Evolutionary genetics of the human Rh blood group system
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.
KeywordsSegmental Duplication East Asian Population Gene Conversion Event Interbirth Interval Hemolytic Disease
We thank Rachael Cartlidge for assistance with initial development of the RHCE genotyping assays, David Hopkinson for DNA samples with known Rh serotype from the former MRC Blood Group Unit, Luis Barreiro for the HapMap Phase II F ST value database, Joe Pickrell for assistance with the iHS test, Richard Hudson for assistance with simulations, the Sanger Faculty Small Sequencing Projects Group for generating the sequence data, Steve McCarroll, Pardis Sabeti, and Molly Przeworski for helpful discussions, and two reviewers for insightful comments and suggestions on the manuscript. We acknowledge the participants who contributed samples for this study. This work was funded by National Institutes of Health Grant P41-HG004221 (to C.L.), The Wellcome Trust (WT098051, C.T.-S. and Y.X.), Medical Research Council New Investigator Award GO801123 (to E.J.H.), and National Institutes of Health Grant R01-HD21244 (to C.O.).
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