Fertility Selection in the Rh-factor system of humans
The Rh
blood-type is due to the presence or absence of a RBC-surface
antigen coded by an allele at the RHD locus
on Chromosome 1. R is dominant to r. When
the R allele is present in either homozygotes or
heterozygotes (RR or Rr, respectively), the
antigen produces the Rh+ phenotype; rr
homozygotes that lack the antigen are Rh-
phenotypes. Rh phenotypes are typically reported
together with the ABO blood-type: the most common
blood-type in persons of European descent is O+.
One type of Hemolytic Disease of Newborns (HDN) occurs when the mother is rr (lacking the antigen) and gives birth to a child with an R allele from an RR or Rr father. If this risk is undetected, the fetal R antigen sensitizes the mother to produces the anti-R antibody, which attacks fetal blood cells and causes HDN. Typically, the first R- child only sensitizes the rr mother and is not at risk: the second and subsequent fetuses are at severe risk because the antibody titre has been raised by the first fetus, and the result is often spontaneous abortion, stillbirth, or a severely anemic newborn. If the risk is known from the maternal and paternal blood-types, treatment of the mother during the first pregnancy with IgG immuno-suppressors such as Rhogam prevents development of the antibody, and the pregnancy can proceed to term. Treatment must be repeated at each subsequent pregnancy, and is ineffective if not applied during the first, sensitizing pregnancy. Note again that the fetus of an rr father and an R- mother is not at risk, because the disease is due to exposure to R antigen exposure in utero.
Besides the immediate medical concerns for individuals, the Rh system has consequences for population and evolutionary genetics.
(I) For any individual marriage, risk probabilities are calculated from Mendelian first principles, as shown in the table: if the mother is rr, 100%, 50%, and 0% of fetuses with RR, Rr, and rr fathers, respectively, are at risk. Where the mother is RR or Rr, none of the fetuses are at risk, no matter the genotype of the father. Thus the genetic counseling question arises always & only when the mother is Rh-. [See Note below]
(II) In terms of population genetics, if we want to calculate the fraction of the population at risk, we require knowledge of the frequency f of each of the three genotypes, fRR, fRr, and frr. The selection scheme is additive selection: half of the fetuses of Rr x rr mothers are at risk, which is equivalent to a selection coefficient of (1-s). All of the fetuses of RR x rr mothers are at risk, and the fitness of such marriages is (1-2s).
The novel selective regime here is that fetuses with identical genotypes Rr have different viability, according to the maternal environment. Mothers with identical genotypes rr have different fertility, according to the father's genotype.
(III) In terms of evolutionary genetics, different population have different frequencies of the two alleles, and alternative outcomes are expected if either R or r is rare.
(1) If R is relatively rare [say, f(R) = 0.1], relatively few men are Rh+, and most of these are Rr: f(Rr) = (2)(0.1)(0.9) = 0.18. A large majority of women are Rh- [f(rr) = 0.92 = 0.81]. The proportion of marriages between Rh+ men and Rh- is then (0.18)(0.81) = 0.146 of the total, which will be at a selective disadvantage (1 - s) to marriages between Rh- men and Rh- women [proportion (0.81)(0.81) = 0.656 with no selective disadvantage (s = 0). Selection acts effectively only on Rh+ men, and the expectation is that f(R), already rare, will decrease further.
(2) If r is relatively rare [say, f(r) = 0.1],almost all women are R+ [f(RR) = 0.92 = 0.81 or f(Rr) = (2)(0.9(0.1) = 0.18] and never subject to selection (s = 0). Expected blood type frequencies among men are the same. These women will be at a selective advantage relative to the rare Rh- women [f(rr) = 0.12 = 0.01], most of whom will marry Rh+ men [(0.01)(0.81 + 0.18) ~ 0.01], and therefore be at a selective disadvantage (typically 1 - 2s). As in III.1 above, RR or Rr men who marry rr women will be at a selective disadvantage, as they are expected to have fewer viable offspring. The expectation is that f(r) will decrease further. As we have seen however, this selection is inefficient against a rare recessive rr genotype.
When either R or r is rare, selection ought to decrease its frequency further: the residual polymorphism is unstable. The fact that many human populations are polymorphic for the Rh-factor blood-type suggests that something else is going on. One suggestion is that alternative Rh types were (pre)-historically favored in different, separated populations, so that the polymorphism now observed within populations was originally maintained among polytypic populations, and that human history has only recently allowed these populations to interbreed.
[Note on Genetics Counseling: Explanations of the Mendelian genetics of single-locus medico-genetic conditions is the least of it. Counselors must address the tendency of one partner or the other to assign or assume blame for allelic combinations that pre-dispose towards the condition. This is strongly influenced by societal norms. In case (I) above, there is sometimes a tendency to 'blame the Mother', because HDN is limited to the fetuses of a certain rr maternal genotype. Phrased alternatively, because HDN arises only by the combination of a paternal R with a maternal r, which is a matter of paternal certainty (RR) or chance (Rr), this might be seen as shifting the onus to the Father. Secondary questions are responsibilities assumed in an RR father x rr mother marriage where there is the possibility of children and prophylactic treatment is mandatory, or an Rr father x rr mother marriage where pre-natal testing is (arguably) necessary, followed by prophylactic treatment as required. Tertiary questions arise in the case of an unplanned pregnancy, especially if the genotype of the father is unknown].
