Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 16, Pages 10539-10544Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.162046399
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Funding
- NCRR NIH HHS [RR-00064, M01 RR000064] Funding Source: Medline
- NIAID NIH HHS [R01 AI043279, R21 AI046326, R37 AI046326, AI46326, AI43279, R01 AI046326] Funding Source: Medline
- NIGMS NIH HHS [GM-59290, R01 GM059290] Funding Source: Medline
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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 AN 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.
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