Spread of an inactive form of caspase-12 in humans is due to recent positive selection.
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.
Xue
Yali
Y
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs CB10 1SA, United Kingdom.
Daly
Allan
A
Yngvadottir
Bryndis
B
Liu
Mengning
M
Coop
Graham
G
Kim
Yuseob
Y
Sabeti
Pardis
P
Chen
Yuan
Y
Stalker
Jim
J
Huckle
Elizabeth
E
Burton
John
J
Leonard
Steven
S
Rogers
Jane
J
Tyler-Smith
Chris
C
D001483:Base Sequence; D053454:Caspase 12; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D018388:Codon, Terminator; D017931:DNA Primers; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic
D018388:Codon, Terminator; D017931:DNA Primers; C506444:CASP12 protein, human; D053454:Caspase 12; D020169:Caspases