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 Citations (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.

Original language	English
Journal	Nature Genetics
Volume	42
Issue number	11
Pages (from-to)	969-72
Number of pages	4
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.680
Publication status	Published - Nov 2010

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

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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, vol. 42, no. 11, pp. 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.",

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doi = "10.1038/ng.680",

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AU - Li, Yingrui

AU - Vinckenbosch, Nicolas

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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

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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.

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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

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DO - 10.1038/ng.680

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EP - 972

JO - Nature: New biology

JF - Nature: New biology

IS - 11

ER -

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

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Keywords

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