title: A strong signature of balancing selection in the 5' cis-regulatory region of CCR5.
abstract: CCR5 encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for HIV-type 1 (HIV-1). Varied HIV-1 susceptibility and time to progression to AIDS have been associated with polymorphisms in CCR5. Many of these polymorphisms are located in the 5' cis-regulatory region of CCR5, suggesting that it may have been a target of natural selection. We characterized CCR5 sequence variation in this region in 400 chromosomes from worldwide populations and compared it to a genome-wide analysis of 100 Alu polymorphisms typed in the same populations. Variation was substantially higher than expected and characterized by an excess of intermediate-frequency alleles. A genealogy of CCR5 haplotypes had deep branch lengths despite markedly little differentiation among populations. This finding suggested a deviation from neutrality not accounted for by population structure, which was confirmed by tests for natural selection. These results are strong evidence that balancing selection has shaped the pattern of variation in CCR5 and suggest that HIV-1 resistance afforded by CCR5 5' cis-regulatory region haplotypes may be the consequence of adaptive changes to older pathogens.
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA. mike@genetics.utah.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.forename: Enrique
authors.initials: E
authors.lastname: Gonzalez
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: Diane M
authors.initials: DM
authors.lastname: Dunn
authors.forename: W Scott
authors.initials: WS
authors.lastname: Watkins
authors.forename: Stephen
authors.initials: S
authors.lastname: Wooding
authors.forename: Anne C
authors.initials: AC
authors.lastname: Stone
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Ahuja
mesh_terms: D000483:Alleles; D000818:Animals; D019143:Evolution, Molecular; D005787:Gene Frequency; D006071:Gorilla gorilla; D006801:Humans; D002679:Pan troglodytes; D019713:Receptors, CCR5 / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012641:Selection, Genetic
chemical_list: D019713:Receptors, CCR5