These are the publications of the Neurogenetics of Vocal Communication Group

Displaying 1 - 44 of 44
  • Lattenkamp, E. Z., Nagy, M., Drexl, M., Vernes, S. C., Wiegrebe, L., & Knörnschild, M. (2021). Hearing sensitivity and amplitude coding in bats are differentially shaped by echolocation calls and social calls. Proceedings of the Royal Society B: Biological Sciences, 288(1942): 20202600. doi:10.1098/rspb.2020.2600.

    Abstract

    Differences in auditory perception between species are influenced by phylogenetic origin and the perceptual challenges imposed by the natural environment, such as detecting prey- or predator-generated sounds and communication signals. Bats are well suited for comparative studies on auditory perception since they predominantly rely on echolocation to perceive the world, while their social calls and most environmental sounds have low frequencies. We tested if hearing sensitivity and stimulus level coding in bats differ between high and low-frequency ranges by measuring auditory brainstem responses (ABRs) of 86 bats belonging to 11 species. In most species, auditory sensitivity was equally good at both high- and low-frequency ranges, while amplitude was more finely coded for higher frequency ranges. Additionally, we conducted a phylogenetic comparative analysis by combining our ABR data with published data on 27 species. Species-specific peaks in hearing sensitivity correlated with peak frequencies of echolocation calls and pup isolation calls, suggesting that changes in hearing sensitivity evolved in response to frequency changes of echolocation and social calls. Overall, our study provides the most comprehensive comparative assessment of bat hearing capacities to date and highlights the evolutionary pressures acting on their sensory perception.

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  • Hoeksema, N., Wiesmann, M., Kiliaan, A., Hagoort, P., & Vernes, S. C. (2020). Bats and the comparative neurobiology of vocal learning. In A. Ravignani, C. Barbieri, M. Flaherty, Y. Jadoul, E. Lattenkamp, H. Little, M. Martins, K. Mudd, & T. Verhoef (Eds.), The Evolution of Language: Proceedings of the 13th International Conference (Evolang13) (pp. 165-167). Nijmegen: The Evolution of Language Conferences.
  • Hoeksema, N., Villanueva, S., Mengede, J., Salazar Casals, A., Rubio-García, A., Curcic-Blake, B., Vernes, S. C., & Ravignani, A. (2020). Neuroanatomy of the grey seal brain: Bringing pinnipeds into the neurobiological study of vocal learning. In A. Ravignani, C. Barbieri, M. Flaherty, Y. Jadoul, E. Lattenkamp, H. Little, M. Martins, K. Mudd, & T. Verhoef (Eds.), The Evolution of Language: Proceedings of the 13th International Conference (Evolang13) (pp. 162-164). Nijmegen: The Evolution of Language Conferences.
  • Jebb, D., Huang, Z., Pippel, M., Hughes, G. M., Lavrichenko, K., Devanna, P., Winkler, S., Jermiin, L. S., Skirmuntt, E. C., Katzourakis, A., Burkitt-Gray, L., Ray, D. A., Sullivan, K. A. M., Roscito, J. G., Kirilenko, B. M., Dávalos, L. M., Corthals, A. P., Power, M. L., Jones, G., Ransome, R. D. and 9 moreJebb, D., Huang, Z., Pippel, M., Hughes, G. M., Lavrichenko, K., Devanna, P., Winkler, S., Jermiin, L. S., Skirmuntt, E. C., Katzourakis, A., Burkitt-Gray, L., Ray, D. A., Sullivan, K. A. M., Roscito, J. G., Kirilenko, B. M., Dávalos, L. M., Corthals, A. P., Power, M. L., Jones, G., Ransome, R. D., Dechmann, D., Locatelli, A. G., Puechmaille, S. J., Fedrigo, O., Jarvis, E. D., Hiller, M., Vernes, S. C., Myers, E. W., & Teeling, E. C. (2020). Six reference-quality genomes reveal evolution of bat adaptations. Nature, 583, 578-584. doi:10.1038/s41586-020-2486-3.

    Abstract

    Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our ‘Tool to infer Orthologs from Genome Alignments’ (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease

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  • Lattenkamp, E. Z., Linnenschmidt, M., Mardus, E., Vernes, S. C., Wiegrebe, L., & Schutte, M. (2020). Impact of auditory feedback on bat vocal development. In A. Ravignani, C. Barbieri, M. Flaherty, Y. Jadoul, E. Lattenkamp, H. Little, M. Martins, K. Mudd, & T. Verhoef (Eds.), The Evolution of Language: Proceedings of the 13th International Conference (Evolang13) (pp. 249-251). Nijmegen: The Evolution of Language Conferences.
  • Lattenkamp, E. Z. (2020). Vocal learning in the pale spear-nosed bat, Phyllostomus discolor. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • Lattenkamp, E. Z., Vernes, S. C., & Wiegrebe, L. (2020). Vocal production learning in the pale spear-nosed bat, Phyllostomus discolor. Biology Letters, 16: 20190928. doi:10.1098/rsbl.2019.0928.

