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

Yingrui Li; Nicolas Vinckenbosch; Geng Tian; Emilia Huerta-Sanchez; Tao Jiang; Hui Jiang; Anders Albrechtsen; Gitte Andersen; Hongzhi Cao; Thorfinn Sand Korneliussen; Niels Grarup; Yiran Guo; Ines Hellman; Xin Jin; Qibin Li; Jiangtao Liu; Xiao Liu; Thomas Sparsø; Meifang Tang; Honglong Wu; Renhua Wu; Chang Yu; Hancheng Zheng; Arne Astrup; Lars Bolund; Johan Holmkvist; Torben Jørgensen; Karsten Kristiansen; Ole Schmitz; Thue W Schwartz; Xiuqing Zhang; Ruiqiang Li; Huanming Yang; Jian Wang; Torben Hansen; Oluf Pedersen; Rasmus Nielsen; Jun Wang

doi:10.1038/ng.680

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

Yingrui Li, Nicolas Vinckenbosch, Geng Tian, Emilia Huerta-Sanchez, Tao Jiang, Hui Jiang, Anders Albrechtsen, Gitte Andersen, Hongzhi Cao, Thorfinn Sand Korneliussen, Niels Grarup, Yiran Guo, Ines Hellman, Xin Jin, Qibin Li, Jiangtao Liu, Xiao Liu, Thomas Sparsø, Meifang Tang, Honglong WuRenhua Wu, Chang Yu, Hancheng Zheng, Arne Astrup, Lars Bolund, Johan Holmkvist, Torben Jørgensen, Karsten Kristiansen, Ole Schmitz, Thue W Schwartz, Xiuqing Zhang, Ruiqiang Li, Huanming Yang, Jian Wang, Torben Hansen, Oluf Pedersen, Rasmus Nielsen, Jun Wang

245 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	42
Udgave nummer	11
Sider (fra-til)	969-72
Antal sider	4
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.680
Status	Udgivet - nov. 2010

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10.1038/ng.680

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Li, Y., Vinckenbosch, N., Tian, G., Huerta-Sanchez, E., Jiang, T., Jiang, H., Albrechtsen, A., Andersen, G., Cao, H., Korneliussen, T. S., Grarup, N., Guo, Y., Hellman, I., Jin, X., Li, Q., Liu, J., Liu, X., Sparsø, T., Tang, M., ... Wang, J. (2010). Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nature Genetics, 42(11), 969-72. https://doi.org/10.1038/ng.680

Li, Y, Vinckenbosch, N, Tian, G, Huerta-Sanchez, E, Jiang, T, Jiang, H, Albrechtsen, A, Andersen, G, Cao, H, Korneliussen, TS , Grarup, N, Guo, Y, Hellman, I, Jin, X, Li, Q, Liu, J, Liu, X, Sparsø, T, Tang, M, Wu, H, Wu, R, Yu, C, Zheng, H, Astrup, A, Bolund, L, Holmkvist, J, Jørgensen, T, Kristiansen, K, Schmitz, O, Schwartz, TW, Zhang, X, Li, R, Yang, H, Wang, J, Hansen, T , Pedersen, O , Nielsen, R & Wang, J 2010, 'Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants', Nature Genetics, bind 42, nr. 11, s. 969-72. https://doi.org/10.1038/ng.680

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title = "Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants",

abstract = "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.",

keywords = "Base Sequence, Chromosomes, Human, X, Exons, Gene Conversion, Gene Frequency, Genes, Recessive, Genetic Variation, Genetics, Population, Human Genome Project, Humans, Introns, Polymorphism, Single Nucleotide, Untranslated Regions",

author = "Yingrui Li and Nicolas Vinckenbosch and Geng Tian and Emilia Huerta-Sanchez and Tao Jiang and Hui Jiang and Anders Albrechtsen and Gitte Andersen and Hongzhi Cao and Korneliussen, {Thorfinn Sand} and Niels Grarup and Yiran Guo and Ines Hellman and Xin Jin and Qibin Li and Jiangtao Liu and Xiao Liu and Thomas Spars{\o} and Meifang Tang and Honglong Wu and Renhua Wu and Chang Yu and Hancheng Zheng and Arne Astrup and Lars Bolund and Johan Holmkvist and Torben J{\o}rgensen and Karsten Kristiansen and Ole Schmitz and Schwartz, {Thue W} and Xiuqing Zhang and Ruiqiang Li and Huanming Yang and Jian Wang and Torben Hansen and Oluf Pedersen and Rasmus Nielsen and Jun Wang",

year = "2010",

month = nov,

doi = "10.1038/ng.680",

language = "English",

volume = "42",

pages = "969--72",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants

AU - Li, Yingrui

AU - Vinckenbosch, Nicolas

AU - Tian, Geng

AU - Huerta-Sanchez, Emilia

AU - Jiang, Tao

AU - Jiang, Hui

AU - Albrechtsen, Anders

AU - Andersen, Gitte

AU - Cao, Hongzhi

AU - Korneliussen, Thorfinn Sand

AU - Grarup, Niels

AU - Guo, Yiran

AU - Hellman, Ines

AU - Jin, Xin

AU - Li, Qibin

AU - Liu, Jiangtao

AU - Liu, Xiao

AU - Sparsø, Thomas

AU - Tang, Meifang

AU - Wu, Honglong

AU - Wu, Renhua

AU - Yu, Chang

AU - Zheng, Hancheng

AU - Astrup, Arne

AU - Bolund, Lars

AU - Holmkvist, Johan

AU - Jørgensen, Torben

AU - Kristiansen, Karsten

AU - Schmitz, Ole

AU - Schwartz, Thue W

AU - Zhang, Xiuqing

AU - Li, Ruiqiang

AU - Yang, Huanming

AU - Wang, Jian

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Nielsen, Rasmus

AU - Wang, Jun

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

KW - Base Sequence

KW - Chromosomes, Human, X

KW - Exons

KW - Gene Conversion

KW - Gene Frequency

KW - Genes, Recessive

KW - Genetic Variation

KW - Genetics, Population

KW - Human Genome Project

KW - Humans

KW - Introns

KW - Polymorphism, Single Nucleotide

KW - Untranslated Regions

U2 - 10.1038/ng.680

DO - 10.1038/ng.680

M3 - Journal article

C2 - 20890277

SN - 1061-4036

VL - 42

SP - 969

EP - 972

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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