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The persistence and evolutionary consequences of vestigial behaviours
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Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders
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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. - 2021
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Abstract:
Funding: This work was funded by a Marie Curie Career Integration Grant and by a Max Planck Research Group Grant both awarded to SCV. The work of the Newbury lab is funded by the Medical Research Council (G1000569/1 and MR/J003719/1). XSC, AG, CF and SEF were supported by the Max Planck Society. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provided core support for ALSPAC. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust (090532/Z/09/Z). JH was supported by a scholarship from the Agency for Science, Technology, and Research, Singapore. The work of SDS is supported by the grant HD027802 from NIH. ; 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. ; Publisher PDF ; Peer reviewed
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Keyword:
3' Untranslated Regions/genetics; Adult; Autistic disorder/genetics; Binding sites/genetics; Bipolar disorder/genetics; Child; Cohort studies; DAS; DNA; Female; Gene expression regulation/genetics; Genetic predisposition to Disease; Genetic variation/genetics; Genomics; High-throughput nucleotide sequencing/methods; Humans; intergenic/genetics; Language development disorders/genetics; Male; Mental disorders/genetics; microRNAs/genetics; Nervous system diseases/genetics; Neurodevelopmental disorders/genetics; QH301; QH301 Biology; QH426; QH426 Genetics; RC0321; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry; Schizophrenia/genetics; Sequence analysis/methods
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URL: https://doi.org/10.1038/mp.2017.30
http://hdl.handle.net/10023/21699
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Hyperkinetic stereotyped movements in a boy with biallelic CNTNAP2 variants
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Genomic imprinting as a window into human language evolution
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The effects of genetic ancestry on elite sprint athlete status in the West African diaspora
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Copy number variation screen identifies a rare de novo deletion at chromosome 15q13.1-13.3 in a child with language impairment
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Genome-wide screening for DNA variants associated with reading and language traits
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Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort
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Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment
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Mosaic maternal ancestry in the Great Lakes region of East Africa
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Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family
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Reading and language disorders : the importance of both quantity and quality
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Counselling uncertainty: genetics professionals' accounts of (non)directiveness and trust/distrust
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Counselling uncertainty: genetics professionals' accounts of (non)directiveness and trust/distrust
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Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool
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Statistical issues in modelling the ancestry from Y-chromosome and surname data
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A genetic-based HAC technique for parallel clustering of bilingual Malay-English corpora
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The spatial and temporal dimensions of reflective questions in genetic counselling
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