Based on CNV and exome-sequencing studies of autism spectrum disorders (ASD) it has been established that de novo germline mutation is an important contributor to risk, and ASD risk alleles have particularly high mutation rates. It is hypothesized that genes that contribute high risk for ASD generally lie within genomic regions of hypermutability. In this project, a whole-genome sequencing approach in families will be applied to identify genomic regions of hypermutability and determine the association of mutational hotspots with disease in a large independent sample. Intrinsic characteristics of the genome and extrinsic factors such as parental age that influence rates of germline mutation will be investigated. The findings of this study will yield fundamental insights into the genetic basis of ASD and the interplay between genes and environment.