Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants

被引：248

作者：

Li, Yingrui ^{[1
]}

Vinckenbosch, Nicolas ^{[2
]}

Tian, Geng ^{[1
]}

Huerta-Sanchez, Emilia ^{[2
,3
]}

Jiang, Tao ^{[1
]}

Jiang, Hui ^{[1
]}

Albrechtsen, Anders ^{[4
]}

Andersen, Gitte ^{[5
]}

Cao, Hongzhi ^{[1
]}

Korneliussen, Thorfinn ^{[4
]}

Grarup, Niels ^{[5
]}

Guo, Yiran ^{[1
]}

Hellman, Ines ^{[6
]}

Jin, Xin ^{[1
,7
]}

Li, Qibin ^{[1
]}

Liu, Jiangtao ^{[1
]}

Liu, Xiao ^{[1
]}

Sparso, Thomas ^{[5
]}

Tang, Meifang ^{[1
]}

Wu, Honglong ^{[1
]}

Wu, Renhua ^{[1
]}

Yu, Chang ^{[1
]}

Zheng, Hancheng ^{[1
,7
]}

Astrup, Arne ^{[8
]}

Bolund, Lars ^{[1
,9
,10
]}

Holmkvist, Johan ^{[5
]}

Jorgensen, Torben ^{[11
,12
]}

Kristiansen, Karsten ^{[1
,4
]}

Schmitz, Ole ^{[13
,14
]}

Schwartz, Thue W. ^{[15
]}

Zhang, Xiuqing ^{[1
]}

Li, Ruiqiang ^{[1
,4
]}

Yang, Huanming ^{[1
]}

Wang, Jian ^{[1
]}

Hansen, Torben ^{[5
,16
]}

Pedersen, Oluf ^{[5
,17
,18
]}

Nielsen, Rasmus ^{[2
,3
,4
]}

Wang, Jun ^{[1
,4
]}

机构：

[1] BGI Shenzhen, Shenzhen, Peoples R China

[2] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA

[3] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA

[4] Univ Copenhagen, Dept Biol, Copenhagen, Denmark

[5] Hagedorn Res Inst, Copenhagen, Denmark

[6] Univ Vienna, Dept Math, Vienna, Austria

[7] S China Univ Technol, Sch Biosci & Biotechnol, Guangzhou, Guangdong, Peoples R China

[8] Univ Copenhagen, Fac Life Sci, Dept Human Nutr, Copenhagen, Denmark

[9] Univ Aarhus, Inst Human Genet, Aarhus, Denmark

[10] Danish Ctr Translat Breast Canc Res, Copenhagen, Denmark

[11] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[12] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark

[13] Aarhus Univ Hosp, Dept Endocrinol & Diabet, DK-8000 Aarhus, Denmark

[14] Univ Aarhus, Dept Clin Pharmacol, Aarhus, Denmark

[15] Univ Copenhagen, Mol Pharmacol Lab, Copenhagen, Denmark

[16] Univ So Denmark, Fac Hlth Sci, Odense, Denmark

[17] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark

[18] Univ Copenhagen, Inst Biomed Sci, Copenhagen, Denmark

来源：

NATURE GENETICS | 2010年 / 42卷 / 11期

基金：

中国国家自然科学基金; 瑞士国家科学基金会; 美国国家科学基金会;

关键词：

GENOME; SELECTION; NUCLEOTIDE; INFERENCE; PATTERNS; GENES; POLYMORPHISM; DIVERSITY; EVOLUTION; CAPTURE;

D O I：

10.1038/ng.680

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Targeted capture combined with massively parallel exome sequencing is a promising approach to identify genetic variants implicated in human traits. We report exome sequencing of 200 individuals from Denmark with targeted capture of 18,654 coding genes and sequence coverage of each individual exome at an average depth of 12-fold. On average, about 95% of the target regions were covered by at least one read. We identified 121,870 SNPs in the sample population, including 53,081 coding SNPs (cSNPs). Using a statistical method for SNP calling and an estimation of allelic frequencies based on our population data, we derived the allele frequency spectrum of cSNPs with a minor allele frequency greater than 0.02. We identified a 1.8-fold excess of deleterious, non-syonomyous cSNPs over synonymous cSNPs in the low-frequency range (minor allele frequencies between 2% and 5%). This excess was more pronounced for X-linked SNPs, suggesting that deleterious substitutions are primarily recessive.

引用

页码：969 / U82

页数：6

共 27 条

[1] Direct selection of human genomic loci by microarray hybridization [J].