Abstract
Rhesus factor polymorphism has been an evolutionary enigma since its discovery in 1939. Carriers of the rarer allele should be eliminated by selection against Rhesus positive children born to Rhesus negative mothers. Here I used an ecologic regression study to test the hypothesis that Rhesus factor polymorphism is stabilized by heterozygote advantage. The study was performed in 65 countries for which the frequencies of RhD phenotypes and specific disease burden data were available. I performed multiple multivariate covariance analysis with five potential confounding variables: GDP, latitude (distance from the equator), humidity, medical care expenditure per capita and frequencies of smokers. The results showed that the burden associated with many diseases correlated with the frequencies of particular Rhesus genotypes in a country and that the direction of the relation was nearly always the opposite for the frequency of Rhesus negative homozygotes and that of Rhesus positive heterozygotes. On the population level, a Rhesus-negativity-associated burden could be compensated for by the heterozygote advantage, but for Rhesus negative subjects this burden represents a serious problem.
Highlights
Polymorphism in the Rhesus factor, namely the existence of a large deletion in the RHD gene [1] in a substantial fraction of the human population, has been an evolutionary enigma since the discovery of this factor in the 1930’s [2,3,4,5]
A multiple multivariate analysis was performed with these 23 factors as dependent variables and frequencies of Rhesus negative homozygotes, Rhesus positive heterozygotes and five potential confounding variables: GDP, latitude, humidity, medical care expenditure per capita and frequencies of smokers in the population for 65 countries with the RhD genotype frequency data as independent variables
Post hoc simple multivariate analyses showed that the frequency of Rhesus negative homozygotes correlated with five of 23 factors that together explained 17.7% of variability between different countries in Disability Adjusted Life Year (DALY) (Table 1)
Summary
Polymorphism in the Rhesus factor, namely the existence of a large deletion in the RHD gene [1] in a substantial fraction of the human population, has been an evolutionary enigma since the discovery of this factor in the 1930’s [2,3,4,5]. Before the introduction of prophylactic treatment in 1968, the carriers of the rarer variant of the gene, namely Rhesus negative women in in a population of Rhesus positive subjects or Rhesus positive men in population of Rhesus negative subjects, had lower fitness. This is because RhD-positive children born to pre-immunized RhD-negative mothers were at a higher risk of fetal and newborn death or health impairment from the haemolytic disease. Mutants or migrants with the rarer variant of the RHD gene could not invade the population and any already existing RhD polymorphism should be unstable. It has been suggested that this polymorphism can be stabilized when the disadvantage of carriers of the locally rarer allele is counterbalanced by higher viability of their heterozygote
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