De Novo Variation in Coding and Noncoding Regions: What We Can Learn from the Data about Etiological Pathways

For autism spectrum disorder (ASD), the largest exome sequencing study to date implicates 102 genes in risk. This risk gene set, as well as the de novo mutations observed in the sample, serve as a springboard for additional explorations into etiological pathways. Gene expression from human cortical cells highlights enrichment of risk genes in both excitatory and inhibitory neuronal lineages, implying that disruption of these genes alters the development of both neuronal types. Complementing these single cell analyses, a new approach called MIND can estimate subject- and cell-type-specific (CTS) gene expression from tissue. CTS expression of the BrainSpan atlas, which profiles expression patterns of the developing human brain, reveals clear CTS co-expression networks that identify a cluster of co-expressed risk genes, implicate immature neurons in risk, and links the transition from neural progenitors to neurons as one potential origin of atypical neurodevelopment in ASD. Two other analyses lend additional insights: evaluation of de novo mutations that disrupt protein interactions and their interaction networks; and whole-genome sequencing results, which suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD. Together, these results broaden our understanding of the neurobiology of ASD.