Next-generation sequencing1–5 coupled with efficient DNA capture6–8 enable exome sequencing as a new approach to study the genetic basis of human phenotypes. A number of genes underlying Mendelian diseases have been mapped using this approach6, 9–15. Exome sequencing has also been applied to tumors16–20, where sample purity, read-mapping, and chromosomal rearrangements are critical and form a very distinctive set of issues. In this Perspective, we restrict our attention to complex traits. In complex trait genetics, exome sequencing studies bring to light rare coding variants that are undetected by microarray-based genome-wide association studies (GWAS). The promise of exome sequencing studies of complex traits is based on the success of candidate gene studies21–26 and has firm roots in population genetic theory27–35.
