The Case for Selection at CCR5-Δ32

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Δ32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Δ32 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-Δ32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Δ32 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 atCCR5-Δ32 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.

[1]  Peter Donnelly,et al.  A comparison of bayesian methods for haplotype reconstruction from population genotype data. , 2003, American journal of human genetics.

[2]  L Kruglyak,et al.  Parametric and nonparametric linkage analysis: a unified multipoint approach. , 1996, American journal of human genetics.

[3]  S. Gabriel,et al.  Calibrating a coalescent simulation of human genome sequence variation. , 2005, Genome research.

[4]  M. Bamshad,et al.  Signatures of natural selection in the human genome , 2003, Nature Reviews Genetics.

[5]  Timothy B Sackton,et al.  A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees , 2005, PLoS biology.

[6]  M. Nei,et al.  Estimation of fixation indices and gene diversities , 1983, Annals of human genetics.

[7]  S. Gabriel,et al.  Quality and completeness of SNP databases , 2003, Nature Genetics.

[8]  Matthew W. Hahn,et al.  Positive Selection on MMP3 Regulation Has Shaped Heart Disease Risk , 2004, Current Biology.

[9]  M. Nei.  Molecular Evolutionary Genetics , 1987 .

[10]  L. Jorde,et al.  A method for detecting recent selection in the human genome from allele age estimates. , 2003, Genetics.

[11]  Steve Olson.  Population genetics. Seeking the signs of selection. , 2002, Science.

[12]  Pardis C Sabeti,et al.  Detecting recent positive selection in the human genome from haplotype structure , 2002, Nature.

[13]  M. Shriver,et al.  Interrogating a high-density SNP map for signatures of natural selection. , 2002, Genome research.

[14]  D. Gudbjartsson,et al.  A high-resolution recombination map of the human genome , 2002, Nature Genetics.

[15]  M. Carrington,et al.  Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences. , 1999, Human molecular genetics.

[16]  H. Ostrer,et al.  Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. , 1998, American journal of human genetics.

[17]  Seeking the Signs of Selection , 2002, Science.

[18]  J J Goedert,et al.  Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene , 1996, Science.

[19]  J. Thoday.  Population Genetics , 1956, Nature.

[20]  Deborah A Nickerson,et al.  Population History and Natural Selection Shape Patterns of Genetic Variation in 132 Genes , 2004, PLoS biology.

[21]  Pardis C Sabeti,et al.  Searching for signals of evolutionary selection in 168 genes related to immune function , 2006, Human Genetics.

[22]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[23]  Michael Cullen,et al.  An integrated haplotype map of the human major histocompatibility complex. , 2003, American journal of human genetics.

[24]  M. Bamshad,et al.  A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Kreitman,et al.  A Population Genetic Test of Selection at the Molecular Level , 1995, Science.

[26]  M. Bamshad,et al.  Contrasting effects of natural selection on human and chimpanzee CC chemokine receptor 5. , 2005, American journal of human genetics.

[27]  Andrew G. Clark,et al.  Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That Confer Malarial Resistance , 2001, Science.

[28]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[29]  M. Carrington,et al.  Novel alleles of the chemokine-receptor gene CCR5. , 1997, American journal of human genetics.

[30]  M. Daly,et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms , 2001, Nature.

[31]  S. Duncan,et al.  Reappraisal of the historical selective pressures for the CCR5-Δ32 mutation , 2005, Journal of Medical Genetics.

[32]  Justin C. Fay,et al.  Hitchhiking under positive Darwinian selection. , 2000, Genetics.

[33]  H. Ostrer,et al.  Dating the Origin of the CCR 5D 32 AIDS-Resistance Allele by the Coalescence of Haplotypes , 2007 .

[34]  R. Hudson.  Gene genealogies and the coalescent process. , 1990 .