "type" : "article-journal", "volume" : "276" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Li, Weidenfeld, & Morrisey, 2004; Shu et al., 2001)", "plainTextFormattedCitation" : "(Li, Weidenfeld, & Morrisey, 2004; Shu et al., 2001)", "previouslyFormattedCitation" : "(Li, Weidenfeld, & Morrisey, 2004; Shu et al., 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Li, Weidenfeld, & Morrisey, 2004; Shu et al., 2001)-4889511239500Figure SEQ Figure \* ARABIC 10: The fronto-cerebellar network connects the frontal cortex to the cerebellum and the cerebellum via the thalamus back to the frontal cortex (see the red arrows). The fronto-striatal network connects the frontal cortex to the accumbens nucleus (see the yellow arrows). Source: Pediatric research (2011) 69, 69R-76R.So, even though the way in which FOXP2 affects those circuits is still not determined, a mutation of the gene does have a great effect on those many different regions within the brain. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/35097076", "ISSN" : "0028-0836", "abstract" : "Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity1. Although studies of twins consistently indicate that a significant genetic component is involved1, 2, 3, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait4. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval6. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.", "author" : [ { "dropping-particle" : "", "family" : "Lai", "given" : "Cecilia S. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hurst", "given" : "Jane A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "Faraneh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "6855", "issued" : { "date-parts" : [ [ "2001", "10", "4" ] ] }, "page" : "519-523", "title" : "A forkhead-domain gene is mutated in a severe speech and language disorder", "title-short" : "Nature", "type" : "article-journal", "volume" : "413" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lai et al., 2001)", "plainTextFormattedCitation" : "(Lai et al., 2001)", "previouslyFormattedCitation" : "(Lai et al., 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lai et al., 2001) “I’m not a person who necessarily believes that one gene is going to tell us everything, but this was really quite remarkable and does place FOXP2 in a relatively central position,” says Geschwind. He talks about how FOXP2 is partially responsible for quite some networks previously associated with language. Especially since those networks seem to cover rather a lot about our understanding of language. But how influential does FOXP2 remain if we take a closer look at the weight of those networks for the development of language? ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature08549", "ISSN" : "1476-4687", "PMID" : "19907493", "abstract" : "The signalling pathways controlling both the evolution and development of language in the human brain remain unknown. So far, the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction. It has been proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this two-amino-acid change occurred around the time of language emergence in humans. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here we demonstrate that these two human-specific amino acids alter FOXP2 function by conferring differential transcriptional regulation in vitro. We extend these observations in vivo to human and chimpanzee brain, and use network analysis to identify novel relationships among the differentially expressed genes. These data provide experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the central nervous system (CNS). Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.", "author" : [ { "dropping-particle" : "", "family" : "Konopka", "given" : "Genevieve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bomar", "given" : "Jamee M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winden", "given" : "Kellen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coppola", "given" : "Giovanni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jonsson", "given" : "Zophonias O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Fuying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peng", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Preuss", "given" : "Todd M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wohlschlegel", "given" : "James A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geschwind", "given" : "Daniel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7270", "issued" : { "date-parts" : [ [ "2009", "11", "12" ] ] }, "page" : "213-7", "publisher" : "Macmillan Publishers Limited. All rights reserved", "title" : "Human-specific transcriptional regulation of CNS development genes by FOXP2.", "title-short" : "Nature", "type" : "article-journal", "volume" : "462" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Konopka et al., 2009a)", "plainTextFormattedCitation" : "(Konopka et al., 2009a)", "previouslyFormattedCitation" : "(Konopka et al., 2009a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Konopka et al., 2009a)Comparison of the above with the biological mechanisms of languageWe just looked at the neural processes in which FOXP2 is involved. The most prominent processes being the fronto-striatal and fronto-cerebellar networks, and networks evidential for the learning, planning and execution of orofacial and speech motor sequences. Now we will place those processes on the scale to get a better understanding of just how important they are for the development of speech and language. Fronto-striatal circuits are involved in motor, cognitive and behavioural functions within the brain. If one looks at the executive functions of this circuit – selection and perception of important information, manipulation of information in working memory, planning and organization, behavioural control and decision making ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrn1605", "ISBN" : "1471-003X (Print)\\n1471-003X (Linking)", "ISSN" : "1471-003X", "PMID" : "15685218", "abstract" : "That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech. [ABSTRACT FROM AUTHOR]", "author" : [ { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Copp", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Neuroscience", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "131-138", "title" : "FOXP2 and the neuroanatomy of speech and language", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vargha-Khadem et al., 2005)", "plainTextFormattedCitation" : "(Vargha-Khadem et al., 2005)", "previouslyFormattedCitation" : "(Vargha-Khadem et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vargha-Khadem et al., 2005) – it sounds logical that it would also involve language, even though language is probably just one point within the broad spectrum of tasks that can be partially defined by this circuit. All those executive functions can be related to language and speech in one way or another. The same goes for the fronto-cerebellar networks. The left hemisphere version of this circuit is responsible for activating responses to stimuli, while the right version searches for the response that is given for certain stimuli. Again, this might be involved with language – considering responses that need to be given and received in a conversation – but probably among many other tasks. Even though the pathways of both networks are partially similar, they do mainly touch upon different parts of the human brain, as shown in figure 10. Next, FOXP2 was also involved with the networks that are evidential for learning, planning and the execution of orofacial and speech motor sequences. Learning and planning are both, once more, very relevant for language, but are also essential for other characteristics. And even though most functions are often applicable for multiple features, it also makes for not being able to exclude other options in defending the purpose or main target of a gene.The influence of FOXP2 on the execution of orofacial and speech motor sequences marks for a more framed argument. The fine muscle movement is of high significance for our ability to produce speech, and most other functions that are executed by these movements, could probably still be executed even if the muscle were less refined. This is not the case for language. For language, those muscle movements need to be extremely refined in order for us to pronounce all the words correctly and make ourselves understandable. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrn1605", "ISBN" : "1471-003X (Print)\\n1471-003X (Linking)", "ISSN" : "1471-003X", "PMID" : "15685218", "abstract" : "That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech. [ABSTRACT FROM AUTHOR]", "author" : [ { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gadian", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Copp", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishkin", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Neuroscience", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "131-138", "title" : "FOXP2 and the neuroanatomy of speech and language", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Vargha-Khadem et al., 2005)", "plainTextFormattedCitation" : "(Vargha-Khadem et al., 2005)", "previouslyFormattedCitation" : "(Vargha-Khadem et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Vargha-Khadem et al., 2005) Other genes involved in languageFOXP2 is the first gene to be discovered that has to do with language and speech, but our abilities for language and speech most probably have a complex genetic architecture. And just like the situation that lead to the discovery of the FOXP2 gene, most genes underpinning human speech and language were found via studies of developmental communication disorders. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s11065-014-9277-2", "ISSN" : "1573-6660", "PMID" : "25597031", "abstract" : "The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.", "author" : [ { "dropping-particle" : "", "family" : "Graham", "given" : "Sarah A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deriziotis", "given" : "Pelagia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychology review", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "3" ] ] }, "page" : "3-26", "title" : "Insights into the genetic foundations of human communication.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Graham et al., 2015)", "plainTextFormattedCitation" : "(Graham et al., 2015)", "previouslyFormattedCitation" : "(Graham et al., 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Graham et al., 2015) What will follow is a brief overview of the genes found or presumed to be associated with certain disorders that can be placed in the collective developmental communication disorders. Childhood Apraxia of Speech (CAS)CAS is a motor speech disorder, that gives children trouble pronouncing words, due to the fact that their brain has difficulty planning the movements of body parts that are necessary for speech, such as the lips, jaw and tongue. However, it is not a muscle weakness. This is also the disorder that the affected half of the KE family has been diagnosed with. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ng0298-168", "ISSN" : "1061-4036", "PMID" : "9462748", "abstract" : "Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.", "author" : [ { "dropping-particle" : "", "family" : "Fisher", "given" : "S E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watkins", "given" : "K E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "A P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pembrey", "given" : "M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature genetics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1998", "3" ] ] }, "page" : "168-70", "title" : "Localisation of a gene implicated in a severe speech and language disorder.", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Fisher, Vargha-Khadem, Watkins, Monaco, & Pembrey, 1998)", "plainTextFormattedCitation" : "(Fisher, Vargha-Khadem, Watkins, Monaco, & Pembrey, 1998)", "previouslyFormattedCitation" : "(Fisher, Vargha-Khadem, Watkins, Monaco, & Pembrey, 1998)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Fisher, Vargha-Khadem, Watkins, Monaco, & Pembrey, 1998)Even though a small amount of people suffering from CAS also have a mutation in their FOXP2 gene, the BCL11A gene is probably of higher importance. BCL11A is a transcription factor which plays a role in regulating the expression of hemoglobine. