Large-scale GWAS of complex traits have consistently demonstrated that, with few exceptions, common variants have modest effects, often requiring tens of thousands of samples for their detection. Exome sequencing provides a complementary approach by comprehensively assessing the role of all coding variation, both common and rare. With incessant mutations occurring in each protein-coding gene (at a rate of ∼10−5 per gene for non-synonymous variants36–39) and fitness loss of less than 1% 29–31, 34 for most novel non-synonymous mutations, almost every gene is expected to harbor functionally important variants that can be tested through sequencing, even if these variants are rare. Therefore, the strong interest in exome sequencing stems from three factors: the potential to identify many genes underlying complex traits, straightforward functional annotation of coding variation, and cost being substantially lower (around 5 times) than whole-genome sequencing.
