Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection

Area of Science:

• Population Genetics
• Human Evolutionary Genetics
• Molecular Anthropology

Background:

• The hemoglobin E variant (HbE) is prevalent in malaria-endemic Southeast Asia.
• HbE carrier status provides partial protection against Plasmodium falciparum malaria.
• Understanding HbE's evolutionary history sheds light on human adaptation to endemic diseases.

Purpose of the Study:

• To investigate the impact of natural selection on linkage disequilibrium (LD) around the HbE variant.
• To infer the evolutionary origins and history of the HbE variant in a Thai population.
• To demonstrate the utility of high-resolution LD mapping for detecting positively selected recent genetic variants.

Main Methods:

• Analysis of pairwise LD between the HbE variant and 43 surrounding biallelic markers in a Thai population.
• Construction of an inferred haplotype network to assess the origin of the HbE variant.
• Forward-in-time computer simulations to estimate the age of the HbE variant under various selection models.

Main Results:

• Significant LD was observed for HbE extending beyond 100 kb, indicating recent positive selection.
• No significant LD was detected between non-HbE variants and the same markers.
• The haplotype network suggests a single origin of the HbE variant in the studied population.
• Simulations estimate the HbE variant arose between 1,240 and 4,440 years ago.

Conclusions:

• The HbE mutation is a recent genetic variant that has rapidly increased in allele frequency.
• Evidence strongly supports positive natural selection acting on the HbE variant.
• High-resolution LD mapping is an effective tool for identifying recent, selected human genetic variants.