Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes

被引：1216

作者：

Tennessen, Jacob A. ^{[1
]}

Bigham, Abigail W. ^{[2
]}

O'Connor, Timothy D. ^{[1
]}

Fu, Wenqing ^{[1
]}

Kenny, Eimear E. ^{[3
]}

Gravel, Simon ^{[3
]}

McGee, Sean ^{[1
]}

Do, Ron ^{[4
,5
]}

Liu, Xiaoming ^{[6
]}

Jun, Goo ^{[7
]}

Kang, Hyun Min ^{[7
]}

Jordan, Daniel ^{[8
]}

Leal, Suzanne M. ^{[9
]}

Gabriel, Stacey ^{[4
]}

Rieder, Mark J. ^{[1
]}

Abecasis, Goncalo ^{[7
]}

Altshuler, David ^{[4
]}

Nickerson, Deborah A. ^{[1
]}

Boerwinkle, Eric ^{[6
,10
]}

Sunyaev, Shamil ^{[4
,8
]}

Bustamante, Carlos D.

Bamshad, Michael J. ^{[1
,2
]}

Akey, Joshua M. ^{[1
]}

机构：

[1] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[2] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[3] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[6] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[7] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[8] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA

[9] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[10] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

来源：

SCIENCE | 2012年 / 337卷 / 6090期

关键词：

POSITIVE SELECTION; DISCOVERY; SPECTRUM;

D O I：

10.1126/science.1219240

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111x in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of similar to 313 genes per genome, and similar to 95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.

引用

页码：64 / 69

页数：6

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