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1365-2141.2010.08105.x", "ISSN" : "1365-2141", "PMID" : "20201948", "abstract" : "The study of haemoglobin switching has represented a focus in haematology due in large part to the clinical relevance of the fetal to adult haemoglobin switch for developing targeted approaches to ameliorate the severity of the beta-haemoglobinopathies. Additionally, the process by which this switch occurs represents an important paradigm for developmental gene regulation. In this review, we provide an overview of both the embryonic primitive to definitive switch in haemoglobin expression, as well as the fetal to adult switch that is unique to humans and old world monkeys. We discuss the nature of these switches and models of their regulation. The factors that have been suggested to regulate this process are then discussed. With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients.", "author" : [ { "dropping-particle" : "", "family" : "Sankaran", "given" : "Vijay G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Jian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Orkin", "given" : "Stuart H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British journal of haematology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2010", "4" ] ] }, "page" : "181-94", "title" : "Advances in the understanding of haemoglobin switching.", "type" : "article-journal", "volume" : "149" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.mcn.2009.07.006", "ISSN" : "1095-9327", "PMID" : "19616629", "abstract" : "The extension of axon branches is important for target innervation but how axon branching is regulated is currently not well understood. Here, we report that Bcl11A/CTIP1/Evi9, a zinc finger transcription factor, downregulates axon branching. Knockdown of Bcl11A induced axon branching and multi-axon formation, as well as dendrite outgrowth. Due to alternative splicing, a single Bcl11A gene encodes two protein products, Bcl11A-L and -S. Bcl11A-L was found to be the main Bcl11A player in regulation of neurite arborization; Bcl11A-S is an antagonist of Bcl11A-L. Time-lapse study further suggests that Bcl11A-L knockdown enhances axon dynamics and increases the duration of axon outgrowth. Finally, the expression of DCC and MAP1b, two molecules involved in direction and branching of axon outgrowth, is controlled by Bcl11A-L. DCC overexpression rescues the phenotype induced by Bcl11A-L knockdown. In conclusion, this report provides the first evidence that Bcl11A is important for neurite arborization.", "author" : [ { "dropping-particle" : "", "family" : "Kuo", "given" : "Ting-Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hong", "given" : "Chen-Jei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsueh", "given" : "Yi-Ping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular and cellular neurosciences", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "11" ] ] }, "page" : "195-207", "title" : "Bcl11A/CTIP1 regulates expression of DCC and MAP1b in control of axon branching and dendrite outgrowth.", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kuo, Hong, & Hsueh, 2009; Sankaran, Xu, & Orkin, 2010)", "plainTextFormattedCitation" : "(Kuo, Hong, & Hsueh, 2009; Sankaran, Xu, & Orkin, 2010)", "previouslyFormattedCitation" : "(Kuo, Hong, & Hsueh, 2009; Sankaran, Xu, & Orkin, 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kuo, Hong, & Hsueh, 2009; Sankaran, Xu, & Orkin, 2010) The ERC1 gene seems also related to language, and a deletion of it was found in patients who suffered from delayed speech development, and who had been therefore diagnosed with CAS. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ejhg.2012.116", "ISSN" : "1476-5438", "PMID" : "22713806", "abstract" : "Speech sound disorders are heterogeneous conditions, and sporadic and familial cases have been described. However, monogenic inheritance explains only a small proportion of such disorders, in particular in cases with childhood apraxia of speech (CAS). Deletions of <5 Mb involving the 12p13.33 locus is one of the least commonly deleted subtelomeric regions. Only four patients have been reported with such a deletion diagnosed with fluorescence in situ hybridisation telomere analysis or array CGH. To further delineate this rare microdeletional syndrome, a French collaboration together with a search in the Decipher database allowed us to gather nine new patients with a 12p13.33 subtelomeric or interstitial rearrangement identified by array CGH. Speech delay was found in all patients, which could be defined as CAS when patients had been evaluated by a speech therapist (5/9 patients). Intellectual deficiency was found in 5/9 patients only, and often associated with psychiatric manifestations of various severity. Two such deletions were inherited from an apparently healthy parent, but reevaluation revealed abnormal speech production at least in childhood, suggesting variable expressivity. The ELKS/ERC1 gene, which encodes for a synaptic factor, is found in the smallest region of overlap. These results reinforce the hypothesis that deletions of the 12p13.33 locus may be responsible for variable phenotypes including CAS associated with neurobehavioural troubles and that the presence of CAS justifies a genetic work-up.", "author" : [ { "dropping-particle" : "", "family" : "Thevenon", "given" : "Julien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Callier", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Andrieux", "given" : "Joris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delobel", "given" : "Bruno", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "David", "given" : "Albert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sukno", "given" : "Sylvie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Minot", "given" : "Delphine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mosca Anne", "given" : "Laure", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marle", "given" : "Nathalie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanlaville", "given" : "Damien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonnet", "given" : "Marl\u00e8ne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masurel-Paulet", "given" : "Alice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levy", "given" : "Fabienne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaunt", "given" : "Lorraine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farrell", "given" : "Sandra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caignec", "given" : "C\u00e9dric", "non-dropping-particle" : "Le", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Toutain", "given" : "Annick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carmignac", "given" : "Virginie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mugneret", "given" : "Francine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clayton-Smith", "given" : "Jill", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thauvin-Robinet", "given" : "Christel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Faivre", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "European journal of human genetics : EJHG", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "82-8", "title" : "12p13.33 microdeletion including ELKS/ERC1, a new locus associated with childhood apraxia of speech.", "type" : "article-journal", "volume" : "21" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Thevenon et al., 2013)", "plainTextFormattedCitation" : "(Thevenon et al., 2013)", "previouslyFormattedCitation" : "(Thevenon et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Thevenon et al., 2013) Unbalanced 4q;16q translocation and microdeletions in 16p11.2 have also been found to probably increase the risk of CAS. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ejhg.2012.165", "ISSN" : "1476-5438", "PMID" : "22909774", "abstract" : "We report clinical findings that extend the phenotype of the ~550 kb 16p11.2 microdeletion syndrome to include a rare, severe, and persistent pediatric speech sound disorder termed Childhood Apraxia of Speech (CAS). CAS is the speech disorder identified in a multigenerational pedigree ('KE') in which half of the members have a mutation in FOXP2 that co-segregates with CAS, oromotor apraxia, and low scores on a nonword repetition task. Each of the two patients in the current report completed a 2-h assessment protocol that provided information on their cognitive, language, speech, oral mechanism, motor, and developmental histories and performance. Their histories and standard scores on perceptual and acoustic speech tasks met clinical and research criteria for CAS. Array comparative genomic hybridization analyses identified deletions at chromosome 16p11.2 in each patient. These are the first reported cases with well-characterized CAS in the 16p11.2 syndrome literature and the first report of this microdeletion in CAS genetics research. We discuss implications of findings for issues in both literatures.", "author" : [ { "dropping-particle" : "", "family" : "Raca", "given" : "Gordana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baas", "given" : "Becky S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kirmani", "given" : "Salman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laffin", "given" : "Jennifer J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Craig A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Strand", "given" : "Edythe A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jakielski", "given" : "Kathy J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shriberg", "given" : "Lawrence D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "European journal of human genetics : EJHG", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "455-9", "publisher" : "Macmillan Publishers Limited", "title" : "Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome.", "title-short" : "Eur J Hum Genet", "type" : "article-journal", "volume" : "21" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/ejhg.2012.166", "ISSN" : "1476-5438", "PMID" : "22909776", "author" : [ { "dropping-particle" : "", "family" : "Newbury", "given" : "Dianne F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mari", "given" : "Francesca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sadighi Akha", "given" : "Elham", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macdermot", "given" : "Kay D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Canitano", "given" : "Roberto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Jenny C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Renieri", "given" : "Alessandra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "Samantha J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "European journal of human genetics : EJHG", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "361-5", "title" : "Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder.", "type" : "article-journal", "volume" : "21" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Newbury et al., 2013; Raca et al., 2013)", "plainTextFormattedCitation" : "(Newbury et al., 2013; Raca et al., 2013)", "previouslyFormattedCitation" : "(Newbury et al., 2013; Raca et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Newbury et al., 2013; Raca et al., 2013)It is difficult to state how many cases of CAS are caused by a mutation in the FOXP2 gene, since most published studies are looking into a rather small amount of cases. