Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.
Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.
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DOI：
10.1016/j.cell.2012.11.019
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发表时间：
2012-12-21
期刊：
影响因子：
64.5
通讯作者：
Sebat J
中科院分区：
文献类型：
--
作者：
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
新生突变在自闭症谱系障碍（Autism Spectrum Disorders，ASD）中起重要作用。值得注意的是，致病性拷贝数变体（CNV）的特征在于高突变率。我们推测，超变是ASD基因的一个属性，也可能包括核苷酸取代热点。我们通过全基因组测序研究了ASD及其父母的单卵双胞胎的种系突变的全球模式。突变率在整个基因组中变化很大（100倍），可以用DNA序列和染色质结构的内在特征来解释。个体基因组内密集的突变簇可归因于复合突变或基因转换。超突变性是与ASD和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，区域超突变是人类遗传变异和疾病风险模式的重要因素。
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.
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影响因子：
64.8
作者：
Kong A;Frigge ML;Masson G;Besenbacher S;Sulem P;Magnusson G;Gudjonsson SA;Sigurdsson A;Jonasdottir A;Jonasdottir A;Wong WS;Sigurdsson G;Walters GB;Steinberg S;Helgason H;Thorleifsson G;Gudbjartsson DF;Helgason A;Magnusson OT;Thorsteinsdottir U;Stefansson K
通讯作者：
Stefansson K
影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
14.9
作者：
Chen WH;Minguez P;Lercher MJ;Bork P
通讯作者：
Bork P
影响因子：
17.7
作者：
Laumonnier, Frederic;Roger, Sebastien;Briault, Sylvain
通讯作者：
Briault, Sylvain
影响因子：
4
作者：
Ellegren, H;Smith, NGC;Webster, MT
通讯作者：
Webster, MT