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Sequence diversity of the Rh blood group system in Basques.

ABSTRACT: Basques show specific cultural, demographic, and genetic characteristics that have placed them as an isolated and unique population within Europe, such as their non-Indo-European language, Euskara. They have historically lived along the Western Pyrenees, between Spain and France, in one of the most important European glacial refugia during the Last Glacial Maximum. The most striking genetic characteristic is their highest frequency of the RhD blood group negative allele, a variant related to the hemolytic disease of the newborn. Both demographic and adaptive processes have been suggested as possible causes of the high frequency of RhD negative in Basques, but neither hypothesis has been clearly demonstrated. While previous studies on the Rh system in Basques have been mostly focused on serological and genotyping diversity, in this work we analyze genotyping and next generation sequencing data in order to provide a general framework of the genetic scenario of the system in Basques. In particular, we genotyped the most relevant variants of the system (D/d, E/e, and C/c), and sequenced three ~6?kb flanking regions surrounding the Rh genes in Basques and also in other populations for comparison. Our results are in agreement with previous studies, with Basques presenting the highest frequency of the RHD deletion (47.2%). Haplotype analyses of D/d, E/e, and C/c variants confirmed an association between the RhC allele, previously suggested to be under positive selection, and the RhD positive variant in non-sub-Saharan populations, including Basques. We also found extreme differentiation for the C/c variant when comparing sub-Saharan to non-sub-Saharan populations.

SUBMITTER: Flores-Bello A

PROVIDER: S-EPMC6244411 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Sequence diversity of the Rh blood group system in Basques.

Flores-Bello André A Mas-Ponte David D Rosu Miruna E ME Bosch Elena E Calafell Francesc F Comas David D

European journal of human genetics : EJHG 20180808 12

Basques show specific cultural, demographic, and genetic characteristics that have placed them as an isolated and unique population within Europe, such as their non-Indo-European language, Euskara. They have historically lived along the Western Pyrenees, between Spain and France, in one of the most important European glacial refugia during the Last Glacial Maximum. The most striking genetic characteristic is their highest frequency of the RhD blood group negative allele, a variant related to the ...[more]

PMID: 30089826

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Project description: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.

Dataset Information

Sequence diversity of the Rh blood group system in Basques.

Publications

Sequence diversity of the Rh blood group system in Basques.

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