    Abstract

    Vocal production learning (VPL), or the ability to modify vocalizations through the imitation of sounds, is a rare trait in the animal kingdom. While humans are exceptional vocal learners, few other mammalian species share this trait. Owing to their singular ecology and lifestyle, bats are highly specialized for the precise emission and reception of acoustic signals. This specialization makes them ideal candidates for the study of vocal learning, and several bat species have previously shown evidence supportive of vocal learning. Here we use a sophisticated automated set-up and a contingency training paradigm to explore the vocal learning capacity of pale spear-nosed bats. We show that these bats are capable of directional change of the fundamental frequency of their calls according to an auditory target. With this study, we further highlight the importance of bats for the study of vocal learning and provide evidence for the VPL capacity of the pale spear-nosed bat.

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  • Mengede, J., Devanna, P., Hörpel, S., Firzla, U., & Vernes, S. C. (2020). Studying the genetic bases of vocal learning in bats. In A. Ravignani, C. Barbieri, M. Flaherty, Y. Jadoul, E. Lattenkamp, H. Little, M. Martins, K. Mudd, & T. Verhoef (Eds.), The Evolution of Language: Proceedings of the 13th International Conference (Evolang13) (pp. 280-282). Nijmegen: The Evolution of Language Conferences.
  • Ravignani, A., Barbieri, C., Flaherty, M., Jadoul, Y., Lattenkamp, E. Z., Little, H., Martins, M., Mudd, K., & Verhoef, T. (Eds.). (2020). The Evolution of Language: Proceedings of the 13th International Conference (Evolang13). Nijmegen: The Evolution of Language Conferences. doi:10.17617/2.3190925.

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  • Vernes, S. C., & Wilkinson, G. S. (2020). Behaviour, biology, and evolution of vocal learning in bats. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 375(1789): 20190061. doi:10.1098/rstb.2019.0061.

    Abstract

    The comparative approach can provide insight into the evolution of human speech, language and social communication by studying relevant traits in animal systems. Bats are emerging as a model system with great potential to shed light on these processes given their learned vocalizations, close social interactions, and mammalian brains and physiology. A recent framework outlined the multiple levels of investigation needed to understand vocal learning across a broad range of non-human species, including cetaceans, pinnipeds, elephants, birds and bats. Here, we apply this framework to the current state-of-the-art in bat research. This encompasses our understanding of the abilities bats have displayed for vocal learning, what is known about the timing and social structure needed for such learning, and current knowledge about the prevalence of the trait across the order. It also addresses the biology (vocal tract morphology, neurobiology and genetics) and evolution of this trait. We conclude by highlighting some key questions that should be answered to advance our understanding of the biological encoding and evolution of speech and spoken communication. This article is part of the theme issue 'What can animal communication teach us about human language?'

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    earlier version of article on BioRxiv
  • Vernes, S. C. (2020). Understanding bat vocal learning to gain insight into speech and language. In A. Ravignani, C. Barbieri, M. Flaherty, Y. Jadoul, E. Lattenkamp, H. Little, M. Martins, K. Mudd, & T. Verhoef (Eds.), The Evolution of Language: Proceedings of the 13th International Conference (Evolang13) (pp. 6). Nijmegen: The Evolution of Language Conferences.
  • Devanna, P., Dediu, D., & Vernes, S. C. (2019). The Genetics of Language: From complex genes to complex communication. In S.-A. Rueschemeyer, & M. G. Gaskell (Eds.), The Oxford Handbook of Psycholinguistics (2nd ed., pp. 865-898). Oxford: Oxford University Press.

    Abstract

    This chapter discusses the genetic foundations of the human capacity for language. It reviews the molecular structure of the genome and the complex molecular mechanisms that allow genetic information to influence multiple levels of biology. It goes on to describe the active regulation of genes and their formation of complex genetic pathways that in turn control the cellular environment and function. At each of these levels, examples of genes and genetic variants that may influence the human capacity for language are given. Finally, it discusses the value of using animal models to understand the genetic underpinnings of speech and language. From this chapter will emerge the complexity of the genome in action and the multidisciplinary efforts that are currently made to bridge the gap between genetics and language.
  • Lattenkamp, E. Z., Shields, S. M., Schutte, M., Richter, J., Linnenschmidt, M., Vernes, S. C., & Wiegrebe, L. (2019). The vocal repertoire of pale spear-nosed bats in a social roosting context. Frontiers in Ecology and Evolution, 7: 116. doi:10.3389/fevo.2019.00116.

