SCOOTER82a_Livingstone_Frequencies of Hemoglobin Variants ...

Indonesian Archipelago to New Guinea and
northward through Thailand, Laos, and China, {3
-thalassemia does have higher frequencies in the
absence of high frequencies of hemoglobin E.
The replacement of other {3 chain mutants,
including all the {3-thalassemias and other hemoglobin
variants, by either hemoglobin S or
hemoglobin E is due to the higher relative fitnesses
of the latter two genes, where the fitness
of the gene is a combination of the heterozygote
and the homozygote fitnesses. Since simultaneous
heterozygosity for two abnormal alleles or
homozygosity for any of them results in a
decreased relative fitness compared to normal
homozygotes, these abnormal variants are in
competition with one another. The better competitor
tends to eliminate the other alleles, and
the enormous fitness advantage of heterozygotes
for hemoglobin S has caused the rapid diffusion
of this allele in the Old World. The very
high fitness of heterozygotes for hemoglobin S
can be inferred from the very high frequencies
of this gene in tropical Africa where the homozygotes
have a fitness close to O. Homozygosity
in Africa is associated with a very high mortality
and the few homozygotes that do survive have
very few offspring. In order to balance this
decrease in fitness and attain a gene frequency
of 0.15 to 0.20, the heterozygotes must have an
advantage of 25% or more over normal
homozygotes.
Similar analyses of other hemoglobin variants
yield much lower estimates of their heterozygote
fitnesses. The much larger relative fitness of
hemoglobin S heterozygotes is the primary reason
that much more evidence has been found
for this difference in fitness and for their resistance
to malaria. To detect a 5% difference in
fitness, as is probable for hemoglobins C or E
whose homozygotes have a minimal decrease in
fitness, would be difficult if not impossible with
the sample sizes of most tests performed so far.
The ability of a particular allele to increase in frequency
at the expense of other abnormal alleles,
when it starts at a very low frequency, is largely
dependent on the fitness of the heterozygote
with a normal allele (Cavalli-Sforza and Bodmer
1971). Hemoglobin S has spread so far and so
fast because of the much greater fitness of the
hemoglobin S heterozygote compared to the
other {3 hemoglobin variants.
Recent work on the complete DNA structure
of the {3 hemoglobin locus has made it possible
to detect the pathways of the diffusion of the relatively
few hemoglobin S mutants that are
responsible for most instances of this gene in
human populations (Kan and Dozy 1980). The
examination of more populations has complicated
the proposed migration routes (Mears et
al. 1981), and there is now evidence of a considerable
amount of mutation, crossing-over, or
gene conversion at the {3 globin locus (Antonarakis
et al. 1984). Nevertheless, these data may
allow good estimates of the origin of the hemoglobin
S genes in America. Combining the studies
of Antonarakis et al. (1984) and Pagnier et al.
(1984), one can estimate that most of the hemoglobin
S genes in American Blacks come from
the area of Benin (108), while the next most
common are from Central Africa (32) and the
least common from the Senegal area (11). Data
from Southeast Asia on the hemoglobin E genes
indicate that more than one mutation is found in
the Cambodians (Antonarakis et al. 1982), but
data on the geographical distributions of these
different mutants are not available at present.
However, separate mutations to hemoglobin E
have been found in European populations
8
(Kazazian et al. 1984b). It is also possible to trace
the diffusion of some {3-thalassemia variants
(Thein et al. 1984).
The hemoglobin variants are thus the first loci
for which the effects of both selection and
migration can be determined. With the assumption
that malaria is the major cause of high frequencies
of the hemoglobin variants, the fitnesses
of the various genotypes can be
estimated, and now the direction of migration
and perhaps some estimate of its amount can be
determined. For these genes we are hence in a
much better position to apply genetic theory to
the interpretation of their 'distributions. We can
then obtain some idea of the effect of other
forces of genetic change such as population
size, inbreeding, or marriage patterns. Although
such interpretations require the estimation of
many parameters, models involving simulations
of the forces of evolution can contribute to our
understanding of the distributions of the various
hemoglobin alleles, for example, Livingstone
(1976) on the hemoglobin history of West
Africa.
Nevertheless, many problems remain, as a
perusal of the approximately 8000 frequencies
recorded in this compilation would readily
show. The major one seems to be the great variety
of red cell genetic variants that are found in
the major geographic areas of the Old World.
Southeast Asia is so different from Africa, India,
and the Middle East that there would appear to
be other differences in selection involved. First,
ovalocytosis is prevalent from Malaya through
the Indonesian Archipelago to New Guinea. This
trait does seem to confer some resistance to
malaria (Serjeantson et al. 1977, Kidson et al.
1981) and occurs all over the world in low frequencies.
I saw a few cases in Liberia amongthe