Association of DC-SIGN Promoter Polymorphism with Increased Risk for Parenteral, but Not Mucosal, Acquisition of Human Immunodeficiency Virus Type 1 Infection

There is considerable debate about the fundamental mechanisms that underlie and restrict acquisition of human immunodeficiency virus type 1 (HIV-1) infection. In light of recent studies demonstrating the ability of C type lectins to facilitate infection with HIV-1, we explored the potential relationship between polymorphisms in the DC-SIGN promoter and risk for acquisition of HIV-1 according to route of infection. Using samples obtained from 1,611 European-American participants at risk for parenteral (n = 713) or mucosal (n = 898) infection, we identified single-nucleotide polymorphisms in the DC-SIGN promoter using single-strand conformation polymorphism. Individuals at risk for parenterally acquired infection who had −336C were more susceptible to infection than were persons with −336T (odds ratio = 1.87, P = 0.001). This association was not observed in those at risk for mucosally acquired infection. A potential role for DC-SIGN specific to systemic acquisition and dissemination of infection is suggested

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

Searching for signals of evolutionary selection in 168 genes related to immune function.

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data

Comparisons with Empirical and Simulation Data

<div><p>(A) and (B) Plots of relative EHH versus frequency for <i>CCR5</i> in comparison to HapMap data (release 16) for Chromosome 3 in European-Americans (A) and 1,000 simulations of 400 chromosomes in European-Americans (B). Green dots represent the comparison haplotypes and the lines represent, from bottom to top, the 50th, 75th, 95th, and 99th percentiles. The red dots represent the results for eight <i>CCR5-</i>Δ<i>32</i>-bearing chromosomes in (A) and 32 <i>CCR5-</i>Δ<i>32</i>-bearing chromosomes in (B) for the centromere-proximal side, and the blue dots represent results for the centromere-distal side.</p> <p>(C) EHL of the haplotypes of frequency 6%–10% from the HapMap (solid green line) and from simulations (dotted green line) in comparison to <i>CCR5-</i>Δ<i>32</i> (red line).</p></div

EHH Breakdown of EHH over Distance between the <i>CCR5-</i>Δ<i>32</i> Mutation and 63 SNPs at Increasing Distances from the Mutation

<div><p>(A) Map of SNPs typed.</p> <p>(B) Comparison between Δ<i>32</i> and a single non-Δ<i>32</i> class of haplotypes. It should be noted that the Δ<i>32</i>-bearing chromosomes appear (red) to have greatly extended LD compared to the non-Δ<i>32</i>-bearing chromosomes (black).</p> <p>(C) Breakdown using the eight-marker haplotype containing the Δ<i>32</i> mutation. There are five haplotypes in European-Americans (frequencies: 42%, 31%, 10%, 8%, and 8%, respectively). Full haplotype sequences and frequencies in other populations are given in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030378#st003" target="_blank">Table S3</a>. Notice that two of the non-Δ<i>32</i>-bearing chromosomes (black) appear to have the similar extended LD when compared to the Δ<i>32</i>-bearing chromosomes centromere-distal to <i>CCR5</i> (red). Centromere-proximal Δ<i>32</i>-bearing chromosomes still have the most extended LD, indicated with an arrow.</p></div

Model of Haplotype-Based Selection Approach

<p>The image compares this approach, where the variants at the gene being studied are fully elaborated, to a model where the variants are not fully elaborated. At the top, multiple SNPs are genotyped to fully define the variants that exist in the gene. The resultant observed haplotype structure is shown in both bifurcation diagram and EHH plot formats (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030378#s3" target="_blank">Materials and Methods</a>). At the bottom, only one SNP is genotyped, collapsing all other variants into a seemingly diverse super-haplotype and creating an impression of extension for the remaining haplotype.</p