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1086/430841", "ISSN" : "0002-9297", "PMID" : "15877281", "abstract" : "FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.", "author" : [ { "dropping-particle" : "", "family" : "MacDermot", "given" : "Kay D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonora", "given" : "Elena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sykes", "given" : "Nuala", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coupe", "given" : "Anne-Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lai", "given" : "Cecilia S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vernes", "given" : "Sonja C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vargha-Khadem", "given" : "Faraneh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKenzie", "given" : "Fiona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Robert L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of human genetics", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2005", "6" ] ] }, "page" : "1074-80", "title" : "Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.", "type" : "article-journal", "volume" : "76" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(MacDermot et al., 2005)", "plainTextFormattedCitation" : "(MacDermot et al., 2005)", "previouslyFormattedCitation" : "(MacDermot et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(MacDermot et al., 2005) This also results in an uncertainty on whether other genes might play a bigger role in the development of CAS than FOXP2, even though it is thought that the BCL11A gene is probably of higher importance. Fact remains that also in the research of the BCL11A gene, the sample size consisted of a handful of cases. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1365-2141.2010.08105.x", "ISSN" : "1365-2141", "PMID" : "20201948", "abstract" : "The study of haemoglobin switching has represented a focus in haematology due in large part to the clinical relevance of the fetal to adult haemoglobin switch for developing targeted approaches to ameliorate the severity of the beta-haemoglobinopathies. Additionally, the process by which this switch occurs represents an important paradigm for developmental gene regulation. In this review, we provide an overview of both the embryonic primitive to definitive switch in haemoglobin expression, as well as the fetal to adult switch that is unique to humans and old world monkeys. We discuss the nature of these switches and models of their regulation. The factors that have been suggested to regulate this process are then discussed. With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients.", "author" : [ { "dropping-particle" : "", "family" : "Sankaran", "given" : "Vijay G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Jian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Orkin", "given" : "Stuart H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British journal of haematology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2010", "4" ] ] }, "page" : "181-94", "title" : "Advances in the understanding of haemoglobin switching.", "type" : "article-journal", "volume" : "149" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.mcn.2009.07.006", "ISSN" : "1095-9327", "PMID" : "19616629", "abstract" : "The extension of axon branches is important for target innervation but how axon branching is regulated is currently not well understood. Here, we report that Bcl11A/CTIP1/Evi9, a zinc finger transcription factor, downregulates axon branching. Knockdown of Bcl11A induced axon branching and multi-axon formation, as well as dendrite outgrowth. Due to alternative splicing, a single Bcl11A gene encodes two protein products, Bcl11A-L and -S. Bcl11A-L was found to be the main Bcl11A player in regulation of neurite arborization; Bcl11A-S is an antagonist of Bcl11A-L. Time-lapse study further suggests that Bcl11A-L knockdown enhances axon dynamics and increases the duration of axon outgrowth. Finally, the expression of DCC and MAP1b, two molecules involved in direction and branching of axon outgrowth, is controlled by Bcl11A-L. DCC overexpression rescues the phenotype induced by Bcl11A-L knockdown. In conclusion, this report provides the first evidence that Bcl11A is important for neurite arborization.", "author" : [ { "dropping-particle" : "", "family" : "Kuo", "given" : "Ting-Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hong", "given" : "Chen-Jei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsueh", "given" : "Yi-Ping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular and cellular neurosciences", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "11" ] ] }, "page" : "195-207", "title" : "Bcl11A/CTIP1 regulates expression of DCC and MAP1b in control of axon branching and dendrite outgrowth.", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kuo et al., 2009; Sankaran et al., 2010)", "plainTextFormattedCitation" : "(Kuo et al., 2009; Sankaran et al., 2010)", "previouslyFormattedCitation" : "(Kuo et al., 2009; Sankaran et al., 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kuo et al., 2009; Sankaran et al., 2010)StutteringStuttering is a disease that affects the fluency of someone’s speech, often by repeating the first sound of words. However, most of the time affected individuals have no further issues concerning their language, cognition or motor function. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cub.2016.02.068", "ISSN" : "09609822", "author" : [ { "dropping-particle" : "", "family" : "Barnes", "given" : "Terra\u00a0D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wozniak", "given" : "David\u00a0F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gutierrez", "given" : "Joanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Han", "given" : "Tae-Un", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holy", "given" : "Timothy\u00a0E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Biology", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2016", "4", "25" ] ] }, "language" : "English", "page" : "1009-1018", "publisher" : "Elsevier", "title" : "A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Barnes et al., 2016)", "plainTextFormattedCitation" : "(Barnes et al., 2016)", "previouslyFormattedCitation" : "(Barnes et al., 2016)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Barnes et al., 2016)The GNPTAB, GNPTG and NAGPA genes are affected in patients who stutter. Linkage studies in several populations have been performed, implicating multiple genomic loci and different modes of inheritance. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4238/2014.March.24.13", "ISSN" : "1676-5680", "PMID" : "24737434", "abstract" : "Although twin, adoption, and family studies demonstrate that genetic factors are involved in the origins of stuttering, the mode of transmission of the disorder in families is not well defined and stuttering is considered a genetically complex trait. We performed a genome-wide linkage scan in a group of 43 Brazilian families, each containing multiple cases of persistent developmental stuttering. Linkage analysis under a dominant model of inheritance generated significant evidence of linkage in two Brazilian families, with a combined maximum single-point LOD score of 4.02 and a multipoint LOD score of 4.28 on chromosome 10q21. This demonstrated the presence of a novel variant gene at this locus that predisposes individuals to stuttering, which provides an opportunity to identify novel genetic mechanisms that underlie this disorder.", "author" : [ { "dropping-particle" : "", "family" : "Domingues", "given" : "C E F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olivera", "given" : "C M C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Oliveira", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Juste", "given" : "F S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Andrade", "given" : "C R F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Giacheti", "given" : "C M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moretti-Ferreira", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genetics and molecular research : GMR", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "2094-101", "title" : "A genetic linkage study in Brazil identifies a new locus for persistent developmental stuttering on chromosome 10.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1146/annurev-genom-090810-183119", "ISSN" : "1545-293X", "PMID" : "21663442", "abstract" : "Vocal communication mediated by speech and language is a uniquely human trait, and has served an important evolutionary role in the development of our species. Deficits in speech and language functions can be of numerous types, including aphasia, stuttering, articulation disorders, verbal dyspraxia, and specific language impairment; language deficits are also related to dyslexia. Most communication disorders are prominent in children, where they are common. A number of these disorders have been shown to cluster in families, suggesting that genetic factors are involved, but their etiology at the molecular level is not well understood. In the past decade, genetic methods have proven to be powerful for understanding these etiologies. Linkage studies and molecular genetic analyses in a large family containing multiple individuals affected with verbal dyspraxia led to the discovery of mutations in the FOXP2 gene. This gene encodes a forkhead domain transcription factor, a finding that has led researchers to a new avenue of investigation into the substrates and mechanisms that underlie human speech development. In studies of stuttering, linkage and candidate gene approaches in consanguineous families identified mutations in the lysosomal enzyme-targeting pathway genes GNPTAB, GNPTG, and NAGPA, revealing a role for inherited defects in cell metabolism in this disorder. In specific language impairment, linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci. Although only a small fraction of all cases of speech and language disorders can be explained by genetic findings to date, the significant progress made thus far suggests that genetic approaches will continue to provide important avenues for research on this group of disorders.", "author" : [ { "dropping-particle" : "", "family" : "Kang", "given" : "Changsoo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annual review of genomics and human genetics", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2011", "1" ] ] }, "page" : "145-64", "title" : "Genetics of speech and language disorders.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1007/s00439-011-1134-2", "ISSN" : "1432-1203", "PMID" : "22205390", "author" : [ { "dropping-particle" : "", "family" : "Raza", "given" : "Muhammad Hashim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amjad", "given" : "Rana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riazuddin", "given" : "Sheikh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Human genetics", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "3" ] ] }, "page" : "311-3", "title" : "Studies in a consanguineous family reveal a novel locus for stuttering on chromosome 16q.", "type" : "article-journal", "volume" : "131" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1007/s00439-012-1252-5", "ISSN" : "1432-1203", "PMID" : "23239121", "abstract" : "We describe a pedigree of 71 individuals from the Republic of Cameroon in which at least 33 individuals have a clinical diagnosis of persistent stuttering. The high concentration of stuttering individuals suggests that the pedigree either contains a single highly penetrant gene variant or that assortative mating led to multiple stuttering-associated variants being transmitted in different parts of the pedigree. No single locus displayed significant linkage to stuttering in initial genome-wide scans with microsatellite and SNP markers. By dividing the pedigree into five subpedigrees, we found evidence for linkage to previously reported loci on 3q and 15q, and to novel loci on 2p, 3p, 14q, and a different region of 15q. Using the two-locus mode of Superlink, we showed that combining the recessive locus on 2p and a single-locus additive representation of the 15q loci is sufficient to achieve a two-locus score over 6 on the entire pedigree. For this 2p\u00a0+\u00a015q analysis, we show LOD scores ranging from 4.69 to 6.57, and the scores are sensitive to which marker is chosen for 15q. Our findings provide strong evidence for linkage at several loci.", "author" : [ { "dropping-particle" : "", "family" : "Raza", "given" : "M Hashim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gertz", "given" : "E Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mundorff", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lukong", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuster", "given" : "Judith", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sch\u00e4ffer", "given" : "Alejandro A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Human genetics", "id" : "ITEM-4", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "385-96", "title" : "Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.", "type" : "article-journal", "volume" : "132" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Domingues et al., 2014; Kang & Drayna, 2011; M Hashim Raza et al., 2013; Muhammad Hashim Raza, Amjad, Riazuddin, & Drayna, 2012)", "plainTextFormattedCitation" : "(Domingues et al., 2014; Kang & Drayna, 2011; M Hashim Raza et al., 2013; Muhammad Hashim Raza, Amjad, Riazuddin, & Drayna, 2012)", "previouslyFormattedCitation" : "(Domingues et al., 2014; Kang & Drayna, 2011; M Hashim Raza et al., 2013; Muhammad Hashim Raza, Amjad, Riazuddin, & Drayna, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Domingues et al., 2014; Kang & Drayna, 2011; Hashim Raza et al., 2013; Hashim Raza, Amjad, Riazuddin, & Drayna, 2012) After a linkage peak was found on chromosome 12, sequencing of all the genes in that specific region resulted in identifying a missense mutation in the GNPTAB gene. