TY - JOUR
T1 - Spread of an inactive form of caspase-12 in humans is due to recent positive selection
AU - Xue, Yali
AU - Daly, Allan
AU - Yngvadottir, Bryndis
AU - Liu, Mengning
AU - Coop, Graham
AU - Kim, Yuseob
AU - Sabeti, Pardis
AU - Chen, Yuan
AU - Stalker, Jim
AU - Huckle, Elizabeth
AU - Burton, John
AU - Leonard, Steven
AU - Rogers, Jane
AU - Tyler-Smith, Chris
N1 - Funding Information:
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Donnelly, for advice; Benjamin Voight, Sridhar Kudaravalli, and Jonathan Pritchard, for permission to refer to their unpublished work; and two referees, for suggesting improvements to the manuscript.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.
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33645462359&partnerID=8YFLogxK
U2 - 10.1086/503116
DO - 10.1086/503116
M3 - Article
C2 - 16532395
AN - SCOPUS:33645462359
VL - 78
SP - 659
EP - 670
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -