Speaker: Paul W. Sternberg, Ph.D.
Affiliation: Bren Professor of Biology, Division of Biology and Biological Engineering, California Institute of Technology
Date: April 29, 2020
Talk title: Modeling ASD genetics in C. elegans
Abstract: ASD genetics is complicated by many de novo variants, with potentially dominant effects of even missense variants. C. elegans is useful for intensive genetic analyses, with a track record of inferences transferring to human genetics. We are thus using C. elegans to address fundamental questions in ASD genetics. To assess potential functional consequences of missense variants of unknown significance identified by the Simons Foundation SFARI program, we edited the C. elegans equivalent of human missense variants into C. elegans orthologs of affected genes and compared the phenotypes of missense variants to loss-of-function and other non-null alleles. We find that a majority of the missense variants we can study in C. elegans have phenotypic effects, in some cases using sensitive RNA-seq based phenotypic assays. Some missense variants are partial loss-of-function, while others are weak gain-of-function. Loci of current focus include orthologs of CHD7/8, PAX6, FOXP2 and BRAF. We have also started to look at interactions among variants, and seek to “probandize” rather than “humanize” C. elegans.