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa0902630", "ISSN" : "1533-4406", "PMID" : "20147709", "abstract" : "BACKGROUND: Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12.\n\nMETHODS: We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America.\n\nRESULTS: We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms.\n\nCONCLUSIONS: Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.", "author" : [ { "dropping-particle" : "", "family" : "Kang", "given" : "Changsoo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riazuddin", "given" : "Sheikh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mundorff", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krasnewich", "given" : "Donna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "Penelope", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mullikin", "given" : "James C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2010", "2", "25" ] ] }, "page" : "677-85", "title" : "Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering.", "type" : "article-journal", "volume" : "362" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kang et al., 2010)", "plainTextFormattedCitation" : "(Kang et al., 2010)", "previouslyFormattedCitation" : "(Kang et al., 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kang et al., 2010) Further targeted sequencing found even more missense variants in GNPTAB, and in the related genes GNPTG and NAGPA. Yet the mechanisms that lie behind these mutations and how they result in stuttering remain unclear. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa0902630", "ISSN" : "1533-4406", "PMID" : "20147709", "abstract" : "BACKGROUND: Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12.\n\nMETHODS: We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America.\n\nRESULTS: We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms.\n\nCONCLUSIONS: Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.", "author" : [ { "dropping-particle" : "", "family" : "Kang", "given" : "Changsoo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riazuddin", "given" : "Sheikh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mundorff", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krasnewich", "given" : "Donna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "Penelope", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mullikin", "given" : "James C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2010", "2", "25" ] ] }, "page" : "677-85", "title" : "Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering.", "type" : "article-journal", "volume" : "362" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.cub.2016.02.068", "ISSN" : "09609822", "author" : [ { "dropping-particle" : "", "family" : "Barnes", "given" : "Terra\u00a0D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wozniak", "given" : "David\u00a0F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gutierrez", "given" : "Joanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Han", "given" : "Tae-Un", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holy", "given" : "Timothy\u00a0E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Biology", "id" : "ITEM-2", "issue" : "8", "issued" : { "date-parts" : [ [ "2016", "4", "25" ] ] }, "language" : "English", "page" : "1009-1018", "publisher" : "Elsevier", "title" : "A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Barnes et al., 2016; Kang et al., 2010)", "plainTextFormattedCitation" : "(Barnes et al., 2016; Kang et al., 2010)", "previouslyFormattedCitation" : "(Barnes et al., 2016; Kang et al., 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Barnes et al., 2016; Kang et al., 2010)They are all involved with enciphering enzymes that affect the mannose-6-phospate pathway for lysosomal enzyme targeting. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ymgme.2012.07.012", "ISSN" : "1096-7206", "PMID" : "22884962", "abstract" : "Lysosomal hydrolases have long been known to be responsible for the degradation of different substrates in the cell. These acid hydrolases are synthesized in the rough endoplasmic reticulum and transported through the Golgi apparatus to the trans-Golgi network (TGN). From there, they are delivered to endosomal/lysosomal compartments, where they finally become active due to the acidic pH characteristic of the lysosomal compartment. The majority of the enzymes leave the TGN after modification with mannose-6-phosphate (M6P) residues, which are specifically recognized by M6P receptors (MPRs), ensuring their transport to the endosomal/lysosomal system. Although M6P receptors play a major role in the intracellular transport of newly synthesized lysosomal enzymes in mammalian cells, several lines of evidence suggest the existence of alternative processes of lysosomal targeting. Among them, the two that are mediated by the M6P alternative receptors, lysosomal integral membrane protein (LIMP-2) and sortilin, have gained unequivocal support. LIMP-2 was shown to be implicated in the delivery of beta-glucocerebrosidase (GCase) to the lysosomes, whereas sortilin has been suggested to be a multifunctional receptor capable of binding several different ligands, including neurotensin and receptor-associated protein (RAP), and of targeting several proteins to the lysosome, including sphingolipid activator proteins (prosaposin and GM2 activator protein), acid sphingomyelinase and cathepsins D and H. Here, we review the current knowledge on these two proteins: their discovery, study, structural features and cellular function, with special attention to their role as alternative receptors to lysosomal trafficking. Recent studies associating both LIMP2 and sortilin to disease are also extensively reviewed.", "author" : [ { "dropping-particle" : "", "family" : "Coutinho", "given" : "Maria Francisca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prata", "given" : "Maria Jo\u00e3o", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alves", "given" : "Sandra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular genetics and metabolism", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2012", "11" ] ] }, "page" : "257-66", "title" : "A shortcut to the lysosome: the mannose-6-phosphate-independent pathway.", "type" : "article-journal", "volume" : "107" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Coutinho, Prata, & Alves, 2012)", "plainTextFormattedCitation" : "(Coutinho, Prata, & Alves, 2012)", "previouslyFormattedCitation" : "(Coutinho, Prata, & Alves, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Coutinho, Prata, & Alves, 2012)More current research by the same team as Kang et al found an excess of rare coding variants in GNPTAB and NAGPA. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.nbd.2014.04.019", "ISSN" : "1095-953X", "PMID" : "24807205", "abstract" : "A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.", "author" : [ { "dropping-particle" : "", "family" : "Han", "given" : "Tae-Un", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Park", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Domingues", "given" : "Carlos F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moretti-Ferreira", "given" : "Danilo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paris", "given" : "Emily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sainz", "given" : "Eduardo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gutierrez", "given" : "Joanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drayna", "given" : "Dennis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of disease", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "9" ] ] }, "page" : "23-31", "title" : "A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering.", "type" : "article-journal", "volume" : "69" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Han et al., 2014)", "plainTextFormattedCitation" : "(Han et al., 2014)", "previouslyFormattedCitation" : "(Han et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Han et al., 2014) Another team, Barnes et al (2016), showed that mice with a human GNPTAB stuttering mutation let out fewer vocalizations and had longer pauses between the vocalizations. However, most research is still conducted by the same research group, and more independent replication research should be done concerning this theme. Currently, we cannot yet determine what the overall contribution to stuttering is of the mutations in the GNPTAB, GNPTG and NAGPA genes. Specific Language Impairment (SLI) and DyslexiaSLI is a disorder in which a child is unable to develop language normally, while not suffering from a general slow development, physical abnormality of the speech apparatus or other disorders and diseases which otherwise could have caused it. Someone with dyslexia has trouble reading which is, just like with SLI, not related to slow development or general problems with overall intelligence. Because SLI and dyslexia have high levels of comorbidity, it is thought that the nature of the flaws in the genetic architecture might be similar. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1146/annurev.psych.60.110707.163548", "ISSN" : "0066-4308", "PMID" : "18652545", "abstract" : "In this article, we critically review the evidence for overlap among three developmental disorders, namely speech sound disorder (SSD), language impairment (LI), and reading disability (RD), at three levels of analysis: diagnostic, cognitive, and etiological. We find that while overlap exists at all three levels, it varies by comorbidity subtype, and the relations among these three disorders are complex and not fully understood. We evaluate which comorbidity models can be rejected or supported as explanations for why and how these three disorders overlap and what new data are needed to better define their relations.", "author" : [ { "dropping-particle" : "", "family" : "Pennington", "given" : "Bruce F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bishop", "given" : "Dorothy V M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annual review of psychology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009", "1" ] ] }, "page" : "283-306", "title" : "Relations among speech, language, and reading disorders.