Autism risk genes are evolutionarily ancient and maintain a unique feature landscape that echoes their function / Emily L. CASANOVA in Autism Research, 12-6 (June 2019)  

Public ISBD [article]  inAutism Research > 12-6 (June 2019) . - p.860-869 Titre : Autism risk genes are evolutionarily ancient and maintain a unique feature landscape that echoes their function Type de document : Texte imprimé et/ou numérique Auteurs : Emily L. CASANOVA, Auteur ; A. E. SWITALA, Auteur ; S. DANDAMUDI, Auteur ; A. R. HICKMAN, Auteur ; J. VANDENBRINK, Auteur ; J. L. SHARP, Auteur ; F. A. FELTUS, Auteur ; Manuel F. CASANOVA, Auteur Année de publication : 2019 Article en page(s) : p.860-869 Langues : Anglais (eng) Mots-clés : DNA transposons  central nervous system  developmental  genes  retroelements Index. décimale : PER Périodiques Résumé : Previous research on autism risk (ASD), developmental regulatory (DevReg), and central nervous system (CNS) genes suggests they tend to be large in size, enriched in nested repeats, and mutation intolerant. The relevance of these genomic features is intriguing yet poorly understood. In this study, we investigated the feature landscape of these gene groups to discover structural themes useful in interpreting their function, developmental patterns, and evolutionary history. ASD, DevReg, CNS, housekeeping, and whole genome control (WGC) groups were compiled using various resources. Multiple gene features of interest were extracted from NCBI/UCSC Bioinformatics. Residual variation intolerance scores, Exome Aggregation Consortium pLI scores, and copy number variation data from Decipher were used to estimate variation intolerance. Gene age and protein-protein interactions (PPI) were estimated using Ensembl and EBI Intact databases, respectively. Compared to WGC: ASD, DevReg, and CNS genes are longer, produce larger proteins, maintain greater numbers/density of conserved noncoding elements and transposable elements, produce more transcript variants, and are comparatively variation intolerant. After controlling for gene size, mutation tolerance, and clinical association, ASD genes still retain many of these same features. In addition, we also found that ASD genes that are extremely mutation intolerant have larger PPI networks. These data support many of the recent findings within the field of autism genetics but also expand our understanding of the evolution of these broad gene groups, their potential regulatory complexity, and the extent to which they interact with the cellular network. Autism Res 2019, 12: 860-869. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism risk genes are more ancient compared to other genes in the genome. As such, they exhibit physical features related to their age, including long gene and protein size and regulatory sequences that help to control gene expression. They share many of these same features with other genes that are expressed in the brain and/or are associated with prenatal development. En ligne : https://dx.doi.org/10.1002/aur.2112 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=400 [article] Autism risk genes are evolutionarily ancient and maintain a unique feature landscape that echoes their function [Texte imprimé et/ou numérique] / Emily L. CASANOVA, Auteur ; A. E. SWITALA, Auteur ; S. DANDAMUDI, Auteur ; A. R. HICKMAN, Auteur ; J. VANDENBRINK, Auteur ; J. L. SHARP, Auteur ; F. A. FELTUS, Auteur ; Manuel F. CASANOVA, Auteur . - 2019 . - p.860-869. Langues : Anglais (eng) in Autism Research > 12-6 (June 2019) . - p.860-869 Mots-clés : DNA transposons  central nervous system  developmental  genes  retroelements Index. décimale : PER Périodiques Résumé : Previous research on autism risk (ASD), developmental regulatory (DevReg), and central nervous system (CNS) genes suggests they tend to be large in size, enriched in nested repeats, and mutation intolerant. The relevance of these genomic features is intriguing yet poorly understood. In this study, we investigated the feature landscape of these gene groups to discover structural themes useful in interpreting their function, developmental patterns, and evolutionary history. ASD, DevReg, CNS, housekeeping, and whole genome control (WGC) groups were compiled using various resources. Multiple gene features of interest were extracted from NCBI/UCSC Bioinformatics. Residual variation intolerance scores, Exome Aggregation Consortium pLI scores, and copy number variation data from Decipher were used to estimate variation intolerance. Gene age and protein-protein interactions (PPI) were estimated using Ensembl and EBI Intact databases, respectively. Compared to WGC: ASD, DevReg, and CNS genes are longer, produce larger proteins, maintain greater numbers/density of conserved noncoding elements and transposable elements, produce more transcript variants, and are comparatively variation intolerant. After controlling for gene size, mutation tolerance, and clinical association, ASD genes still retain many of these same features. In addition, we also found that ASD genes that are extremely mutation intolerant have larger PPI networks. These data support many of the recent findings within the field of autism genetics but also expand our understanding of the evolution of these broad gene groups, their potential regulatory complexity, and the extent to which they interact with the cellular network. Autism Res 2019, 12: 860-869. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism risk genes are more ancient compared to other genes in the genome. As such, they exhibit physical features related to their age, including long gene and protein size and regulatory sequences that help to control gene expression. They share many of these same features with other genes that are expressed in the brain and/or are associated with prenatal development. En ligne : https://dx.doi.org/10.1002/aur.2112 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=400

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression / Emily L. CASANOVA in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 18p. Titre : Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression Type de document : Texte imprimé et/ou numérique Auteurs : Emily L. CASANOVA, Auteur ; J. L. SHARP, Auteur ; H. CHAKRABORTY, Auteur ; N. S. SUMI, Auteur ; Manuel F. CASANOVA, Auteur Article en page(s) : 18p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/epidemiology/genetics/psychology  Autistic Disorder/epidemiology/genetics/psychology  Body Patterning/genetics  Cell Nucleus/metabolism  Chromatin Assembly and Disassembly/genetics  Comorbidity  Databases, Genetic  Epigenomics  Epilepsy/epidemiology/genetics/psychology  Gene Expression Regulation  Gene Ontology  Genetic Association Studies  Humans  Intellectual Disability/epidemiology/genetics  Nerve Tissue Proteins/genetics/physiology  Neurogenesis/genetics  Nuclear Proteins/genetics/physiology  Penetrance  Protein Interaction Maps/genetics  Risk  Syndrome  Body patterning  Chromatin assembly and disassembly  Epilepsy  Mental retardation  Regulation of gene expression Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions. En ligne : http://dx.doi.org/10.1186/s13229-016-0082-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression [Texte imprimé et/ou numérique] / Emily L. CASANOVA, Auteur ; J. L. SHARP, Auteur ; H. CHAKRABORTY, Auteur ; N. S. SUMI, Auteur ; Manuel F. CASANOVA, Auteur . - 18p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 18p. Mots-clés : Autism Spectrum Disorder/epidemiology/genetics/psychology  Autistic Disorder/epidemiology/genetics/psychology  Body Patterning/genetics  Cell Nucleus/metabolism  Chromatin Assembly and Disassembly/genetics  Comorbidity  Databases, Genetic  Epigenomics  Epilepsy/epidemiology/genetics/psychology  Gene Expression Regulation  Gene Ontology  Genetic Association Studies  Humans  Intellectual Disability/epidemiology/genetics  Nerve Tissue Proteins/genetics/physiology  Neurogenesis/genetics  Nuclear Proteins/genetics/physiology  Penetrance  Protein Interaction Maps/genetics  Risk  Syndrome  Body patterning  Chromatin assembly and disassembly  Epilepsy  Mental retardation  Regulation of gene expression Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions. En ligne : http://dx.doi.org/10.1186/s13229-016-0082-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328

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