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 ∼100-500 thousand years ago (KYA) and was initially neutral or almost neutral but that positive selection beginning ∼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.
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We thank Joe Greenhill and Jonathan Bailey, for their contributions to generating sequence data; Chris Gillson, for assistance; Kate Rice and Bob Griffiths, for useful discussions; Peter Donnelly, for advice; Benjamin Voight, Sridhar Kudaravalli, and Jonathan Pritchard, for permission to refer to their unpublished work; and two referees, for suggesting improvements to the manuscript. We particularly thank Molly Przeworski for her advice and suggestions during the course of this study and for comments on the manuscript. This work was supported by The Wellcome Trust.