    Abstract

    Commonly known for their ability to echolocate, bats also use a wide variety of social vocalizations to communicate with one another. However, the full vocal repertoires of relatively few bat species have been studied thus far. The present study examined the vocal repertoire of the pale spear-nosed bat, Phyllostomus discolor, in a social roosting context. Based on visual examination of spectrograms and subsequent quantitative analysis of syllables, eight distinct syllable classes were defined, and their prevalence in different behavioral contexts was examined. Four more syllable classes were observed in low numbers and are described here as well. These results show that P. discolor possesses a rich vocal repertoire, which includes vocalizations comparable to previously reported repertoires of other bat species as well as vocalizations previously undescribed. Our data provide detailed information about the temporal and spectral characteristics of syllables emitted by P. discolor, allowing for a better understanding of the communicative system and related behaviors of this species. Furthermore, this vocal repertoire will serve as a basis for future research using P. discolor as a model organism for vocal communication and vocal learning and it will allow for comparative studies between bat species.

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  • Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., & Gaetano, C. (2019). P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation. The FASEB Journal, 33(3), 4107-4123. doi:10.1096/fj.201800788R.

    Abstract

    The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N-terminal region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.—Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.

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  • Van Rhijn, J. R. (2019). The role of FoxP2 in striatal circuitry. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • Vernes, S. C. (2019). Neuromolecular approaches to the study of language. In P. Hagoort (Ed.), Human language: From genes and brain to behavior (pp. 577-593). Cambridge, MA: MIT Press.
  • Wirthlin, M., Chang, E. F., Knörnschild, M., Krubitzer, L. A., Mello, C. V., Miller, C. T., Pfenning, A. R., Vernes, S. C., Tchernichovski, O., & Yartsev, M. M. (2019). A modular approach to vocal learning: Disentangling the diversity of a complex behavioral trait. Neuron, 104(1), 87-99. doi:10.1016/j.neuron.2019.09.036.

    Abstract

    Vocal learning is a behavioral trait in which the social and acoustic environment shapes the vocal repertoire of individuals. Over the past century, the study of vocal learning has progressed at the intersection of ecology, physiology, neuroscience, molecular biology, genomics, and evolution. Yet, despite the complexity of this trait, vocal learning is frequently described as a binary trait, with species being classified as either vocal learners or vocal non-learners. As a result, studies have largely focused on a handful of species for which strong evidence for vocal learning exists. Recent studies, however, suggest a continuum in vocal learning capacity across taxa. Here, we further suggest that vocal learning is a multi-component behavioral phenotype comprised of distinct yet interconnected modules. Discretizing the vocal learning phenotype into its constituent modules would facilitate integration of findings across a wider diversity of species, taking advantage of the ways in which each excels in a particular module, or in a specific combination of features. Such comparative studies can improve understanding of the mechanisms and evolutionary origins of vocal learning. We propose an initial set of vocal learning modules supported by behavioral and neurobiological data and highlight the need for diversifying the field in order to disentangle the complexity of the vocal learning phenotype.

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  • Becker, M., Devanna, P., Fisher, S. E., & Vernes, S. C. (2018). Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. Frontiers in Molecular Neuroscience, 11: 47. doi:10.3389/fnmol.2018.00047.

    Abstract

    Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
  • Devanna, P., Van de Vorst, M., Pfundt, R., Gilissen, C., & Vernes, S. C. (2018). Genome-wide investigation of an ID cohort reveals de novo 3′UTR variants affecting gene expression. Human Genetics, 137(9), 717-721. doi:10.1007/s00439-018-1925-9.

    Abstract

    Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression. Nevertheless the functional characterization of non-coding variants remains challenging. We describe the identification and characterization of de novo non-coding variation in 3′UTR regulatory regions within an ID cohort of 50 patients. This cohort was previously screened for structural and coding pathogenic variants via CNV, whole exome and whole genome analysis. We identified 44 high-confidence single nucleotide non-coding variants within the 3′UTR regions of these 50 genomes. Four of these variants were located within predicted miRNA binding sites and were thus hypothesised to have regulatory consequences. Functional testing showed that two of the variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM. Both these variants were found in the same individual and their functional consequences may point to a potential role for such variants in intellectual disability.

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  • Devanna, P., Chen, X. S., Ho, J., Gajewski, D., Smith, S. D., Gialluisi, A., Francks, C., Fisher, S. E., Newbury, D. F., & Vernes, S. C. (2018). Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders. Molecular Psychiatry, 23(5), 1375-1384. doi:10.1038/mp.2017.30.

    Abstract

    Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

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  • Lattenkamp, E. Z., Kaiser, S., Kaucic, R., Großmann, M., Koselj, K., & Goerlitz, H. R. (2018). Environmental acoustic cues guide the biosonar attention of a highly specialised echolocator. Journal of Experimental Biology, 221(8): jeb165696. doi:10.1242/jeb.165696.