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Pennington & Bishop, 2009)", "plainTextFormattedCitation" : "(Pennington & Bishop, 2009)", "previouslyFormattedCitation" : "(Pennington & Bishop, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Pennington & Bishop, 2009)Over a decade ago, the first leads to the genetic architecture underpinning these disorders were identified via linkage studies. Via association screening of polymorphic markers within the target interval, KIAA0319, DCDC2, and MRPL19/C2ORF3 were identified as involved genes with dyslexia and for SLI CMIP and ATP2C2 were found. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ajhg.2009.07.004", "ISSN" : "1537-6605", "PMID" : "19646677", "abstract" : "Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.", "author" : [ { "dropping-particle" : "", "family" : "Newbury", "given" : "Dianne F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winchester", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Addis", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paracchini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckingham", "given" : "Lyn-Louise", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clark", "given" : "Ann", "non-dropping-particle" : "", 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"abstract" : "DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.", "author" : [ { "dropping-particle" : "", "family" : "Anthoni", "given" : "Heidi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zucchelli", "given" : "Marco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matsson", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M\u00fcller-Myhsok", "given" : "Bertram", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fransson", "given" : "Ingegerd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schumacher", "given" : "Johannes", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Massinen", "given" : "Satu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Onkamo", "given" : "P\u00e4ivi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Warnke", "given" : "Andreas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griesemann", "given" : "Heide", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoffmann", "given" : "Per", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nopola-Hemmi", "given" : "Jaana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyytinen", "given" : "Heikki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schulte-K\u00f6rne", "given" : "Gerd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kere", "given" : "Juha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "N\u00f6then", "given" : "Markus M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peyrard-Janvid", "given" : "Myriam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Human molecular genetics", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2007", "3", "15" ] ] }, "page" : "667-77", "title" : "A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1086/426404", "ISSN" : "0002-9297", "PMID" : "15514892", "abstract" : "Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of approximately 12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.", "author" : [ { "dropping-particle" : "", "family" : "Francks", "given" : "Clyde", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paracchini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Shelley D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richardson", "given" : "Alex J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scerri", "given" : "Tom S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cardon", "given" : "Lon R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marlow", "given" : "Angela J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "MacPhie", "given" : "I Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walter", "given" : "Janet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pennington", "given" : "Bruce F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olson", "given" : "Richard K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeFries", "given" : "John C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stein", "given" : "John F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of human genetics", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "2004", "12" ] ] }, "page" : "1046-58", "title" : "A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States.", "type" : "article-journal", "volume" : "75" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1073/pnas.0508591102", "ISSN" : "0027-8424", "PMID" : "16278297", "abstract" : "DYX2 on 6p22 is the most replicated reading disability (RD) locus. By saturating a previously identified peak of association with single nucleotide polymorphism markers, we identified a large polymorphic deletion that encodes tandem repeats of putative brain-related transcription factor binding sites in intron 2 of DCDC2. Alleles of this compound repeat are in significant disequilibrium with multiple reading traits. RT-PCR data show that DCDC2 localizes to the regions of the brain where fluent reading occurs, and RNA interference studies show that down-regulation alters neuronal migration. The statistical and functional studies are complementary and are consistent with the latest clinical imaging data for RD. Thus, we propose that DCDC2 is a candidate gene for RD.", "author" : [ { "dropping-particle" : "", "family" : "Meng", "given" : "Haiying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Shelley D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hager", "given" : "Karl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Held", "given" : "Matthew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olson", "given" : "Richard K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pennington", "given" : "Bruce F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeFries", "given" : "John C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gelernter", "given" : "Joel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Reilly-Pol", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Somlo", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Skudlarski", "given" : "Pawel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shaywitz", "given" : "Sally E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shaywitz", "given" : "Bennett A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchione", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paramasivam", "given" : "Murugan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LoTurco", "given" : "Joseph J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Page", "given" : "Grier P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruen", "given" : "Jeffrey R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences of the United States of America", "id" : "ITEM-4", "issue" : "47", "issued" : { "date-parts" : [ [ "2005", "11", "22" ] ] }, "page" : "17053-8", "title" : "DCDC2 is associated with reading disability and modulates neuronal development in the brain.", "type" : "article-journal", "volume" : "102" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Anthoni et al., 2007; Francks et al., 2004; Meng et al., 2005; Newbury et al., 2009)", "plainTextFormattedCitation" : "(Anthoni et al., 2007; Francks et al., 2004; Meng et al., 2005; Newbury et al., 2009)", "previouslyFormattedCitation" : "(Anthoni et al., 2007; Francks et al., 2004; Meng et al., 2005; Newbury et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Anthoni et al., 2007; Francks et al., 2004; Meng et al., 2005; Newbury et al., 2009)These genes seem to be mostly located in non-coding regions of the genome, which makes any further research difficult since the biological role of much non-coding DNA is poorly understood. This is mainly an issue in designing appropriate assays to further test these genes. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s11065-014-9277-2", "ISSN" : "1573-6660", "PMID" : "25597031", "abstract" : "The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.", "author" : [ { "dropping-particle" : "", "family" : "Graham", "given" : "Sarah A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deriziotis", "given" : "Pelagia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychology review", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "3" ] ] }, "page" : "3-26", "title" : "Insights into the genetic foundations of human communication.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Graham et al., 2015)", "plainTextFormattedCitation" : "(Graham et al., 2015)", "previouslyFormattedCitation" : "(Graham et al., 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Graham et al., 2015)But many studies have tried to test these candidate genes and the results are varied. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1176/appi.ajp.2008.07121872", "ISSN" : "1535-7228", "PMID" : "18829873", "abstract" : "OBJECTIVE: The authors previously identified a haplotype on chromosome 6p22 defined by three single-nucleotide polymorphisms (SNPs) that was associated with dyslexia (reading disability) in two independent samples of families that included at least one sibling with severe reading impairment. The authors also showed that this haplotype is associated with a reduction in expression of the KIAA0319 gene. In addition, a completely independent study detected an association between KIAA0319 markers and reading disability. In the current study, the authors tested whether the KIAA0319 gene influences reading skills in the general population, rather than having an effect restricted to reading disability.\n\nMETHOD: The authors genotyped four SNPs that previously showed association with reading disability in the population of 7-9-year-old children in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large longitudinal cohort for which reading-related phenotypes were available for more than 6,000 individuals. The authors conducted quantitative analysis for both single markers and haplotypes.\n\nRESULTS: The rs2143340 SNP, which effectively tags the three-SNP risk haplotype, was significantly associated with a test for reading ability. The risk haplotype itself also showed association with poor reading performance, and as in previous research, the association was stronger when the analysis was controlled for IQ.\n\nCONCLUSIONS: These results both support a role of the KIAA0319 gene in the development of dyslexia and suggest that this gene influences reading ability in the general population. Moreover, the data implicate the three-SNP haplotype and its tagging SNP rs2143340 as genetic risk factors for poor reading performance.", "author" : [ { "dropping-particle" : "", "family" : "Paracchini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steer", "given" : "Colin D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckingham", "given" : "Lyn-Louise", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "Andrew P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ring", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scerri", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stein", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pembrey", "given" : "Marcus E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ragoussis", "given" : "Jiannis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Golding", "given" : "Jean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of psychiatry", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2008", "12" ] ] }, "page" : "1576-84", "title" : "Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population.", "type" : "article-journal", "volume" : "165" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1007/s11689-011-9091-6", "ISSN" : "1866-1955", "PMID" : "21894572", "abstract" : "Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations.", "author" : [ { "dropping-particle" : "", "family" : "Paracchini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of neurodevelopmental disorders", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2011", "12", "6" ] ] }, "language" : "En", "page" : "365-73", "publisher" : "BioMed Central", "title" : "Dissection of genetic associations with language-related traits in population-based cohorts.", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.biopsych.2011.02.005", "ISSN" : "1873-2402", "PMID" : "21457949", "abstract" : "BACKGROUND: Several susceptibility genes have been proposed for dyslexia (reading disability; RD) and specific language impairment (SLI). RD and SLI show comorbidity, but it is unclear whether a common genetic component is shared.