In a genotype survey of 4,166 individuals, Stephens et al. (1998)identified a cline of CCR5-del32 allele frequencies of 0 to 14% acrossEurasia, whereas the variant is absent among native African, AmericanIndian, and East Asian ethnic groups. Haplotype analysis of 192Caucasian chromosomes revealed strong linkage disequilibrium betweenCCR5 and 2 microsatellite loci. By use of coalescence theory tointerpret modern haplotype genealogy, Stephens et al. (1998) estimatedthe origin of the CCR5-del32-containing ancestral haplotype to beapproximately 700 years ago, with an estimated range of 275 to 1,875years. The geographic cline of mutation frequencies and its recentemergence are consistent with a historic strong selective event (i.e.,an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving itsfrequency upward in ancestral Caucasian populations. Majumder and Dey (2001) studied 1,438 unrelated individuals belonging to40 ethnic groups from India. The CCR5del32 allele was absent in mostethnic populations, but was present in some populations of the northernand western regions. The authors suggested that the allele might havebeen introduced by Caucasian gene flow, consistent with the historicalfact that Caucasoid migrants from central Asia and western Eurasia hadentered India about 8,000 to 10,000 earlier. Using a population genetic model based on the demography of Europe,Duncan et al. (2005) suggested that annual widespread epidemics ofplague, a viral hemorrhagic fever, from 1347 until 1670 forced up thefrequency of the delta-32 mutation. Novembre et al. (2005) evaluated the selection hypothesis for the originand maintenance of the delta-32 mutation in Europe. Assuming uniformselection across Europe and western Asia, they found support fornorthern European origin of delta-32 and Viking-mediated dispersal,which was originally proposed by Lucotte and Mercier (1998). On theother hand, if gradients in selection intensity were assumed, Novembreet al. (2005) estimated the origin to be outside of northern Europe andselection intensities to be strongest in the northwestern part of thecontinent. Using denser genetic maps and more extensive control data than previousstudies, Sabeti et al. (2005) determined that genetic variation atdelta-32 is not exceptional relative to other loci across the genome.They estimated that the delta-32 allele arose more than 5,000 years ago,considerably earlier than the origin proposed by Stephens et al. (1998).While not ruling out selection, especially given the biology of thegene, Sabeti et al. (2005) concluded that the results imply that thepattern of genetic variation at delta-32 is consistent with neutralevolution. Glass et al. (2006) analyzed the distribution of CCR5 delta-32 inindependent cohorts of West Nile virus (see 610379)-seropositiveindividuals. They observed a strong deviation from Hardy-Weinbergequilibrium due to an increased frequency of delta-32 homozygotes. Thedelta-32 homozygotes also had increased risk of fatal WNV infection.Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor forsymptomatic WNV infection. Goulding et al. (2005) genotyped 283 Irish women exposed to hepatitis Cvirus (HCV; see 609532) genotype-1b from a single donor for CCR5, CCR2(601267), and CCL5 (187011) polymorphisms. They found that CCR5 delta-32heterozygotes showed significantly higher spontaneous clearance of HCVcompared with wildtype CCR5 homozygotes. In addition, the authorsobserved a trend toward lower hepatic inflammation scores in CCR5delta-32 heterozygotes compared with wildtype CCR5 homozygotes. Nosignificant relationships were found with CCR2 or CCL5.
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