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.
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs CB10 1SA, United Kingdom.
Yali
Y
Xue
Allan
A
Daly
Bryndis
B
Yngvadottir
Mengning
M
Liu
Graham
G
Coop
Yuseob
Y
Kim
Pardis
P
Sabeti
Yuan
Y
Chen
Jim
J
Stalker
Elizabeth
E
Huckle
John
J
Burton
Steven
S
Leonard
Jane
J
Rogers
Chris
C
Tyler-Smith
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