Extended Linkage Disequilibrium Surrounding the Hemoglobin E Variant Due to Malarial Selection

Abstract

The hemoglobin E variant (HbE; ( beta )26Glu-->Lys) is concentrated in parts of Southeast Asia where malaria is endemic, and HbE carrier status has been shown to confer some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the HbE variant, we analyzed biallelic markers surrounding the HbE variant in a Thai population. Pairwise LD analysis of HbE and 43 surrounding biallelic markers revealed LD of HbE extending beyond 100 kb, whereas no LD was observed between non-HbE variants and the same markers. The inferred haplotype network suggests a single origin of the HbE variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicate that the HbE variant arose 1,240-4,440 years ago. These results support the conjecture that the HbE mutation occurred recently, and the allele frequency has increased rapidly. Our study provides another clear demonstration that a high-resolution LD map across the human genome can detect recent variants that have been subjected to positive selection.

The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans

“…Significant LD was detected over 20 kb around FY (Duffy) in a non-African sample, consistent with recent selection by P. vivax (Hamblin et al 2002). At HB (b-globin), long-range LD was detected among SNPs spanning nearly 100 kb in association with HB-E alleles in a Thai population, consistent with selection by malaria (Ohashi et al 2004). And at LCT, significant LD has been reported, spanning .800 kb in association with lactase persistence alleles in a EuropeanAmerican population (Bersaglieri et al 2004).…”

Population genetics of malaria resistance in humans

“…However, the E allele found in China is on the same haplotype as that found in Thailand (Ohashi et al, 2005), suggesting that it does not have a different origin. From forward simulations, which used the amount of linkage disequilibrium close to the variant and the observed allele frequency, the age of the E allele was estimated to be about 100.3 generations (Ohashi et al, 2004), or 2508 years, and the estimated selection coefficient between genotypes AA and AE was 0.079.…”

An investigation of the protective effect of alpha+‐thalassaemia against severe Plasmodium falciparum amongst children in Kumasi, Ghana

“…It is distributed throughout much of Southeast Asia and has gene frequencies of approximately between 13-50% in Thailand (Hutagalung, et al, 1999, Fucharoen et al, 1998. It has been suggested that the positive selection against Plasmodium falciparum has been responsible for the rather high population frequency of HbE in the region (Ohashi et al, 2004).…”