title: An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people.
abstract: 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.
authors.affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA. matthew.r.nelson@gsk.com
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Daniel
authors.initials: D
authors.lastname: Wegmann
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ehm
authors.forename: Darren
authors.initials: D
authors.lastname: Kessner
authors.forename: Pamela
authors.initials: P
authors.lastname: St Jean
authors.forename: Claudio
authors.initials: C
authors.lastname: Verzilli
authors.forename: Judong
authors.initials: J
authors.lastname: Shen
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Tang
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.forename: Dana
authors.initials: D
authors.lastname: Fraser
authors.forename: Liling
authors.initials: L
authors.lastname: Warren
authors.forename: Jennifer
authors.initials: J
authors.lastname: Aponte
authors.forename: Matthew
authors.initials: M
authors.lastname: Zawistowski
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Woollard
authors.forename: Simon
authors.initials: S
authors.lastname: Topp
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.forename: Keith
authors.initials: K
authors.lastname: Nangle
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Abecasis
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zöllner
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Chissoe
authors.forename: John
authors.initials: J
authors.lastname: Novembre
authors.forename: Vincent
authors.initials: V
authors.lastname: Mooser
mesh_terms: D001741:Black or African American / Q000235:genetics; D044466:Asian People; D004194:Disease / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D005843:Geography; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058990:Molecular Targeted Therapy; D020412:Multifactorial Inheritance; D059645:Mutation Rate; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011158:Population Growth; D018401:Sample Size; D012641:Selection, Genetic; D044465:White People / Q000235:genetics