\n\nMETHODS: We have investigated whether candidate genes for RD and SLI affect specific cognitive traits or have broad effect on cognition. We have analyzed common risk variants within RD (MRPL19/C2ORF3, KIAA0319, and DCDC2) and language impairment (CMIP and ATP2C2) candidate loci in the Avon Longitudinal Study of Parents and Children cohort (n = 3725), representing children born in southwest England in the early 1990s.\n\nRESULTS: We detected associations between reading skills and KIAA0319, DCDC2, and CMIP. We show that DCDC2 is specifically associated with RD, whereas variants in CMIP and KIAA0319 are associated with reading skills across the ability range. The strongest associations were restricted to single-word reading and spelling measures, suggesting that these genes do not extend their effect to other reading and language-related skills. Inclusion of individuals with comorbidity tends to strengthen these associations. Our data do not support MRPL19/C2ORF3 as a locus involved in reading abilities nor CMIP/ATP2C2 as genes regulating language skills.\n\nCONCLUSIONS: We provide further support for the role of KIAA0319 and DCDC2 in contributing to reading abilities and novel evidence that the language-disorder candidate gene CMIP is also implicated in reading processes. Additionally, we present novel data to evaluate the prevalence and comorbidity of RD and SLI, and we recommend not excluding individuals with comorbid RD and SLI when designing genetic association studies for RD.", "author" : [ { "dropping-particle" : "", "family" : "Scerri", "given" : "Tom S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "Andrew P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckingham", "given" : "Lyn-Louise", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Newbury", "given" : "Dianne F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "Laura L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bishop", "given" : "Dorothy V M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paracchini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological psychiatry", "id" : "ITEM-3", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "8", "1" ] ] }, "page" : "237-45", "title" : "DCDC2, KIAA0319 and CMIP are associated with reading-related traits.", "type" : "article-journal", "volume" : "70" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1002/dys.1464", "ISSN" : "1099-0909", "PMID" : "24133036", "abstract" : "Dyslexia is a highly heritable learning disorder with a complex underlying genetic architecture. Over the past decade, researchers have pinpointed a number of candidate genes that may contribute to dyslexia susceptibility. Here, we provide an overview of the state of the art, describing how studies have moved from mapping potential risk loci, through identification of associated gene variants, to characterization of gene function in cellular and animal model systems. Work thus far has highlighted some intriguing mechanistic pathways, such as neuronal migration, axon guidance, and ciliary biology, but it is clear that we still have much to learn about the molecular networks that are involved. We end the review by highlighting the past, present, and future contributions of the Dutch Dyslexia Programme to studies of genetic factors. In particular, we emphasize the importance of relating genetic information to intermediate neurobiological measures, as well as the value of incorporating longitudinal and developmental data into molecular designs.", "author" : [ { "dropping-particle" : "", "family" : "Carrion-Castillo", "given" : "Amaia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Franke", "given" : "Barbara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Dyslexia (Chichester, England)", "id" : "ITEM-4", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "11" ] ] }, "page" : "214-40", "title" : "Molecular genetics of dyslexia: an overview.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Carrion-Castillo, Franke, & Fisher, 2013; Paracchini, 2011; Paracchini et al., 2008; Scerri et al., 2011)", "plainTextFormattedCitation" : "(Carrion-Castillo, Franke, & Fisher, 2013; Paracchini, 2011; Paracchini et al., 2008; Scerri et al., 2011)", "previouslyFormattedCitation" : "(Carrion-Castillo, Franke, & Fisher, 2013; Paracchini, 2011; Paracchini et al., 2008; Scerri et al., 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Carrion-Castillo, Franke, & Fisher, 2013; Paracchini, 2011; Paracchini et al., 2008; Scerri et al., 2011) Some studies support the claim of association of the candidate genes with either dyslexia or SLI, while others disagree. It has been implied that this might be partially due to arbitrary statistical thresholds or that the first studies that looked at the genetic architecture of these disorders presented false-positives. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/dys.1464", "ISSN" : "1099-0909", "PMID" : "24133036", "abstract" : "Dyslexia is a highly heritable learning disorder with a complex underlying genetic architecture. Over the past decade, researchers have pinpointed a number of candidate genes that may contribute to dyslexia susceptibility. Here, we provide an overview of the state of the art, describing how studies have moved from mapping potential risk loci, through identification of associated gene variants, to characterization of gene function in cellular and animal model systems. Work thus far has highlighted some intriguing mechanistic pathways, such as neuronal migration, axon guidance, and ciliary biology, but it is clear that we still have much to learn about the molecular networks that are involved. We end the review by highlighting the past, present, and future contributions of the Dutch Dyslexia Programme to studies of genetic factors. In particular, we emphasize the importance of relating genetic information to intermediate neurobiological measures, as well as the value of incorporating longitudinal and developmental data into molecular designs.", "author" : [ { "dropping-particle" : "", "family" : "Carrion-Castillo", "given" : "Amaia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Franke", "given" : "Barbara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Dyslexia (Chichester, England)", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "11" ] ] }, "page" : "214-40", "title" : "Molecular genetics of dyslexia: an overview.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.3390/genes5020285", "ISBN" : "10.3390/genes5020285", "ISSN" : "2073-4425", "PMID" : "24705331", "abstract" : "Reading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing genetic factors to be complex in nature. To date, only a few genes have been implicated in these traits. Their functional characterization has provided novel insight into the biology of neurodevelopmental disorders. However, the lack of biological markers and clear diagnostic criteria have prevented the collection of the large sample sizes required for well-powered genome-wide screens. One of the main challenges of the field will be to combine careful clinical assessment with high throughput genetic technologies within multidisciplinary collaborations.", "author" : [ { "dropping-particle" : "", "family" : "Newbury", "given" : "Dianne F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paracchini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genes", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2014", "1", "4" ] ] }, "language" : "en", "page" : "285-309", "publisher" : "Multidisciplinary Digital Publishing Institute", "title" : "Reading and language disorders: the importance of both quantity and quality.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Carrion-Castillo et al., 2013; Newbury, Monaco, & Paracchini, 2014)", "plainTextFormattedCitation" : "(Carrion-Castillo et al., 2013; Newbury, Monaco, & Paracchini, 2014)", "previouslyFormattedCitation" : "(Carrion-Castillo et al., 2013; Newbury, Monaco, & Paracchini, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Carrion-Castillo et al., 2013; Newbury, Monaco, & Paracchini, 2014)Epilepsy-Aphasia Spectrum Disorders (EAS)EAS disorders is the collective name for patients suffering from epilepsy that affiliated with language impairments. It is not yet quite clear what the genetic foundations are for EAS disorders, but in 10 – 20 % of the cases in which patients suffered from EAS, heterozygous disruptions of GRIN2A have been found ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS)(1,2). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 x 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). 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Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor \u03b12 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology.", "author" : [ { "dropping-particle" : "", "family" : "Lesca", "given" : "Gaetan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rudolf", "given" : "Gabrielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruneau", "given" : "Nadine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lozovaya", "given" : "Natalia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labalme", "given" : "Audrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boutry-Kryza", "given" : "Nadia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salmi", "given" : "Manal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsintsadze", "given" : "Timur", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Addis", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Motte", "given" : "Jacques", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wright", "given" : "Sukhvir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsintsadze", "given" : "Vera", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michel", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doummar", "given" : "Diane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lascelles", "given" : "Karine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Strug", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Waters", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bellescize", "given" : "Julitta", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vrielynck", "given" : "Pascal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saint Martin", "given" : "Anne", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ville", "given" : "Dorothee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ryvlin", "given" : "Philippe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arzimanoglou", "given" : "Alexis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hirsch", "given" : "Edouard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vincent", "given" : "Angela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pal", "given" : "Deb", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burnashev", "given" : "Nail", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanlaville", "given" : "Damien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szepetowski", "given" : "Pierre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature genetics", "id" : "ITEM-2", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1061-6", "publisher" : "Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.", "title" : "GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.", "title-short" : "Nat Genet", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1038/ng.2727", "ISSN" : "1546-1718", "PMID" : "23933818", "abstract" : "Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.", "author" : [ { "dropping-particle" : "", "family" : "Carvill", "given" : "Gemma L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Regan", "given" : "Brigid M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yendle", "given" : "Simone C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Roak", "given" : "Brian