Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Doan, Ryan; Bae, Byoung-Il; Cubelos, Beatriz; Chang, Cindy Y.; Hossain, Amer A.; Al-Saad, Samira; Mukaddes, Nahit Motavallı; Öner, Özgür; Al‐Saffar, Muna; Balkhy, Soher; Gascon, Generoso G.; Nieto, Marta; Walsh, Christopher A.

doi:10.1016/j.cell.2016.08.071

Cited by 271 publications

(356 citation statements)

References 84 publications

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“…Our results are in line with these findings and suggest that, although a higher mutational burden over all genes may have consequences on IQ, mutational burden in a set of genes with a role at critical early developmental stages influences the development of social behavior. Moreover, our findings are also further supported by the recent report that genomic regions that are under accelerated evolution have essential functions in the human brain development and when mutated, may cause increased risk for autism (48). Therefore, understanding the regulatory landscape of dosage-sensitive EGs expressed at critical stages of brain development may reveal risk alleles for many neurodevelopmental and psychiatric disorders.…”

Section: B C Asupporting

confidence: 69%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

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Section: B C Asupporting

confidence: 69%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Disorders of human cognition and social behavior have been associated with human-specific genomic features (27). In addition, it is highly likely that social insects and humans evolved their distinct repertoire of complex social behaviors independently of each other (28), with the forces of natural selection acting differently on social behaviors in insects and humans.…”

Section: Significancementioning

confidence: 99%

Deep evolutionary conservation of autism-related genes

Shpigler

Saul

Corona

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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E. O. Wilson proposed inSociobiology that similarities between human and animal societies reflect common mechanistic and evolutionary roots. When introduced in 1975, this controversial hypothesis was beyond science's ability to test. We used genomic analyses to determine whether superficial behavioral similarities in humans and the highly social honey bee reflect common molecular mechanisms. Here, we report that gene expression signatures for individual bees unresponsive to various salient social stimuli are significantly enriched for autism spectrum disorder-related genes. These signatures occur in the mushroom bodies, a highlevel integration center of the insect brain. Furthermore, our finding of enrichment was unique to autism spectrum disorders; brain gene expression signatures from other honey bee behaviors do not show this enrichment, nor do datasets from other human behavioral and health conditions. These results demonstrate deep conservation for genes associated with a human social pathology and individual differences in insect social behavior, thus providing an example of how comparative genomics can be used to test sociobiological theory.autism | evolution | honey bee | social behavior | transcriptomics

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“…ENCODE-defined transcription factor binding and DNase hypersensitive sites were downloaded from UCSC genome browser (wgEncodeRegTfbsClusteredV2 and wgEncodeRegDnaseClusteredV3). Human accelerated regions (HARs) were obtained from Doan et al 2016 65 .…”

Section: Methodsmentioning

confidence: 99%

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

et al. 2018

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Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here, we present a comparable framework to evaluate rare and de novo noncoding single nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism the contribution of de novo noncoding variation is probably modest compared to de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple testing burden.

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Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Cited by 271 publications

References 84 publications

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Deep evolutionary conservation of autism-related genes

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

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