1 Genome Research and Molecular Bio Medicine, Department of Biology, Faculty of Science, Københavns Universitet2 University of California3 BGI-Shenzhen4 National University of Defense Technology5 Harvard Medical School6 Rady Children's Hospital7 National University of Defense Technology8 Rady Children's Hospital9 Genome Research and Molecular Bio Medicine, Department of Biology, Faculty of Science, Københavns Universitet
De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.