Molecular and population analysis of natural selection on the human haptoglobin duplication

Abstract

Haptoglobin binds free haemoglobin that prevents oxidative damage produced by haemolysis. There is a copy number variant (CNV) in the haptoglobin gene (HP) consisting of two alleles, Hp1 (no duplication), and Hp2 (1.7kb duplication involving two exons). The spread of the Hp2 allele is believed to have taken place under selective pressures conferred by malaria resistance. However, molecular evidence is lacking and Hp did not emerge in genomewide SNPs surveys for evidence of selection. In Europe, there is geographical constancy of Hp2 frequency, indicative of absence of clinal pressures and that modern day European alleles represent a "snapshot" of their out-of-Africa migrations. In this work we test for signatures of natural selection acting on the Hp CNV in a sample from the UK population (Avon Longitudinal Study of Parents and Children, ALSPAC). We present here heterozygosity decay, pairwise F(ST) values observed between ALSPAC and 301 populations from all five populated continents, extended haplotype homozygosity analyses involving the CNV and 80 SNPs surrounding the CNV ~500kb in each direction, and linkage disequilibrium and pairwise haplotypic analyses involving 160 SNPs on chromosome 16q22.1. Taken together, our results represent the first molecular analysis of natural selection in the Hp CNV genetic region.

Figure 1

The r² values observed between the HP CNV (87) and neighbouring SNPs taken from Haploview.

Figure 2

Polymorphism across ∼2 Mb centred on the HP CNV observed in HapMap samples from Europeans (CEU), Africans (YRI), Chinese (CHB) and Japanese (JPT). A decay in heterozygosity around the HP CNV was observed in all population samples. (A) Pattern of heterozygosity variation observed in CEU for a ∼2Mb interval centred on the HP CNV. (B) Pattern of heterozygosity variation observed in CEU, YRI, CHB and JPT for the same ∼2 Mb interval. (C) Heterozygosity decay in a 300Kb region centred on the HP CNV. The two vertical lines represent the interval where HP is located. The asterisk in Figure 1c represents the location of the HP CNV.

Figure 3

EHH analysis of the HP CNV and neighboring SNPs. (A) Frequency of the four haplotypes defined by a core haplotype including the HP CNV. G and A are the ancestral alleles for SNPs rs2000999 and rs152837, respectively. In the first position, A corresponds to Hp1 and C corresponds to Hp2; (B) Bifurcation diagrams for each of the four haplotypes. Division of the diagram reflects breakdown of LD; (C) EHH plotted for the core haplotype at ∼500 kb in both directions from the core haplotype. The decay of EHH for haplotype Hp2-G-G is markedly different from the other haplotypes; (D) Significance of EHH and rEHH values for haplotype Hp2-G-G.