J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lozovaya", "given" : "Natalia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruneau", "given" : "Nadine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burnashev", "given" : "Nail", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khan", "given" : "Adiba", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cook", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geraghty", "given" : "Eileen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sadleir", "given" : "Lynette G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turner", "given" : "Samantha J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsai", "given" : "Meng-Han", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ouvrier", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Damiano", "given" : "John A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berkovic", "given" : "Samuel F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shendure", "given" : "Jay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hildebrand", "given" : "Michael S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szepetowski", "given" : "Pierre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scheffer", "given" : "Ingrid E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mefford", "given" : "Heather C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature genetics", "id" : "ITEM-3", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "1073-6", "publisher" : "Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.", "title" : "GRIN2A mutations cause epilepsy-aphasia spectrum disorders.", "title-short" : "Nat Genet", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/j.pediatrneurol.2013.08.023", "ISSN" : "1873-5150", "PMID" : "24125812", "abstract" : "BACKGROUND: N-methyl-D-aspartate is a key neurotransmitter within the central nervous system and its dysfunction can play an important role in epilepsy. Mutations of genes involving the N-methyl-D-aspartate receptor have been implicated in a wide variety of neuropsychiatric disorders including epilepsy, specifically, within the glutamate receptor ionotropic N-methyl-D-aspartate 2A (GRIN2A).\n\nPATIENTS: We report two patients with a glutamate receptor ionotropic N-methyl-D-aspartate 2A mutation who presented with epilepsy.\n\nCONCLUSIONS: Individuals with a glutamate receptor ionotropic N-methyl-D-aspartate 2A mutation exhibit a broad clinical spectrum.", "author" : [ { "dropping-particle" : "", "family" : "DeVries", "given" : "Seth P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patel", "given" : "Anup D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric neurology", "id" : "ITEM-4", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "12", "1" ] ] }, "language" : "English", "page" : "482-5", "publisher" : "Elsevier", "title" : "Two patients with a GRIN2A mutation and childhood-onset epilepsy.", "type" : "article-journal", "volume" : "49" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Carvill et al., 2013; DeVries & Patel, 2013; Lemke et al., 2013; Lesca et al., 2013)", "plainTextFormattedCitation" : "(Carvill et al., 2013; DeVries & Patel, 2013; Lemke et al., 2013; Lesca et al., 2013)", "previouslyFormattedCitation" : "(Carvill et al., 2013; DeVries & Patel, 2013; Lemke et al., 2013; Lesca et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Carvill et al., 2013; DeVries & Patel, 2013; Lemke et al., 2013; Lesca et al., 2013), a gene that – when mutations have occurred – disrupts the ability of the ion channel to open and close. This channel is central to synaptic plasticity. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ng.2726", "ISSN" : "1546-1718", "PMID" : "23933820", "abstract" : "Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor \u03b12 subunit, GluN2A). 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All Rights Reserved.", "title" : "GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.", "title-short" : "Nat Genet", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.3389/fncel.2014.00160", "ISSN" : "1662-5102", "PMID" : "24959120", "abstract" : "The N-methyl-D-aspartate receptors (NMDARs) are part of a large multiprotein complex at the glutamatergic synapse. The assembly of NMDARs with synaptic proteins offers a means to regulate NMDAR channel properties and receptor trafficking, and couples NMDAR activation to distinct intracellular signaling pathways, thus contributing to the versatility of NMDAR functions. Receptor-protein interactions at the synapse provide a dynamic and powerful mechanism for regulating synaptic efficacy, but can also contribute to NMDAR overactivation-induced excitotoxicity and cellular damage under pathological conditions. An emerging concept is that by understanding the mechanisms and functions of disease-specific protein-protein interactions in the NMDAR complex, we may be able to develop novel therapies based on protein-NMDAR interactions for the treatment of brain diseases in which NMDAR dysfunction is at the root of their pathogenesis.", "author" : [ { "dropping-particle" : "", "family" : "Fan", "given" : "Xuelai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jin", "given" : "Wu Yang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Yu Tian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in cellular neuroscience", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "160", "title" : "The NMDA receptor complex: a multifunctional machine at the glutamatergic synapse.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Fan, Jin, & Wang, 2014; Lesca et al., 2013)", "plainTextFormattedCitation" : "(Fan, Jin, & Wang, 2014; Lesca et al., 2013)", "previouslyFormattedCitation" : "(Fan, Jin, & Wang, 2014; Lesca et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Fan, Jin, & Wang, 2014; Lesca et al., 2013)All in all, these studies that often contradict mostly show the place in which the research to the genetic architecture of language disorders is – still in its infancy. But one way to progress might be via larger sample sizes with the use of GWAS studies – genome-wide association studies to examine the common genetic variations among different individuals. ConclusionWe now have tried to grasp a small part of the immense and complex evolution of language, especially its origins, by examining the role of a specific gene, FOXP2, in the development of language. How did this gene come about, and how does this relate to the evolution of language? After examining the current research on the approximate dates of the development of the human version of FOXP2 and grammar, I created a timeline, shown in figure 11. The evolution of the human FOXP2 was probably critical for the development of speech, and to a further extent for the development of fully human society and cognition. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature01025", "ISSN" : "0028-0836", "PMID" : "12192408", "abstract" : "Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution.", "author" : [ { "dropping-particle" : "", "family" : "Enard", "given" : "Wolfgang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Przeworski", "given" : "Molly", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lai", "given" : "Cecilia S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wiebe", "given" : "Victor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kitano", "given" : "Takashi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monaco", "given" : "Anthony P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "P\u00e4\u00e4bo", "given" : "Svante", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "6900", "issued" : { "date-parts" : [ [ "2002", "8", "22" ] ] }, "page" : "869-72", "title" : "Molecular evolution of FOXP2, a gene involved in speech and language.", "title-short" : "Nature", "type" : "article-journal", "volume" : "418" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Enard, Przeworski, et al., 2002)", "plainTextFormattedCitation" : "(Enard, Przeworski, et al., 2002)", "previouslyFormattedCitation" : "(Enard, Przeworski, et al., 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Enard, Przeworski, et al., 2002) FOXP2 lay down the basis for language, and allowed it to grow, but it remains part of communication as a whole, and specifically to language.Figure SEQ Figure \* ARABIC 11: The figure above displays a rough timeline of the history of the evolution of language. FOXP2 developed to its human form before the divergence of Neanderthals and Homo sapiens. However, grammar did not evolve until after that divergence, proposing that FOXP2 has not been directly involved with the evolving of grammar with the homo sapiens society.Most of the neuronal circuits regulated by FOXP2 are not only (or mainly) language-specific. The fronto-striatal and the fronto-cerebellar networks support functions such as decision making or planning and organization. And while this is a common feature of circuits within the brain, in the case of FOXP2, a gene of which its function is the heart of this debate, it marks only the difficulty of framing the function of FOXP2, without actually progressing the debate. FOXP2’s role in the fronto-cerebellar network does not automatically causally link with its role in the development of language. The fronto-cerebellar network is also found in non-human primates ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/cercor/bhp135", "ISSN" : "1460-2199", "PMID" : "19592571", "abstract" : "Multiple, segregated fronto-cerebellar circuits have been characterized in nonhuman primates using transneuronal tracing techniques including those that target prefrontal areas. Here, we used functional connectivity MRI (fcMRI) in humans (n = 40) to identify 4 topographically distinct fronto-cerebellar circuits that target 1) motor cortex, 2) dorsolateral prefrontal cortex, 3) medial prefrontal cortex, and 4) anterior prefrontal cortex. All 4 circuits were replicated and dissociated in an independent data set (n = 40). Direct comparison of right- and left-seeded frontal regions revealed contralateral lateralization in the cerebellum for each of the segregated circuits. The presence of circuits that involve prefrontal regions confirms that the cerebellum participates in networks important to cognition including a specific fronto-cerebellar circuit that interacts with the default network. Overall, the extent of the cerebellum associated with prefrontal cortex included a large portion of the posterior hemispheres consistent with a prominent role of the cerebellum in nonmotor functions. We conclude by providing a provisional map of the topography of the cerebellum based on functional correlations with the frontal cortex.", "author" : [ { "dropping-particle" : "", "family" : "Krienen", "given" : "Fenna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckner", "given" : "Randy L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cerebral cortex (New York, N.Y. : 1991)", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2009", "10", "1" ] ] }, "page" : "2485-97", "title" : "Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Krienen & Buckner, 2009)", "plainTextFormattedCitation" : "(Krienen & Buckner, 2009)", "previouslyFormattedCitation" : "(Krienen & Buckner, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Krienen & Buckner, 2009), despite their inability to produce language. This network controls many motor functions among the non-human primates. Due to the rather broad function of the fronto-cerebellar network, this is not disturbing for its role in language and speech, but depicts once more the trouble of giving FOXP2 the partial responsibility for language. FOXP2 does seem to play an evidential role in in the networks involved with learning, planning and executing orofacial movements and speech motor sequences. But we defined language as speech that involves grammar, so this is still not a clear argument to build the case for FOXP2 as ‘the gene for language’.FOXP2 has an overarching function and possibly regulates thousands of genes, and those genes might include the other genes involved with language or communication. But the research into the function of these other genes is still in its infancy, and therefore the debate on the true function of these genes remains unresolved. To add to this insecurity, it remains difficult to know to what extent these genes act upon their own, or whether they are directly or indirectly governed by FOXP2. This might imply that for now FOXP2 does remain the most significant language related gene, due to its overarching function, but they all remain parts of the greater whole that is language. In the end it seems that FOXP2 is not responsible for language, but for communication. