Autism spectrum disorders (ASDs) are highly heritable but have a complex genetic architecture. There is significant locus heterogeneity for ASD and distinct subgroups, including syndromic and nonsyndromic cases. Whole-exome sequencing (WES) has emerged as an important tool in understanding ASD. WES studies have revealed an increased burden of de novo variants in people with ASD compared with unaffected individuals. However, due to variants in thousands of different genes — many of which are poorly characterized — interpreting the disease relevance of individual variants has been difficult.
Michael Wangler and Shinya Yamamoto at Baylor College of Medicine plan to use the fruit fly, Drosophila melanogaster, to study a subset of 300 autism candidate genes identified from these genomic datasets. They aim to select genes with missense variation in ASD cases for which loss-of-function studies in Drosophila could inform interpretation of these variants.
To prioritize ASD-linked variants for study, the researchers will compare currently available variants and genes from WES datasets and copy number array datasets from independent cohorts of individuals with autism, cross-referencing the candidate ASD genes with genomic data gathered at Baylor College of Medicine from independent collections of individuals with rare diseases. In this way, comparison of human phenotypes will inform Drosophila experiments downstream.
The team will then study the prioritized genes by collaborating with the Drosophila Gene Disruption Project to generate a set of gene and protein trap lines using the latest technologies in Drosophila genetics. Viable loss-of-function lines will be assessed for gene and protein nervous system expression patterns, and in vivo functional assessments of longevity, fertility, seizure sensitivity, flight and circadian rhythms. Following this rapid phenotypic screening process, the team will assess nervous system-specific functions, and utilize homologous human genes to assess rescue of phenotypes of interest. Further, by generating transgenic ‘rescue’ lines that express human genes in ‘wild-type’ or ASD-related variant forms, the researchers will directly test for functional effects of these ASD variants. This functional analysis pipeline will allow for the rapid study of a large number of ASD genes in a powerful model system, providing much-needed biological information on many of the rare ASD variants.