    Abstract

    Sensory systems experience a trade-off between maximizing the detail and amount of sampled information. Thistrade-off is particularly pronounced in sensorysystemsthat are highlyspecialised fora single task and thus experience limitations in other tasks. We hypothesised that combining sensory input from multiple streams of information may resolve this trade-off and improve detection and sensing reliability. Specifically, we predicted that perceptive limitations experienced by animals reliant on specialised active echolocation can be compensated for by the phylogenetically older and less specialised process of passive hearing. We tested this hypothesis in greater horseshoe bats, which possess morphological and neural specialisations allowing them to identify fluttering prey in dense vegetation using echolocation only. At the same time, their echolocation system is both spatially and temporally severely limited. Here, we show that greater horseshoe bats employ passive hearing to initially detect and localise prey-generated and other environmental sounds, and then raise vocalisation level and concentrate the scanning movements of their sonar beam on the sound source for further investigation with echolocation. These specialised echolocators thus supplement echo-acoustic information with environmental acoustic cues, enlarging perceived space beyond their biosonar range. Contrary to our predictions, we did not find consistent preferences for prey-related acoustic stimuli, indicating the use of passive acoustic cues also for detection of non-prey objects. Our findings suggest that even specialised echolocators exploit a wide range of environmental information, and that phylogenetically older sensory systems can support the evolution of sensory specialisations by compensating for their limitations.
  • Lattenkamp, E. Z., Vernes, S. C., & Wiegrebe, L. (2018). Mammalian models for the study of vocal learning: A new paradigm in bats. In C. Cuskley, M. Flaherty, H. Little, L. McCrohon, A. Ravignani, & T. Verhoef (Eds.), Proceedings of the 12th International Conference on the Evolution of Language (EVOLANG XII) (pp. 235-237). Toruń, Poland: NCU Press. doi:10.12775/3991-1.056.
  • Lattenkamp, E. Z., & Vernes, S. C. (2018). Vocal learning: A language-relevant trait in need of a broad cross-species approach. Current Opinion in Behavioral Sciences, 21, 209-215. doi:10.1016/j.cobeha.2018.04.007.

    Abstract

    Although humans are unmatched in their capacity to produce speech and learn language, comparative approaches in diverse animalmodelsareabletoshedlightonthebiologicalunderpinnings of language-relevant traits. In the study of vocal learning, a trait crucial for spoken language, passerine birds have been the dominant models, driving invaluable progress in understanding the neurobiology and genetics of vocal learning despite being only distantly related to humans. To date, there is sparse evidence that our closest relatives, nonhuman primates have the capability to learn new vocalisations. However, a number of other mammals have shown the capacity for vocal learning, such as some cetaceans, pinnipeds, elephants, and bats, and we anticipate that with further study more species will gain membership to this (currently) select club. A broad, cross-species comparison of vocal learning, coupled with careful consideration of the components underlying this trait, is crucial to determine how human speech and spoken language is biologically encoded and how it evolved. We emphasise the need to draw on the pool of promising species that havethusfarbeenunderstudiedorneglected.Thisisbynomeansa call for fewer studies in songbirds, or an unfocused treasure-hunt, but rather an appeal for structured comparisons across a range of species, considering phylogenetic relationships, ecological and morphological constrains, developmental and social factors, and neurogenetic underpinnings. Herein, we promote a comparative approachhighlightingtheimportanceofstudyingvocallearningina broad range of model species, and describe a common framework for targeted cross-taxon studies to shed light on the biology and evolution of vocal learning.
  • Lattenkamp, E. Z., Vernes, S. C., & Wiegrebe, L. (2018). Volitional control of social vocalisations and vocal usage learning in bats. Journal of Experimental Biology, 221(14): jeb.180729. doi:10.1242/jeb.180729.

    Abstract

    Bats are gregarious, highly vocal animals that possess a broad repertoire of social vocalisations. For in-depth studies of their vocal behaviours, including vocal flexibility and vocal learning, it is necessary to gather repeatable evidence from controlled laboratory experiments on isolated individuals. However, such studies are rare for one simple reason: eliciting social calls in isolation and under operant control is challenging and has rarely been achieved. To overcome this limitation, we designed an automated setup that allows conditioning of social vocalisations in a new context, and tracks spectro-temporal changes in the recorded calls over time. Using this setup, we were able to reliably evoke social calls from temporarily isolated lesser spear-nosed bats (Phyllostomus discolor). When we adjusted the call criteria that could result in food reward, bats responded by adjusting temporal and spectral call parameters. This was achieved without the help of an auditory template or social context to direct the bats. Our results demonstrate vocal flexibility and vocal usage learning in bats. Our setup provides a new paradigm that allows the controlled study of the production and learning of social vocalisations in isolated bats, overcoming limitations that have, until now, prevented in-depth studies of these behaviours.

