西亚试剂：An Abundance of Rare Functional Variants

An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People

Matthew R. Nelson, Daniel Wegmann, Margaret G. Ehm, Darren Kessner, Pamela St. Jean, Claudio Verzilli1, Judong Shen, Zhengzheng Tang, Silviu-Alin Bacanu1, Dana Fraser1, Liling Warren, Jennifer Aponte, Matthew Zawistowski, Xiao Liu, Hao Zhang, Yong Zhang, Jun Li, Yun Li, Li Li1, Peter Woollard1, Simon Topp1, Matthew D. Hall, Keith Nangle, Jun Wang, Gonalo Abecasis, Lon R. Cardon1, Sebastian Zllner, John C. Whittaker, Stephanie L. Chissoe, John Novembre, Vincent Mooser

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (one every 17 bases) and geographically localized, such that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. Overall, we conclude that, due to rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.