De novo mutation (DNM) 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-associated 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. The goal of this study was to characterize regional mutation rates, identify hotspots for de novo mutation and characterize patterns of mutability with respect to functional elements in the genome.
Whole genome sequencing (40X coverage, 500 bp library, 90 bp reads) was performed on ten identical twin pairs concordant for ASD and their parents. Raw sequence files were processed at UCSD with a WGS pipeline consisting of automated tools for alignment and variant calling (BWA, Samtools, GATK 1.2-52). DNM detection was performed using a machine-learning based method forestDNM developed in our laboratory.
Germline de novo mutations (DNMs) displayed a non-random positioning in the genome (P < 10-4). Dense clusters of DNMs (<100 kb apart) could be explained by compound mutation or gene conversion. Clustering on larger scales could be explained by mutation-rate variation throughout the genome. Rates of nucleotide substitution varied by >100-fold, and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Hypermutability was a characteristic of highly-conserved sequences, particularly of essential genes and genes involved in human disease. In addition, genes impacted by DNMs in this study were significantly associated with autism in independent exome-sequencing datasets.
Our findings suggest that regional hypermutability is a significant factor shaping patterns of genetic variation and disease risk in humans.