Reports

Understanding the genetic contribution to human disease requires knowledge of the abundance and distribution of functional genetic diver-sity within and among populations. The “common-disease rare-variant” hypothesis posits that variants affecting health are under purifying selec-tion, and thus should be found only at low frequencies in human popula-tions (1–3). This hypothesis has become increasingly credible, since very large genome-wide association studies of common variants have ex-plained only a fraction of the known heritability of most traits (4, 5). Investigating the role of rare variants for complex trait mapping has led to tests that aggregate rare variants (6), and determine the abundance, distribution, and phenotypic effects of rare variants in human popula-tions (7, 8). Population genetic models predict that mutation rates, the strength of selection, and demography affect the abundance of rare variants, alt-hough the relative importance of each is a long-standing question (9–11)