Department of Anthropology, Pennsylvania State University, University Park, PA 16801, USA.
Hum Genet. 2012 Jul;131(7):1205-16. doi: 10.1007/s00439-012-1147-5. Epub 2012 Feb 25.
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.
人类 Rh 血型系统变异的进化史，由 RHD 和 RHCE 基因的变异决定，长期以来一直是人类遗传学中未解决的难题。在本世纪开发出医疗治疗和干预措施之前，如果 D 阴性（RhD 阴性）妇女的 D 阳性（RhD 阳性）孩子致敏于先前的 D 阳性孩子的血液，那么这些母亲可能会产生抗-D 抗体，从而导致新生儿溶血病。鉴于这种疾病对适应性的有害影响，在欧洲人群中，负责的 RHD 基因缺失变体的可观频率（例如，在我们的研究中为 0.43）似乎令人惊讶。在这项研究中，我们使用了从四个 HapMap 人群样本中生成的新分子和基因组数据，以检验这样一种观点，即对 RHD 缺失的未知适应性益处的正向选择可能抵消了新生儿溶血病的适应性负面影响。我们没有发现正向自然选择影响 RHD 缺失频率的证据。因此，RHD 缺失在欧洲人群中的初始中间频率上升可能仅仅可以通过遗传漂变/奠基者效应来解释，或者可以通过我们的检测能力不足的更古老或更复杂的扫除来解释。然而，我们的模拟再现了先前的发现，即对 RHD 缺失的选择取决于频率，并且在接近 0.5 时较弱或不存在。因此，一旦达到这种频率，就可以通过相对较小的遗传漂变来维持。我们出人意料地观察到非非洲人群中 RHCE 的 C 等位基因的正向选择证据（在具有完整 RHD 基因拷贝的染色体上），其形式为异常高的 F( ST )值和携带 C 等位基因的单一单倍型的高频率。RHCE 的功能尚未得到很好的理解，但是 C/c 抗原变体具有临床意义，可能导致新生儿溶血病，尽管与 D 阴性血型相关的疾病要少得多且严重得多。因此，RHCE C 等位基因的潜在适应性益处目前尚不清楚，但值得进一步探索。