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  • Pika, S., Wilkinson, R., Kendrick, K. H., & Vernes, S. C. (2018). Taking turns: Bridging the gap between human and animal communication. Proceedings of the Royal Society B: Biological Sciences, 285(1880): 20180598. doi:10.1098/rspb.2018.0598.

    Abstract

    Language, humans’ most distinctive trait, still remains a ‘mystery’ for evolutionary theory. It is underpinned by a universal infrastructure—cooperative turn-taking—which has been suggested as an ancient mechanism bridging the existing gap between the articulate human species and their inarticulate primate cousins. However, we know remarkably little about turn-taking systems of non-human animals, and methodological confounds have often prevented meaningful cross-species comparisons. Thus, the extent to which cooperative turn-taking is uniquely human or represents a homologous and/or analogous trait is currently unknown. The present paper draws attention to this promising research avenue by providing an overview of the state of the art of turn-taking in four animal taxa—birds, mammals, insects and anurans. It concludes with a new comparative framework to spur more research into this research domain and to test which elements of the human turn-taking system are shared across species and taxa.
  • Rodenas-Cuadrado, P., Mengede, J., Baas, L., Devanna, P., Schmid, T. A., Yartsev, M., Firzlaff, U., & Vernes, S. C. (2018). Mapping the distribution of language related genes FoxP1, FoxP2 and CntnaP2 in the brains of vocal learning bat species. Journal of Comparative Neurology, 526(8), 1235-1266. doi:10.1002/cne.24385.

    Abstract

    Genes including FOXP2, FOXP1 and CNTNAP2, have been implicated in human speech and language phenotypes, pointing to a role in the development of normal language-related circuitry in the brain. Although speech and language are unique human phenotypes, a comparative approach is possible by addressing language-relevant traits in animal model systems. One such trait, vocal learning, represents an essential component of human spoken language, and is shared by cetaceans, pinnipeds, elephants, some birds and bats. Given their vocal learning abilities, gregarious nature, and reliance on vocalisations for social communication and navigation, bats represent an intriguing mammalian system in which to explore language-relevant genes. We used immunohistochemistry to detail the distribution of FoxP2, FoxP1 and Cntnap2 proteins, accompanied by detailed cytoarchitectural histology in the brains of two vocal learning bat species; Phyllostomus discolor and Rousettus aegyptiacus. We show widespread expression of these genes, similar to what has been previously observed in other species, including humans. A striking difference was observed in the adult Phyllostomus discolor bat, which showed low levels of FoxP2 expression in the cortex, contrasting with patterns found in rodents and non-human primates. We created an online, open-access database within which all data can be browsed, searched, and high resolution images viewed to single cell resolution. The data presented herein reveal regions of interest in the bat brain and provide new opportunities to address the role of these language-related genes in complex vocal-motor and vocal learning behaviours in a mammalian model system.
  • Teeling, E., Vernes, S. C., Davalos, L. M., Ray, D. A., Gilbert, M. T. P., Myers, E., & Bat1K Consortium (2018). Bat biology, genomes, and the Bat1K project: To generate chromosome-level genomes for all living bat species. Annual Review of Animal Biosciences, 6, 23-46. doi:10.1146/annurev-animal-022516-022811.

    Abstract

    Bats are unique among mammals, possessing some of the rarest mammalian adaptations, including true self-powered flight, laryngeal echolocation, exceptional longevity, unique immunity, contracted genomes, and vocal learning. They provide key ecosystem services, pollinating tropical plants, dispersing seeds, and controlling insect pest populations, thus driving healthy ecosystems. They account for more than 20% of all living mammalian diversity, and their crown-group evolutionary history dates back to the Eocene. Despite their great numbers and diversity, many species are threatened and endangered. Here we announce Bat1K, an initiative to sequence the genomes of all living bat species (n∼1,300) to chromosome-level assembly. The Bat1K genome consortium unites bat biologists (>132 members as of writing), computational scientists, conservation organizations, genome technologists, and any interested individuals committed to a better understanding of the genetic and evolutionary mechanisms that underlie the unique adaptations of bats. Our aim is to catalog the unique genetic diversity present in all living bats to better understand the molecular basis of their unique adaptations; uncover their evolutionary history; link genotype with phenotype; and ultimately better understand, promote, and conserve bats. Here we review the unique adaptations of bats and highlight how chromosome-level genome assemblies can uncover the molecular basis of these traits. We present a novel sequencing and assembly strategy and review the striking societal and scientific benefits that will result from the Bat1K initiative.
  • Van Rhijn, J. R., Fisher, S. E., Vernes, S. C., & Nadif Kasri, N. (2018). Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release. Brain Structure and Function, 223(9), 4211-4226. doi:10.1007/s00429-018-1746-6.

    Abstract

    Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive.

