title: Nonsynonymous SNPs: validation characteristics, derived allele frequency patterns, and suggestive evidence for natural selection.
abstract: We experimentally investigated more than 1,200 entries in dbSNP that would change amino-acids (nsSNPs), using various subsets of DNA samples drawn from 18 global populations (approximately 1,000 subjects in total). First, we mined the data for any SNP features that correlated with a high validation rate. Useful predictors of valid SNPs included multiple submissions to dbSNP, having a dbSNP validation statement, and being present in a low number of ESTs. Together, these features improved validation rates by almost 10-fold. Higher-abundance SNPs (e.g., T/C variants) also validated more frequently. Second, we considered derived alleles and noted a considerably (approximately 10%) increased average derived allele frequency (DAF) in Europeans vs. Africans, plus a further increase in some other populations. This was not primarily due to an SNP ascertainment bias, nor to the effects of natural selection. Instead, it can be explained as a drift-based, progressive increase in DAF that occurs over many generations and becomes exaggerated during population bottlenecks. This observation could be used as the basis for novel DAF-based tests for comparing demographic histories. Finally, we considered individual marker patterns and identified 37 SNPs with allele frequency variance or FST values consistent with the effects of population-specific natural selection. Four particularly striking clusters of these markers were apparent, and three of these coincide with genes/regions from among only several dozen such domains previously suggested by others to carry signatures of selection.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Fredman
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Sawyer
authors.forename: Linda
authors.initials: L
authors.lastname: Strömqvist
authors.forename: Salim
authors.initials: S
authors.lastname: Mottagui-Tabar
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Brookes
mesh_terms: D000483:Alleles; D019295:Computational Biology / Q000379:methods; D020224:Expressed Sequence Tags; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic