Spread of an inactive form of caspase-12 in humans is due to recent positive selection

Abstract

The human caspase-12 gene is polymorphic for the presence or absence of a stop codon, which results in the occurrence of both active (ancestral) and inactive (derived) forms of the gene in the population. It has been shown elsewhere that carriers of the inactive gene are more resistant to severe sepsis. We have now investigated whether the inactive form has spread because of neutral drift or positive selection. We determined its distribution in a worldwide sample of 52 populations and resequenced the gene in 77 individuals from the HapMap Yoruba, Han Chinese, and European populations. There is strong evidence of positive selection from low diversity, skewed allele-frequency spectra, and the predominance of a single haplotype. We suggest that the inactive form of the gene arose in Africa approximately 100-500 thousand years ago (KYA) and was initially neutral or almost neutral but that positive selection beginning approximately 60-100 KYA drove it to near fixation. We further propose that its selective advantage was sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased.

Figure 1

Worldwide distribution of the active and inactive forms of the caspase-12 gene in the HGDP-CEPH diversity panel. Circle area is proportional to sample size, up to a maximum of 50 individuals.

Figure 2

Structure of the caspase-12 gene. The exon-intron structure—including exon 3, which is present only in some transcripts—is shown at the top, as is the whole sequenced region and the location of the 8.6-kb LD block. The lower part of the figure shows the LD block identified using Haploview. Each square represents a pairwise value of D′, with the standard color coding (red indicates LOD⩾2 and D^′=1; pink indicates LOD⩾2 and D^′<1; blue indicates LOD<2 and D^′=1; white indicates LOD<2 and D^′<1).

Figure 3

Inferred caspase-12 haplotypes. Only positions that are variable in humans are shown, coded according to whether they carry the same allele as chimpanzee (white) or not (yellow), except that the stop-codon polymorphism is shown in blue or red, respectively. The low diversity and high frequency of derived alleles can be seen in the inactive genes.

Figure 4

Median-joining network of inferred caspase-12 haplotypes from the 8.6-kb LD block. Roots 1, 2, and 3 are discussed in the text. Circle area is proportional to haplotype frequency, and circles are coded according to population.

Figure 5

Top, EHH as a function of genetic distance in the CEU. Bottom, Corresponding haplotype bifurcation diagram.

Figure 6

Likelihood surface for the selection parameter 4N_es