自闭症的全基因组测序确定了新生种系突变的热点。
Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.
机构信息
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA.
出版信息
Cell. 2012 Dec 21;151(7):1431-42. doi: 10.1016/j.cell.2012.11.019.
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.
新生突变在自闭症谱系障碍（ASD）中起着重要作用。值得注意的是，致病性拷贝数变异（CNV）的突变率很高。我们假设高突变率是 ASD 基因的一个特征，也可能包括核苷酸取代热点。我们通过对自闭症单合子双胞胎及其父母的全基因组测序，研究了种系突变的全基因组模式。突变率在整个基因组中差异很大（相差 100 倍），这可以用 DNA 序列和染色质结构的固有特征来解释。单个基因组内的突变密集簇归因于复合突变或基因转换。高突变率是与 ASD 及其他疾病相关的基因的特征。此外，本研究中受突变影响的基因与独立外显子组测序数据集中的 ASD 相关。我们的研究结果表明，区域性高突变是塑造人类遗传变异和疾病风险模式的重要因素。
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