Whole Genome Sequencing in Autism Identifies Hotspots for De Novo Germline Mutation

By J. Michaelson, Yujian Shi, Madhusudan Gujral, Hancheng Zheng, Dheeraj Malhotra, Xin Jin, Min Jian, Guangming Liu, Douglas S. Greer, A. Bhandari and 18 more. 2012

547 citations recorded by the source corpus.

Summary 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 hotspots. 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 datasets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.

Subfields: Genetics

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Citations in the corpus

Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications (2014, background): “Several recent studies have successfully identified disease-causing de novo mutations using sequence data from parent-offspring trios, in both exomes 29–31 and whole genomes 32,33 .”
Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR (2015, background): “Over the past few years, ANNOVAR has been widely adopted in a variety of research studies on human genomes ranging from studies on population samples 19,20 to studies on a single pedigree 21,22 .”
Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes (2020, background): “This con ﬁ rms the presence of mutational mechanisms capable of creating simultaneous mutations separated by considerable distances 16,29,38 – 40 , although further work will be required to fully characterize the underlying processes.”