Journal Article

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

Kessner, Darren, Zöllner, Sebastian, Nelson, Matthew R., Li, Yun, Woollard, Peter, Shen, Judong, Abecasis, Gonçalo, St. Jean, Pamela, Nangle, Keith, Liu, Xiao, Hall, Matthew D., Ehm, Margaret G., Wegmann, Daniel, Bacanu, Silviu-Alin, Fraser, Dana, Chissoe, Stephanie L., Li Li, Topp, Simon, Zawistowski, Matthew, Mooser, Vincent, Warren, Liling, Cardon, Lon R., Whittaker, John C., Tang, Zhengzheng, Zhang, Hao, Wang, Jun, Li, Jun, Verzilli, Claudio, Novembre, John, Aponte, Jennifer, Zhang, Yong

2012

Overview

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 (1 every 17 bases) and geographically localized, so 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. We conclude that because of 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: African Americans - genetics / Alleles / Asian Continental Ancestry Group / Biological and medical sciences / Classical genetics, quantitative genetics, hybrids / Coding / Disease / Disease - genetics / drugs / European Continental Ancestry Group - genetics / Fundamental and applied biological sciences. Psychology / Gene Frequency / genes / Genetic Association Studies / Genetic diversity / Genetic mutation / Genetic Predisposition to Disease / Genetic variance / Genetic Variation / Genetics of eukaryotes. Biological and molecular evolution / Genome, Human / Genomes / Geography / Health risks / High-Throughput Nucleotide Sequencing / Human / Human genetics / human health / Human populations / Humans / Medical genetics / Molecular Targeted Therapy / Multifactorial Inheritance / Mutation / Mutation Rate / Negative selection / people / Pharmacogenetics / Phenotype / Polymorphism, Single Nucleotide / Population genetics / Population Growth / Sample Size / Selection, Genetic / Sequencing