title: The case for selection at CCR5-Delta32.
abstract: The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen at CCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. pardis@broad.mit.edu
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.forename: Emily
authors.initials: E
authors.lastname: Walsh
authors.forename: Steve F
authors.initials: SF
authors.lastname: Schaffner
authors.forename: Patrick
authors.initials: P
authors.lastname: Varilly
authors.forename: Ben
authors.initials: B
authors.lastname: Fry
authors.forename: Holli B
authors.initials: HB
authors.lastname: Hutcheson
authors.forename: Mike
authors.initials: M
authors.lastname: Cullen
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.forename: Jessica
authors.initials: J
authors.lastname: Roy
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: Richard
authors.initials: R
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Reich
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Brien
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D000483:Alleles; D005075:Biological Evolution; D002874:Chromosome Mapping; D003198:Computer Simulation; D019143:Evolution, Molecular; D017353:Gene Deletion; D005787:Gene Frequency; D005821:Genetic Techniques; D014644:Genetic Variation; D016678:Genome; D015894:Genome, Human; D005838:Genotype; D006678:HIV / Q000378:metabolism; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D015233:Models, Statistical; D009154:Mutation; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine; D011995:Recombination, Genetic; D012641:Selection, Genetic; D012984:Software
chemical_list: D019713:Receptors, CCR5; D019707:Receptors, Chemokine