One type of Hemolytic Disease of Newborns (HDN) occurs when the mother is rr (lacking the antigen) and gives birth to a child with an R allele from an RR or Rr father. If this risk is undetected, the fetal R antigen sensitizes the mother to produces the anti-R antibody, which attacks fetal blood cells and causes HDN. Typically, the first R- child only sensitizes the rr mother and is not at risk: the second and subsequent fetuses are at severe risk because the antibody titre has been raised by the first fetus, and the result is often spontaneous abortion, stillbirth, or a severely anemic newborn. If the risk is known from the maternal and paternal blood-types, treatment of the mother during the first pregnancy with IgG immuno-suppressors such as Rhogam prevents development of the antibody, and the pregnancy can proceed to term. Treatment must be repeated at each subsequent pregnancy, and is ineffective if not applied during the first, sensitizing pregnancy. Note again that the fetus of an rr father and an R- mother is not at risk, because the disease is due to exposure to R antigen exposure in utero.
Besides the immediate medical concerns for individuals, the Rh system has consequences for population and evolutionary genetics.
(I) For any individual marriage, risk probabilities are calculated from Mendelian first principles, as shown in the table: if the mother is rr, 100%, 50%, and 0% of fetuses with RR, Rr, and rr fathers, respectively, are at risk. Where the mother is RR or Rr, none of the fetuses are at risk, no matter the genotype of the father. Thus the genetic counseling question arises always & only when the mother is Rh-. [See Note below]
(II) In terms of population genetics, if we want to calculate the fraction of the population at risk, we require knowledge of the frequency f of each of the three genotypes, fRR, fRr, and frr. The selection scheme is additive selection: half of the fetuses of Rr x rr mothers are at risk, which is equivalent to a selection coefficient of (1-s). All of the fetuses of RR x rr mothers are at risk, and the fitness of such marriages is (1-2s).
The novel selective regime here is that fetuses with identical genotypes Rr have different viability, according to the maternal environment. Mothers with identical genotypes rr have different fertility, according to the father's genotype.
(III) In terms of evolutionary genetics, different population have different frequencies of the two alleles, and alternative outcomes are expected if either R or r is rare.
(1) If R is relatively rare [say, f(R) = 0.1], relatively few men are Rh+, and most of these are Rr: f(Rr) = (2)(0.1)(0.9) = 0.18. A large majority of women are Rh- [f(rr) = 0.92 = 0.81]. The proportion of marriages between Rh+ men and Rh- is then (0.18)(0.81) = 0.146 of the total, which will be at a selective disadvantage (1 - s) to marriages between Rh- men and Rh- women [proportion (0.81)(0.81) = 0.656 with no selective disadvantage (s = 0). Selection acts effectively only on Rh+ men, and the expectation is that f(R), already rare, will decrease further.
(2) If r is relatively rare [say, f(r) = 0.1],almost all women are R+ [f(RR) = 0.92 = 0.81 or f(Rr) = (2)(0.9(0.1) = 0.18] and never subject to selection (s = 0). Expected blood type frequencies among men are the same. These women will be at a selective advantage relative to the rare Rh- women [f(rr) = 0.12 = 0.01], most of whom will marry Rh+ men [(0.01)(0.81 + 0.18) ~ 0.01], and therefore be at a selective disadvantage (typically 1 - 2s). As in III.1 above, RR or Rr men who marry rr women will be at a selective disadvantage, as they are expected to have fewer viable offspring. The expectation is that f(r) will decrease further. As we have seen however, this selection is inefficient against a rare recessive rr genotype.
When either R or r is rare, selection ought to decrease its frequency further: the residual polymorphism is unstable. The fact that many human populations are polymorphic for the Rh-factor blood-type suggests that something else is going on. One suggestion is that alternative Rh types were (pre)-historically favored in different, separated populations, so that the polymorphism now observed within populations was originally maintained among polytypic populations, and that human history has only recently allowed these populations to interbreed.
[Note on Genetics Counseling: Explanations of the Mendelian genetics of single-locus medico-genetic conditions is the least of it. Counselors must address the tendency of one partner or the other to assign or assume blame for allelic combinations that pre-dispose towards the condition. This is strongly influenced by societal norms. In case (I) above, there is sometimes a tendency to 'blame the Mother', because HDN is limited to the fetuses of a certain rr maternal genotype. Phrased alternatively, because HDN arises only by the combination of a paternal R with a maternal r, which is a matter of paternal certainty (RR) or chance (Rr), this might be seen as shifting the onus to the Father. Secondary questions are responsibilities assumed in an RR father x rr mother marriage where there is the possibility of children and prophylactic treatment is mandatory, or an Rr father x rr mother marriage where pre-natal testing is (arguably) necessary, followed by prophylactic treatment as required. Tertiary questions arise in the case of an unplanned pregnancy, especially if the genotype of the father is unknown].
Figure © 2013 by Sinauer; Text material © 2022 by Steven M. Carr