Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants
Yingrui Li1,19, Nicolas Vinckenbosch2,19, Geng Tian1,19, Emilia Huerta-Sanchez2,3,19, Tao Jiang1,19, Hui Jiang1, Anders Albrechtsen4, Gitte Andersen5, Hongzhi Cao1, Thorfinn Korneliussen4, Niels Grarup5, Yiran Guo1, Ines Hellman6, Xin Jin1,7, Qibin Li1, Jiangtao Liu1, Xiao Liu1, Thomas Spars?5, Meifang Tang1, Honglong Wu1, Renhua Wu1, Chang Yu1, Hancheng Zheng1,7, Arne Astrup8, Lars Bolund1,9,10, Johan Holmkvist5, Torben J?rgensen11,12, Karsten Kristiansen1,4, Ole Schmitz13,14, Thue W Schwartz15, Xiuqing Zhang1, Ruiqiang Li1,4, Huanming Yang1, Jian Wang1, Torben Hansen5,16, Oluf Pedersen5,17,18, Rasmus Nielsen2,3,4 & Jun Wang1,4
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.