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  • Vernes, S. C. (2018). Vocal learning in bats: From genes to behaviour. In C. Cuskley, M. Flaherty, H. Little, L. McCrohon, A. Ravignani, & T. Verhoef (Eds.), Proceedings of the 12th International Conference on the Evolution of Language (EVOLANG XII) (pp. 516-518). Toruń, Poland: NCU Press. doi:10.12775/3991-1.128.
  • Wanke, K., Devanna, P., & Vernes, S. C. (2018). Understanding neurodevelopmental disorders: The promise of regulatory variation in the 3’UTRome. Biological Psychiatry, 83(7), 548-557. doi:10.1016/j.biopsych.2017.11.006.

    Abstract

    Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome-sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1-2% of the human genome. With the advent of whole-genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and non-coding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of non-coding variants identified per individual can be overwhelming, making it prudent to focus on non-coding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3’UTRome is a region of the non-coding genome that perfectly fulfils these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3’UTRome as binding sites for microRNAs, RNA binding proteins or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3’UTRome will lead to the identification of new risk factors, new candidate disease genes and a better understanding of the molecular mechanisms contributing to NDDs.

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  • Cortázar-Chinarro, M., Lattenkamp, E. Z., Meyer-Lucht, Y., Luquet, E., Laurila, A., & Höglund, J. (2017). Drift, selection, or migration? Processes affecting genetic differentiation and variation along a latitudinal gradient in an amphibian. BMC Evolutionary Biology, 17: 189. doi:10.1186/s12862-017-1022-z.

    Abstract

    Past events like fluctuations in population size and post-glacial colonization processes may influence the relative importance of genetic drift, migration and selection when determining the present day patterns of genetic variation. We disentangle how drift, selection and migration shape neutral and adaptive genetic variation in 12 moor frog populations along a 1700 km latitudinal gradient. We studied genetic differentiation and variation at a MHC exon II locus and a set of 18 microsatellites. Results Using outlier analyses, we identified the MHC II exon 2 (corresponding to the β-2 domain) locus and one microsatellite locus (RCO8640) to be subject to diversifying selection, while five microsatellite loci showed signals of stabilizing selection among populations. STRUCTURE and DAPC analyses on the neutral microsatellites assigned populations to a northern and a southern cluster, reflecting two different post-glacial colonization routes found in previous studies. Genetic variation overall was lower in the northern cluster. The signature of selection on MHC exon II was weaker in the northern cluster, possibly as a consequence of smaller and more fragmented populations. Conclusion Our results show that historical demographic processes combined with selection and drift have led to a complex pattern of differentiation along the gradient where some loci are more divergent among populations than predicted from drift expectations due to diversifying selection, while other loci are more uniform among populations due to stabilizing selection. Importantly, both overall and MHC genetic variation are lower at northern latitudes. Due to lower evolutionary potential, the low genetic variation in northern populations may increase the risk of extinction when confronted with emerging pathogens and climate change.
  • Negwer, M., & Schubert, D. (2017). Talking convergence: Growing evidence links FOXP2 and retinoic acidin shaping speech-related motor circuitry. Frontiers in Neuroscience, 11: 19. doi:10.3389/fnins.2017.00019.

    Abstract

    A commentary on FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways by Devanna, P., Middelbeek, J., and Vernes, S. C. (2014). Front. Cell. Neurosci. 8:305. doi: 10.3389/fncel.2014.00305
  • Vernes, S. C. (2017). What bats have to say about speech and language. Psychonomic Bulletin & Review, 24(1), 111-117. doi:10.3758/s13423-016-1060-3.

    Abstract

    Understanding the biological foundations of language is vital to gaining insight into how the capacity for language may have evolved in humans. Animal models can be exploited to learn about the biological underpinnings of shared human traits, and although no other animals display speech or language, a range of behaviors found throughout the animal kingdom are relevant to speech and spoken language. To date, such investigations have been dominated by studies of our closest primate relatives searching for shared traits, or more distantly related species that are sophisticated vocal communicators, like songbirds. Herein I make the case for turning our attention to the Chiropterans, to shed new light on the biological encoding and evolution of human language-relevant traits. Bats employ complex vocalizations to facilitate navigation as well as social interactions, and are exquisitely tuned to acoustic information. Furthermore, bats display behaviors such as vocal learning and vocal turn-taking that are directly pertinent for human spoken language. Emerging technologies are now allowing the study of bat vocal communication, from the behavioral to the neurobiological and molecular level. Although it is clear that no single animal model can reflect the complexity of human language, by comparing such findings across diverse species we can identify the shared biological mechanisms likely to have influenced the evolution of human language. Keywords
  • Becker, M., Guadalupe, T., Franke, B., Hibar, D. P., Renteria, M. E., Stein, J. L., Thompson, P. M., Francks, C., Vernes, S. C., & Fisher, S. E. (2016). Early developmental gene enhancers affect subcortical volumes in the adult human brain. Human Brain Mapping, 37(5), 1788-1800. doi:10.1002/hbm.23136.

