An excess of rare deleterious mutations revealed by deep resequencing of 200 human exomes

Targeted sequence capture coupled with massively parallel sequencing is a promising approach to identify genetic variants implicated in human diseases (1). Using these technologies, we sequenced the nearly complete set of coding exons in 200 Danes, with an average fold-coverage >12x for each individual exome. In the targeted regions we detected 121,895 single-nucleotide polymorphisms (SNPs), including 53,707 novel SNPs. Using a statistical method for unbiased estimation of allele frequencies we found a strong excess of rare deleterious amino acid changing mutations in our sample. This excess is more pronounced for X-linked SNPs, suggesting that deleterious substitutions are mostly recessive. Our analyses support the hypothesis that common polygenic diseases are caused by many low-frequency variants rather than a few common variants.