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1537-6605", "abstract" : "We previously discovered that mutations of the human FOXP2 gene cause a monogenic communication disorder, primarily characterized by difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech. Affected people have deficits in expressive and receptive linguistic processing and display structural and/or functional abnormalities in cortical and subcortical brain regions. FOXP2 provides a unique window into neural processes involved in speech and language. In particular, its role as a transcription factor gene offers powerful functional genomic routes for dissecting critical neurogenetic mechanisms. Here, we employ chromatin immunoprecipitation coupled with promoter microarrays (ChIP-chip) to successfully identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. We focus on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression in our cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, we demonstrate significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represents the first identification and in vivo verification of neural targets regulated by FOXP2. Our data indicate that FOXP2 has dual functionality, acting to either repress or activate gene expression at occupied promoters. The identified targets suggest roles in modulating synaptic plasticity, neurodevelopment, neurotransmission, and axon guidance and represent novel entry points into in vivo pathways that may be disturbed in speech and language disorders.", "author" : [ { "dropping-particle" : "", "family" : "Vernes", "given" : "Sonja C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spiteri", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nicod", "given" : "J\u00e9r\u00f4me", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groszer", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Jennifer M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Kay E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geschwind", "given" : "Daniel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of human genetics", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2007", "12" ] ] }, "page" : "1232-50", "title" : "High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders.", "type" : "article-journal", "volume" : "81" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "1537-6605", "abstract" : "Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.", "author" : [ { "dropping-particle" : "", "family" : "Spiteri", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Konopka", "given" : "Genevieve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coppola", "given" : "Giovanni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bomar", "given" : "Jamee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oldham", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ou", "given" : "Jing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vernes", "given" : "Sonja C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "Simon E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ren", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geschwind", "given" : "Daniel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of human genetics", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2007", "12" ] ] }, "page" : "1144-57", "title" : "Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain.", "type" : "article-journal", "volume" : "81" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "1476-4687", "abstract" : "The signalling pathways controlling both the evolution and development of language in the human brain remain unknown. So far, the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction. It has been proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this two-amino-acid change occurred around the time of language emergence in humans. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here we demonstrate that these two human-specific amino acids alter FOXP2 function by conferring differential transcriptional regulation in vitro. We extend these observations in vivo to human and chimpanzee brain, and use network analysis to identify novel relationships among the differentially expressed genes. These data provide experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the central nervous system (CNS). Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.", "author" : [ { "dropping-particle" : "", "family" : "Konopka", "given" : "Genevieve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bomar", "given" : "Jamee M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winden", "given" : "Kellen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coppola", "given" : "Giovanni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jonsson", "given" : "Zophonias O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Fuying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peng", "given" : "Sophia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Preuss", "given" : "Todd M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wohlschlegel", "given" : "James A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geschwind", "given" : "Daniel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-3", "issue" : "7270", "issued" : { "date-parts" : [ [ "2009", "11", "12" ] ] }, "page" : "213-7", "publisher" : "Macmillan Publishers Limited. All rights reserved", "title" : "Human-specific transcriptional regulation of CNS development genes by FOXP2.", "title-short" : "Nature", "type" : "article-journal", "volume" : "462" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Konopka et al., 2009b; Spiteri et al., 2007; Vernes et al., 2007)", "plainTextFormattedCitation" : "(Konopka et al., 2009b; Spiteri et al., 2007; Vernes et al., 2007)", "previouslyFormattedCitation" : "(Konopka et al., 2009b; Spiteri et al., 2007; Vernes et al., 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Konopka et al., 2009b; Spiteri et al., 2007; Vernes et al., 2007)Language was made possible by the invention of grammar. But ‘how much grammar does it take to sail a boat?’ asks David Gil (2005): ‘Virtually none’ is the answer. Those practical tasks such as building a boat might have been made easier thanks to grammar, but we would not have needed it. And the ability to built ships is not what made the Homo sapiens thrive the way they did – It is very likely that Homo erectus already built seaworthy rafts. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Gil", "given" : "D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Categorization in Cognitive Science", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "347-379", "title" : "Isolating-Monocategorial-Associated Language", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gil, 2005)", "plainTextFormattedCitation" : "(Gil, 2005)", "previouslyFormattedCitation" : "(Gil, 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Gil, 2005) Grammar would, however, be evolutionary favoured if the group in which the species lives grows ‘too’ big. That is what happened with the Homo sapiens. And by the time that grammar became favourable within our species’ society, we already gained the ability to produce words thanks to the fine motor skills developed due to the (probably one of the) final two mutations in the FOXP2 gene. But even though FOXP2 handed us the ability to talk, it probably did not induce language. Our genetic evolution created the necessities to acquire and produce language, but it has been a cultural change that allowed for language to truly develop.The connection between the human-specific FOXP2 and speech or language remains tricky. What we can learn from the KE-family is that FOXP2 is definitely necessary for speech development. But the crux of the problem remains: FOXP2 is a multifunctional gene, and it should not rigidly be matched to such a complex, high level phenotype as language. Language encompasses so many pathways and demands support from macro to micro levels, from muscles to cells. According to Preuss (2013) ‘it is not even realistic to think that the development of such systems has simple genetic triggers’. Language is just too complex, and too many systems are involved in allowing a person to produce normal language, and get involved in conversations with others, that it seems highly unlikely that one gene could be held responsible for all that. It is more likely that a genetic architecture that underpins language is as complex as language itself. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Preuss", "given" : "TODD M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "1", "25" ] ] }, "language" : "en", "publisher" : "National Academies Press (US)", "title" : "Human Brain Evolution: From Gene Discovery to Phenotype Discovery", "type" : "article" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Preuss, 2013)", "plainTextFormattedCitation" : "(Preuss, 2013)", "previouslyFormattedCitation" : "(Preuss, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Preuss, 2013) In the end, we are left with many theories about the role of FOXP2, and also about the origin of language, but scarce evidence to support them. However, looking at the direct and indirect evidence I gathered in this thesis, I would like to conclude with a final metaphor, one that is also displayed in figure 12. Imagine language being the house we surround ourselves with, it is our home which door allows us to invite people into our lives and socialize. Before we could build that house, we took hold of all the materials needed. Some of those materials will be used to create the foundation of the house. Other material will be used to build the rest of the house – stones, glass for the windows, tiles for the roof. Other genes, and other biological adaptations might have been the stones necessary to build the walls, and FOXP2 might have been the foundation on which the rest could be built. But not until we had enough manpower could and did we truly built the house.8661409779000752475119380Figure SEQ Figure \* ARABIC 12: Language is displayed as a house, that is created from several building blocks (language genes other than FOXP2, biological adaptations and other smaller cultural changes), which we gained throughout time. And the house needed foundations (the human-specific FOXP2). But those foundations and building blocks never became a house, if it weren’t for the manpower needed to truly build it.0Figure SEQ Figure \* ARABIC 12: Language is displayed as a house, that is created from several building blocks (language genes other than FOXP2, biological adaptations and other smaller cultural changes), which we gained throughout time. And the house needed foundations (the human-specific FOXP2). But those foundations and building blocks never became a house, if it weren’t for the manpower needed to truly build it.Not until we, humans, were with enough people did we develop language, even though we already had all the building blocks long before that moment arrived. But that does not diminish the value of FOXP2, hence why it is viewed as the foundation of the house. It might not have been responsible for our development of language, but it was of great necessity.AcknowledgementsI would like to thank prof. Dr. J.C. Billeter for his clear and helpful feedback and his many useful tips during this writing process.Further reading tipsOrigins of the Modern Mind – Merlin DonaldDoctor Dolittle’s Delusion: Animals and the Uniqueness of Human Language – Stephen R. AndersonFrom animals into Gods. 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