Mutations in life’s ‘essential genes’ tied to autism

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

Genes known to be essential to life—the ones humans need to survive and thrive in the womb—also play a critical role in the development of autism spectrum disorder (ASD), suggests a new study. An analysis of genetic samples of over 1,700 families from a repository revealed that elevated levels of mutations in the “essential genes” was significantly associated with an increased risk for ASD and decreased social skills.

Significance

Essential genes (EGs) are necessary for survival and the development of an organism. Our study is focused on investigating the role of EGs in autism spectrum disorder (ASD). With a comprehensive catalog of 3,915 mammalian EGs, we show that there is both an elevated burden of damaging mutations in EGs in ASD probands and also, an enrichment of EGs in known ASD risk genes. Moreover, the analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Overall, we provide evidence that genes that are essential for survival and fitness also contribute to ASD risk and lead to the disruption of normal social behavior.

Abstract

Increased burden of deleterious variants in essential genes in autism spectrum disorder, Proceedings of the National Academy of Sciences, November 7, 2016.

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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.

Author: DES Daughter

Activist, blogger and social media addict committed to shedding light on a global health scandal and dedicated to raise DES awareness.

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