    Abstract

    Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype–phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations.
  • Kos, A., Wanke, K., Gioio, A., Martens, G. J., Kaplan, B. B., & Aschrafi, A. (2016). Monitoring mRNA Translation in Neuronal Processes Using Fluorescent Non-Canonical Amino Acid Tagging. Journal of Histochemistry and Cytochemistry, 64(5), 323-333. doi:10.1369/0022155416641604.

    Abstract

    A steady accumulation of experimental data argues that protein synthesis in neurons is not merely restricted to the somatic compartment, but also occurs in several discrete cellular micro-domains. Local protein synthesis is critical for the establishment of synaptic plasticity in mature dendrites and in directing the growth cones of immature axons, and has been associated with cognitive impairment in mice and humans. Although in recent years a number of important mechanisms governing this process have been described, it remains technically challenging to precisely monitor local protein synthesis in individual neuronal cell parts independent from the soma. This report presents the utility of employing microfluidic chambers for the isolation and treatment of single neuronal cellular compartments. Furthermore, it is demonstrated that a protein synthesis assay, based on fluorescent non-canonical amino acid tagging (FUNCAT), can be combined with this cell culture system to label nascent proteins within a discrete structural and functional domain of the neuron. Together, these techniques could be employed for the detection of protein synthesis within developing and mature neurites, offering an effective approach to elucidate novel mechanisms controlling synaptic maintenance and plasticity.
  • Lattenkamp, E. Z., Mandák, M., & Scherz, M. D. (2016). The advertisement call of Stumpffia be Köhler, Vences, D'Cruze & Glaw, 2010 (Anura: Microhylidae: Cophylinae). Zootaxa, 4205(5), 483-485. doi:10.11646/zootaxa.4205.5.7.

    Abstract

    We describe the calls of Stumpffia be Köhler, Vences, D’Cruze & Glaw, 2010. This is the first call description made for a species belonging to the large-bodied northern Madagascan radiation of Stumpffia Boettger, 1881. Stumpffia is a genus of small (~9–28 mm) microhylid frogs in the Madagascar-endemic subfamily Cophylinae Cope. Little is known about their reproductive strategies. Most species are assumed to lay their eggs in foam nests in the leaf litter of Madagascar’s humid and semi-humid forests (Glaw & Vences 1994; Klages et al. 2013). They exhibit some degree of parental care, with the males guarding the nest after eggs are laid (Klages et al. 2013). The bioacoustic repertoire of these frogs is thought to be limited, and there are two distinct call structures known for the genus: the advertisement call of the type species, S. psologlossa Boettger, 1881, is apparently unique in being a trill of notes repeated in short succession. All other species from which calls are known emit single, whistling or chirping notes (Vences & Glaw 1991; Vences et al. 2006).

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  • Rodenas-Cuadrado, P., Pietrafusa, N., Francavilla, T., La Neve, A., Striano, P., & Vernes, S. C. (2016). Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment. BMC Medical Genetics, 17: 8. doi:10.1186/s12881-016-0272-8.

    Abstract

    Background Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also found in the normal population. Conversely, homozygous mutations are rare in patient populations and have not been found in any unaffected individuals. Case presentation We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Homozygous family members display epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype. Conclusions We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic and molecular investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development.
  • Selten, M., Meyer, F., Ba, W., Valles, A., Maas, D., Negwer, M., Eijsink, V. D., van Vugt, R. W. M., van Hulten, J. A., van Bakel, N. H. M., Roosen, J., van der Linden, R., Schubert, D., Verheij, M. M. M., Kasri, N. N., & Martens, G. J. M. (2016). Increased GABAB receptor signaling in a rat model for schizophrenia. Scientific Reports, 6: 34240. doi:10.1038/srep34240.

    Abstract

    Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20-22. We found changes in the expression of the GABA-synthesizing enzyme GAD67 specifically in the prelimbic-but not the infralimbic region of the medial prefrontal cortex (mPFC), indicative of reduced inhibitory function in this region in APO-SUS rats. While we did not observe changes in basal synaptic transmission onto LII/III pyramidal cells in the mPFC of APO-SUS compared to APO-UNSUS rats, we report reduced paired-pulse ratios at longer inter-stimulus intervals. The GABA(B) receptor antagonist CGP 55845 abolished this reduction, indicating that the decreased paired-pulse ratio was caused by increased GABA(B) signaling. Consistently, we find an increased expression of the GABA(B1) receptor subunit in APO-SUS rats. Our data provide physiological evidence for increased presynaptic GABAB signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.
  • Fisher, S. E., & Vernes, S. C. (2015). Genetics and the Language Sciences. Annual Review of Linguistics, 1, 289-310. doi:10.1146/annurev-linguist-030514-125024.

