PubMed Highlight: Whole-genome sequencing in autism identifies hot spots for de novo germline mutation

In this paper appeared on December in Cell authors apply WGS on 10 monozygotic twins to find new genetic variants associated with autism. Meanwhile, they gave also a better definition and mapping of genomic mutation hotspots, confirming the idea that genetic variations do not occur randomly throughout the genome. Moreover, they found that these highly variable regions seem to occur at highly conserved loci and they affect particularly genes related to brain function and development. Even if the causes of the higher mutational rate are not full understood, the hotspots could play an important role in autism and other genetic diseases. Based on their data, authors also developed a predictive model to gauge a region's mutability index.

Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.

Cell. 2012 Dec 21;151(7):1431-42. doi: 10.1016/j.cell.2012.11.019. 

Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, Jian M, Liu G, Greer D, Bhandari A, Wu W, Corominas R, Peoples A, Koren A, Gore A, Kang S, Lin GN, Estabillo J, Gadomski T, Singh B, Zhang K, Akshoomoff N, Corsello C, McCarroll S, Iakoucheva LM, Li Y, Wang J, Sebat J. 

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.