The Feature Landscape of Autism Risk Genes Indicates Their Enrichment in Developmental Regulation

Background: While there have been many studies investigating the functional enrichment of classes of autism risk genes, few have studied their structural commonalities as an additional indicator of function.

Objectives: The purpose of this study is to investigate characteristic features of autism risk genes in order to better understand the function and evolutionary history of conserved elements and features of these genes.

Methods: Utilizing various bioinformatics approaches, we have studied commonalities across different genomic features, such as gene length, protein complexity, and intronic regulatory content.

Results: We find that autism risk genes tend to be highly conserved and have low allelic variability (i.e., low mutation tolerance). In addition, compared to whole genome control (WGC), these mutation-intolerant genes display long gene length, long peptides indicative of enriched protein complexity, increased numbers of transcript variants, and enrichment of both intronic conserved noncoding elements (CNE) and transposable elements. These latter two features in particular are likely indicative of complex internal regulatory content in these autism risk genes. Most of the structural and functional features investigated here typify gene classes involved in the regulation of development and transcription, as has been reported in previous studies such as Sironi et al (2005).

Conclusions: As we have shown here, gene function is reflected, not only in the structure of the protein, but the structure of the gene as well. From this vantage point, we add further support to the growing body of evidence that suggests that autism risk genes of major effect are enriched in developmental regulation and transcription, both of which help to control the timing of neurogenesis, migration, neuritogenesis, synaptogenesis, and ongoing plasticity (Casanova et al., 2016).