    Abstract

    Theories addressing the biological basis of language must be built on an appreciation of the ways that molecular and neurobiological substrates can contribute to aspects of human cognition. Here, we lay out the principles by which a genome could potentially encode the necessary information to produce a language-ready brain. We describe what genes are; how they are regulated; and how they affect the formation, function, and plasticity of neuronal circuits. At each step, we give examples of molecules implicated in pathways that are important for speech and language. Finally, we discuss technological advances in genomics that are revealing considerable genotypic variation in the human population, from rare mutations to common polymorphisms, with the potential to relate this variation to natural variability in speech and language skills. Moving forward, an interdisciplinary approach to the language sciences, integrating genetics, neurobiology, psychology, and linguistics, will be essential for a complete understanding of our unique human capacities.
  • Rodenas-Cuadrado, P., Chen, X. S., Wiegrebe, L., Firzlaff, U., & Vernes, S. C. (2015). A novel approach identifies the first transcriptome networks in bats: A new genetic model for vocal communication. BMC Genomics, 16: 836. doi:10.1186/s12864-015-2068-1.

    Abstract

    Background Bats are able to employ an astonishingly complex vocal repertoire for navigating their environment and conveying social information. A handful of species also show evidence for vocal learning, an extremely rare ability shared only with humans and few other animals. However, despite their potential for the study of vocal communication, bats remain severely understudied at a molecular level. To address this fundamental gap we performed the first transcriptome profiling and genetic interrogation of molecular networks in the brain of a highly vocal bat species, Phyllostomus discolor. Results Gene network analysis typically needs large sample sizes for correct clustering, this can be prohibitive where samples are limited, such as in this study. To overcome this, we developed a novel bioinformatics methodology for identifying robust co-expression gene networks using few samples (N=6). Using this approach, we identified tissue-specific functional gene networks from the bat PAG, a brain region fundamental for mammalian vocalisation. The most highly connected network identified represented a cluster of genes involved in glutamatergic synaptic transmission. Glutamatergic receptors play a significant role in vocalisation from the PAG, suggesting that this gene network may be mechanistically important for vocal-motor control in mammals. Conclusion We have developed an innovative approach to cluster co-expressing gene networks and show that it is highly effective in detecting robust functional gene networks with limited sample sizes. Moreover, this work represents the first gene network analysis performed in a bat brain and establishes bats as a novel, tractable model system for understanding the genetics of vocal mammalian communication.
  • Rodenas-Cuadrado, P., Ho, J., & Vernes, S. C. (2014). Shining a light on CNTNAP2: Complex functions to complex disorders. European Journal of Human Genetics, 22(2), 171-178. doi:10.1038/ejhg.2013.100.

    Abstract

    The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions
  • Ayub, Q., Yngvadottir, B., Chen, Y., Xue, Y., Hu, M., Vernes, S. C., Fisher, S. E., & Tyler-Smith, C. (2013). FOXP2 targets show evidence of positive selection in European populations. American Journal of Human Genetics, 92, 696-706. doi:10.1016/j.ajhg.2013.03.019.

    Abstract

    Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.
  • Vernes, S. C., & Fisher, S. E. (2013). Genetic pathways implicated in speech and language. In S. Helekar (Ed.), Animal models of speech and language disorders (pp. 13-40). New York: Springer. doi:10.1007/978-1-4614-8400-4_2.

    Abstract

    Disorders of speech and language are highly heritable, providing strong support for a genetic basis. However, the underlying genetic architecture is complex, involving multiple risk factors. This chapter begins by discussing genetic loci associated with common multifactorial language-related impairments and goes on to detail the only gene (known as FOXP2) to be directly implicated in a rare monogenic speech and language disorder. Although FOXP2 was initially uncovered in humans, model systems have been invaluable in progressing our understanding of the function of this gene and its associated pathways in language-related areas of the brain. Research in species from mouse to songbird has revealed effects of this gene on relevant behaviours including acquisition of motor skills and learned vocalisations and demonstrated a role for Foxp2 in neuronal connectivity and signalling, particularly in the striatum. Animal models have also facilitated the identification of wider neurogenetic networks thought to be involved in language development and disorder and allowed the investigation of new candidate genes for disorders involving language, such as CNTNAP2 and FOXP1. Ongoing work in animal models promises to yield new insights into the genetic and neural mechanisms underlying human speech and language
  • Walker, R. M., Hill, A. E., Newman, A. C., Hamilton, G., Torrance, H. S., Anderson, S. M., Ogawa, F., Derizioti, P., Nicod, J., Vernes, S. C., Fisher, S. E., Thomson, P. A., Porteous, D. J., & Evans, K. L. (2012). The DISC1 promoter: Characterization and regulation by FOXP2. Human Molecular Genetics, 21, 2862-2872. doi:10.1093/hmg/dds111.

    Abstract

    Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder, and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterisation of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300bp to -177bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, whilst a region -982bp to -301bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by FOXP2, a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia (DVD). Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.

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