Genic intolerance to functional variation and the interpretation of personal genomes.
Genic intolerance to functional variation and the interpretation of personal genomes.
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DOI：
10.1371/journal.pgen.1003709
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Goldstein DB
中科院分区：
文献类型：
--
作者：
Petrovski S;Wang Q;Heinzen EL;Allen AS;Goldstein DB
解读个人基因组面临的一个核心挑战是确定哪些突变最有可能影响疾病。尽管在评估单个突变的功能影响方面已经取得了进展，但发现这些突变的基因的特征在很大程度上仍未被探索。例如，在健康个体中已知携带很少常见功能变异的基因可能被判定比已知携带许多此类变异的基因更有可能导致某些疾病。然而，到目前为止，还不可能对基因在全基因组范围内对功能基因变异的耐受程度进行定量评估。在此，我们描述了一项利用美国国家心肺血液研究所（NHLBI）外显子组测序项目（ESP）提供的6503个全外显子组序列数据的研究。具体来说，我们开发了一种不耐受评分系统，该系统根据基因中发现的看似中性的变异来评估基因的功能基因变异是比预期多还是少。为了说明这种不耐受评分的用途，我们表明，导致孟德尔疾病的基因对功能基因变异的不耐受程度明显高于不导致任何已知疾病的基因，但导致不同类别遗传疾病的基因之间的不耐受程度存在显著差异。最后我们表明，使用不耐受排名系统有助于解读个人基因组和识别致病突变。
这项工作利用美国国家心肺血液研究所外显子组测序项目的经验性单核苷酸变异数据，引入了一种全基因组评分系统，该系统根据人类基因对人类群体中现存功能基因变异的不耐受程度对人类基因进行排名。人们通常推断，在健康个体中携带相对较少或相对较多常见功能变异的基因可能分别被判定更有可能或更不可能导致某些疾病。我们表明，这种不耐受评分与已知导致孟德尔疾病的基因具有显著的相关性（P<10⁻²⁶）。然而，同样引人注目的是，不同疾病类型中现存基因变异与致病基因之间关系的差异。考虑到由吴等人（2007年）的人类疾病网络所定义的疾病类别，我们发现与发育障碍相关的基因和与免疫障碍相关的基因呈现出几乎相反的模式，前者优先由不耐受功能变异的基因导致，而后者由具有过多常见功能变异的基因导致。最后我们表明，使用不耐受排名系统有助于解读个人基因组，并有助于通过突变所在的基因识别高影响突变。
A central challenge in interpreting personal genomes is determining which mutations most likely influence disease. Although progress has been made in scoring the functional impact of individual mutations, the characteristics of the genes in which those mutations are found remain largely unexplored. For example, genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants. Until now, however, it has not been possible to develop a quantitative assessment of how well genes tolerate functional genetic variation on a genome-wide scale. Here we describe an effort that uses sequence data from 6503 whole exome sequences made available by the NHLBI Exome Sequencing Project (ESP). Specifically, we develop an intolerance scoring system that assesses whether genes have relatively more or less functional genetic variation than expected based on the apparently neutral variation found in the gene. To illustrate the utility of this intolerance score, we show that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes that do not cause any known disease, but with striking variation in intolerance among genes causing different classes of genetic disease. We conclude by showing that use of an intolerance ranking system can aid in interpreting personal genomes and identifying pathogenic mutations. This work uses empirical single nucleotide variant data from the NHLBI Exome Sequencing Project to introduce a genome-wide scoring system that ranks human genes in terms of their intolerance to standing functional genetic variation in the human population. It is often inferred that genes carrying relatively fewer or relatively more common functional variants in healthy individuals may be judged respectively more or less likely to cause certain kinds of disease. We show that this intolerance score correlates remarkably well with genes already known to cause Mendelian diseases (P<10−26). Equally striking, however, are the differences in the relationship between standing genetic variation and disease causing genes for different disease types. Considering disorder classes defined by Goh et al (2007) human disease network, we show a nearly opposite pattern for genes linked to developmental disorders and those linked to immunological disorders, with the former being preferentially caused by genes that do not tolerate functional variation and the latter caused by genes with an excess of common functional variation. We conclude by showing that use of an intolerance ranking system can facilitate interpreting personal genomes and can facilitate identifying high impact mutations through the gene in which they occur.
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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
DOI：
10.1126/science.1219240
发表时间：
2012-07-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tennessen JA;Bigham AW;O'Connor TD;Fu W;Kenny EE;Gravel S;McGee S;Do R;Liu X;Jun G;Kang HM;Jordan D;Leal SM;Gabriel S;Rieder MJ;Abecasis G;Altshuler D;Nickerson DA;Boerwinkle E;Sunyaev S;Bustamante CD;Bamshad MJ;Akey JM;Broad GO;Seattle GO;NHLBI Exome Sequencing Project
通讯作者：
NHLBI Exome Sequencing Project
影响因子：
3.9
作者：
Hicks, Stephanie;Wheeler, David A.;Plon, Sharon E.;Kimmel, Marek
通讯作者：
Kimmel, Marek
影响因子：
64.8
作者：
Sanders, Stephan J.;Murtha, Michael T.;Gupta, Abha R.;Murdoch, John D.;Raubeson, Melanie J.;Willsey, A. Jeremy;Ercan-Sencicek, A. Gulhan;DiLullo, Nicholas M.;Parikshak, Neelroop N.;Stein, Jason L.;Walker, Michael F.;Ober, Gordon T.;Teran, Nicole A.;Song, Youeun;El-Fishawy, Paul;Murtha, Ryan C.;Choi, Murim;Overton, John D.;Bjornson, Robert D.;Carriero, Nicholas J.;Meyer, Kyle A.;Bilguvar, Kaya;Mane, Shrikant M.;Sestan, Nenad;Lifton, Richard P.;Guenel, Murat;Roeder, Kathryn;Geschwind, Daniel H.;Devlin, Bernie;State, Matthew W.
通讯作者：
State, Matthew W.
影响因子：
168.9
作者：
Rauch, Anita;Wieczorek, Dagmar;Strom, Tim M.
通讯作者：
Strom, Tim M.