title: Population differentiation as an indicator of recent positive selection in humans: an empirical evaluation.
abstract: We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.forename: Xuelong
authors.initials: X
authors.lastname: Zhang
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: Allan
authors.initials: A
authors.lastname: Daly
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gillson
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Macarthur
authors.forename: Bryndis
authors.initials: B
authors.lastname: Yngvadottir
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Cara
authors.initials: C
authors.lastname: Woodwark
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.forename: Qasim
authors.initials: Q
authors.lastname: Ayub
authors.forename: S Qasim
authors.initials: SQ
authors.lastname: Mehdi
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004375:Duffy Blood-Group System / Q000235:genetics; D053339:Edar Receptor / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases
chemical_list: C473745:ACKR1 protein, human; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D004375:Duffy Blood-Group System; C506008:EDAR protein, human; D053339:Edar Receptor; C434113:GNB1L protein, human; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011956:Receptors, Cell Surface; C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase; C102169:HERC1 protein, human; D044767:Ubiquitin-Protein Ligases; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes