Natural selection among Eurasians at genomic regions associated with HIV-1 control

Yann C Klimentidis,Mark D Shriver,Brahim Aissani,David B Allison,Sadeep Shrestha

doi:10.1186/1471-2148-11-173

Abstract

BackgroundHIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Here, we examine population differentiation and haplotype patterns at several loci identified through genome-wide association studies on HIV-1 control, as determined by viral-load setpoint, in European and African-American populations. We use genome-wide data from the Human Genome Diversity Project, consisting of 53 world-wide populations, to compare measures of FST and relative extended haplotype homozygosity (REHH) at these candidate loci to the rest of the respective chromosome.ResultsWe find that the Europe-Middle East and Europe-South Asia pairwise FST in the most strongly associated region are elevated compared to most pairwise comparisons with the sub-Saharan African group, which exhibit very low FST. We also find genetic signatures of recent positive selection (higher REHH) at these associated regions among all groups except for sub-Saharan Africans and Native Americans. This pattern is consistent with one in which genetic differentiation, possibly due to diversifying/positive selection, occurred at these loci among Eurasians.ConclusionsThese findings are concordant with those from earlier studies suggesting recent evolutionary change at immunity-related genomic regions among Europeans, and shed light on the potential genetic and evolutionary origin of population differences in HIV-1 control.

Highlights

HIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability
In order to test this hypothesis, we examined patterns of FST and relative extended haplotype homozygosity (REHH) in the genomic regions surrounding both the Human Leukocyte Antigen (HLA) and non-HLA HIV-1 control-associated loci identified through genome-wide association studies (GWAS) in European Americans (EA) and AA
FST analysis We first analyzed FST at the loci with the strongest evidence of association among EA. The region surrounding these two loci, which are in low LD (r2 = 0.06, D’ = 0.86) in a EA population [11], exhibits very low FST compared to random regions of chromosome 6 for all of the pairwise comparisons with sub-Saharan Africans (AFR), suggesting that much less differentiation

Summary

Introduction

HIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Associations with most of these genes appear to be population-specific, and many exhibit marked allele frequency differences between different racial/ethnic groups [3] This interpopulation genomic variability and these differential associations are still poorly understood, and could plausibly be due to natural selection resulting from distinct environmental or cultural pressures in different geographical populations [3]. Studies have shown evidence of positive selection at other genes involved in HIV-1 pathogenesis, such as TRIM5a and APOBEC3G [7,8], while others do not find any such evidence [9]

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