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].
Figure © 2013 by Sinauer;
Text material © 2022 by Steven
M. Carr