Spread of an Inactive Form of Caspase-12 in Humans Is Due to Recent Positive Selection

Harvard University, Cambridge, Massachusetts, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2006; 78(4):659-70. DOI: 10.1086/503116
Source: PubMed


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.

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Available from: James Stalker, Jun 05, 2014
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    • "Whether this difference in CASP12L allele frequency is related to susceptibility to pneumonia is unclear. Differences may simply reflect sampling different subpopulations since Xue et al [22] reported that in some African populations up to 60% of individuals carry the CASP12L allele. "
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    ABSTRACT: Community-acquired pneumonia (CAP) is a common cause of sepsis. Active full-length caspase-12 (CASP12L), confined to the people of African descent, has been associated with increased susceptibility to and mortality from severe sepsis. The objective of this study was to determine whether CASP12L was a marker for susceptibility and/or severity of CAP. We examined three CAP cohorts and two control populations: 241 adult Memphis African American CAP patients, 443 pediatric African American CAP patients, 90 adult South African CAP patients, 120 Memphis healthy adult African American controls and 405 adult Chicago African American controls. Clinical outcomes including mortality, acute respiratory distress syndrome (ARDS), septic shock or severe sepsis, need for mechanical ventilation, and S. pneumoniae bacteremia. Neither in the three individual CAP cohorts nor in the combined CAP cohorts, was mortality in CASP12L carriers significantly different from that in non-CASP12L carriers. No statistically significant association between genotype and any measures of CAP severity was found in any cohort. We conclude that the functional CASP12L allele is not a marker for susceptibility and/or severity of CAP.
    PLoS ONE 02/2014; 9(2):e89194. DOI:10.1371/journal.pone.0089194 · 3.23 Impact Factor
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    • "These tests evaluate whether or not the observed allele and haplotype frequency distributions are consistent with neutrality, given the demographic history of the populations (Schaffner et al. 2005). We observed significant deviations from neutral expectations in non-African populations (Table 2), including an excess of variants in external branches of the phylogeny in the CEU (Fu and Li's D test (Fu and Li 1993); P = 0.038) and a single haplotype that has risen to unexpectedly high frequency in both CEU and CHB (Figure 2b; 47 out of 90 chromosomes; P = 0.045 by the common haplotype frequency test(Xue et al. 2006)). This result is not explained by haplotypes containing the RHD deletion. "
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    ABSTRACT: The evolutionary history of variation in the human Rh blood group system, determined by variants in the RHD and RHCE genes, has long been an unresolved puzzle in human genetics. Prior to medical treatments and interventions developed in the last century, the D-positive (RhD positive) children of D-negative (RhD negative) women were at risk for hemolytic disease of the newborn, if the mother produced anti-D antibodies following sensitization to the blood of a previous D-positive child. Given the deleterious fitness consequences of this disease, the appreciable frequencies in European populations of the responsible RHD gene deletion variant (for example, 0.43 in our study) seem surprising. In this study, we used new molecular and genomic data generated from four HapMap population samples to test the idea that positive selection for an as-of-yet unknown fitness benefit of the RHD deletion may have offset the otherwise negative fitness effects of hemolytic disease of the newborn. We found no evidence that positive natural selection affected the frequency of the RHD deletion. Thus, the initial rise to intermediate frequency of the RHD deletion in European populations may simply be explained by genetic drift/founder effect, or by an older or more complex sweep that we are insufficiently powered to detect. However, our simulations recapitulate previous findings that selection on the RHD deletion is frequency dependent and weak or absent near 0.5. Therefore, once such a frequency was achieved, it could have been maintained by a relatively small amount of genetic drift. We unexpectedly observed evidence for positive selection on the C allele of RHCE in non-African populations (on chromosomes with intact copies of the RHD gene) in the form of an unusually high F( ST ) value and the high frequency of a single haplotype carrying the C allele. RhCE function is not well understood, but the C/c antigenic variant is clinically relevant and can result in hemolytic disease of the newborn, albeit much less commonly and severely than that related to the D-negative blood type. Therefore, the potential fitness benefits of the RHCE C allele are currently unknown but merit further exploration.
    Human Genetics 02/2012; 131(7):1205-16. DOI:10.1007/s00439-012-1147-5 · 4.82 Impact Factor
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    • "The coordinates of the chosen regions were (March 2006, NCBI 36 assembly) chromosome 4: 158,702,285–159,016,211 (314 kb, called chr4:158Mb) and chromosome 10: 22,587,453–22,850,110 (263 kb, called chr10:22Mb). We also included a set of control regions, including CASP12 (13 kb) for which we had the Sanger capillary sequencing data from some of the same individuals (Xue et al. 2006) and 20 kb of unique sequence from the Y chromosome, where there should be no reads mapping in females and no heterozygote calls in males. Fig. 1 Simulation design. "
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    ABSTRACT: We have investigated whether regions of the genome showing signs of positive selection in scans based on haplotype structure also show evidence of positive selection when sequence-based tests are applied, whether the target of selection can be localized more precisely, and whether such extra evidence can lead to increased biological insights. We used two tools: simulations under neutrality or selection, and experimental investigation of two regions identified by the HapMap2 project as putatively selected in human populations. Simulations suggested that neutral and selected regions should be readily distinguished and that it should be possible to localize the selected variant to within 40 kb at least half of the time. Re-sequencing of two ~300 kb regions (chr4:158Mb and chr10:22Mb) lacking known targets of selection in HapMap CHB individuals provided strong evidence for positive selection within each and suggested the micro-RNA gene hsa-miR-548c as the best candidate target in one region, and changes in regulation of the sperm protein gene SPAG6 in the other. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1111-9) contains supplementary material, which is available to authorized users.
    Human Genetics 11/2011; 131(5):665-74. DOI:10.1007/s00439-011-1111-9 · 4.82 Impact Factor
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