Author/Authors :
Jacob J. Michaelson، نويسنده , , Yujian Shi، نويسنده , , Madhusudan Gujral، نويسنده , , Hancheng Zheng، نويسنده , , Dheeraj Malhotra، نويسنده , , Xin Jin، نويسنده , , Minghan Jian، نويسنده , , Guangming Liu، نويسنده , , Douglas Greer، نويسنده , , Abhishek Bhandari، نويسنده , , Wenting Wu، نويسنده , , Roser Corominas، نويسنده , , ?ine Peoples، نويسنده , , Amnon Koren، نويسنده , , Athurva Gore، نويسنده , , Shuli Kang، نويسنده , , Guan Ning Lin، نويسنده , , Jasper Estabillo، نويسنده , , Therese Gadomski، نويسنده , , Balvindar Singh، نويسنده , , et al.، نويسنده ,
Abstract :
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.
