From mouse to human: evolutionary genomics analysis of human orthologs of essential genes.
From mouse to human: evolutionary genomics analysis of human orthologs of essential genes.
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DOI：
10.1371/journal.pgen.1003484
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发表时间：
2013-05
期刊：
影响因子：
4.5
通讯作者：
Bućan M
中科院分区：
文献类型：
--
作者：
Georgi B;Voight BF;Bućan M
理解对于基本发育功能所必需的核心基因集是生物学的核心目标之一。对模式生物的研究通过对导致致死的无效突变的分析，确定了很大一部分必需基因。近期大规模的下一代测序工作提供了有关人类遗传变异的前所未有的数据。然而，人类必需基因的进化和基因组特征从未在全基因组范围内直接被研究过。在此，我们利用可获取的小鼠详细表型资源以及来自人类群体的深度基因组测序数据，对一组2472个小鼠已知必需基因的人类直系同源基因的遗传变异模式和突变负荷进行表征。与强烈的纯化选择作用一致，这些基因表现出相对较低的序列变异水平，等位基因频率偏向更罕见的情况，并且相对于基因组中其余基因，在灵长类和啮齿类谱系中表现出更高的保守性。在个体基因组中，我们观察到在预测为有害的必需基因内约有12个罕见突变。与必需基因中的突变是神经发育疾病的风险因素这一假设一致，我们表明自闭症谱系障碍患者的新生变异更有可能发生在这组基因中。虽然不完整，但我们的人类直系同源基因集显示出与人类必需功能完全一致的特征，因此为人类疾病研究中的序列数据解读提供了资源。
必需基因对于生物体的基本过程是必需的，并且当被破坏时会导致产前或新生儿致死。在这项工作中，我们利用来自近期人类群体深度测序项目的数据，根据进化和群体遗传学特性对2472个小鼠必需基因的人类直系同源基因进行表征。我们发现与非必需基因对照组相比，假定的必需基因内有强烈的纯化选择特征以及序列变异负荷降低。我们还表明，在最近四项自闭症谱系障碍患者新生变异研究中，必需基因内的变异显著富集。我们的结果确立了假定必需基因目录作为人类疾病测序研究分析和解读的重要资源。
Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ∼12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease. Essential genes are necessary for fundamental processes in an organism and lead to pre- or neonatal lethality when disrupted. In this work, we characterize 2,472 human orthologs of mouse essential genes in terms of their evolutionary and population genetics properties using data from recent deep sequencing initiatives in human populations. We find a signature of strong, purifying selection and a reduced load of sequence variants within the putative essential genes when compared to a control-group of non-essential genes. We also show a significant enrichment of variants within essential genes across a set of four recent studies of de novo variants in patients with Autism Spectrum Disorder. Our results establish the catalogue of putative essential genes as an important resource for analysis and interpretation of sequencing studies for human disease.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
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：
Blake JA;Bult CJ;Kadin JA;Richardson JE;Eppig JT;Mouse Genome Database Group
通讯作者：
Mouse Genome Database Group
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.