The role of balancing selection in maintaining human RhD blood group polymorphism: A preregistered cross-sectional study.

Maintenance of genetic polymorphism remains one of the big questions of evolutionary biology, which for a long time tended to be explained by balancing selection. This explanation was later criticized, but now is again accepted as an important mechanism in evolution. Human blood group systems seem affected by balancing selection especially strongly. In this preregistered study, we focused on stable coexistence of RhD-positive and RhD-negative subjects in a population. This is an evolutionary conundrum, because carriers of the less frequent negative allele suffer from lower fecundity due to haemolytic disease of the newborn affecting RhD-positive infants born to RhD-negative women. One explanation of persisting stability of RhD polymorphism points to heterozygote advantage. Over the past decade, numerous studies demonstrated that RhD-positive subjects score better than RhD-negative homozygotes in psychomotor tests and physical health-related variables. Still, evidence of better health and performance of heterozygotes is scarce and merely indirect. We compared the physical and mental health of 2,539 subjects whose RhD genotype was estimated based on their and their parents' RhD phenotype. We confirmed that RhD-negative homozygotes fare worse in terms of physical and mental health than subjects with RhD-positive phenotype and that RhD-positive heterozygotes enjoy better health than both homozygotes. For the first time, we demonstrated that RhD-positive homozygotes might suffer from worse health than RhD-negative homozygotes. Our results strongly support the hypothesis that RhD polymorphism is maintained by heterozygote advantage and that balancing selection may have played an important role in human evolution in this context and in general.