Evolution__3rd_Edition

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The more complex multilocus
models are only needed for
populations in linkage
disequilibrium
The HLA genes work in the immune
response
Some HLA loci are highly
polymorphic
CHAPTER 8 / Two-locus and Multilocus Population Genetics 203
ended up discovering the mimetic polymorphism. In fact, the direction of research in
P. memnon was the other way round; but the general point, that linkage disequilibrium
indicates something interesting, holds true.
Linkage equilibrium can also tell us whether the more complex two-locus theory is
needed in a real case. To a rough approximation, the theory of population genetics for a
single locus is satisfactory for populations in linkage equilibrium. It is when genes
become non-randomly associated that a two-locus model is needed. The case we have
been discussing can show why. At linkage equilibrium, A 1 and A 2 are equally associated
with B 1 . To understand evolution at the A locus we can then ignore the relative fitnesses
of B 1 and B 2 , because if B 1 is fitter than B 2 , the association with B 1 will benefit A 1 and
A 2 equally (and B 2 will equally detract from them). But if A 1 , for instance, is more
associated with B 1 than is A 2 (that is, the population is in linkage disequilibrium), then
any advantage of B 1 over B 2 will passively give rise to an advantage to A 1 . To understand
frequency changes of A 1 we then need to know the relative fitnesses of B 1 and B 2 , and
the degree of association A 1 has with them: we need a two-locus model.
8.6 Human HLA genes are a multilocus gene system
The HLA system in humans is a set of linked genes on human chromosome 6; they
control “histocompatibility” reactions. When an organ is transplanted from one individual
to another, it is immunologically rejected by the recipient in a matter of days a
skin grafts last about 2–15 days, for instance. The rejection implies that the immune
system can distinguish between “self ” and “foreign” cells, and the distinction is generally
believed to be achieved by the products of the HLA genes. The HLA genes code for
transmembrane proteins of immune system cells. Good evidence for their role comes
from the time course of kidney transplant rejection among siblings that either have or
have not been matched for their HLA genes. For kidney transplants between HLAmatched
siblings, over 90% of transplants still survive after 48 months; but among
HLA-unmatched siblings, 90% survive for 4 months and only about 40% for 48
months.
The HLA system contains a number of genes (Figure 8.3). We shall concentrate on
two of them, called HLA-A and HLA-B. Each HLA locus, in a human population, is
highly polymorphic: at the B locus alone there will be maybe 16 alleles with frequencies
of 1–10% and many more rare alleles; for example, a sample of 874 people in France
contained 31 different alleles at the B locus and another 17 alleles at the A locus. These
are exceptionally high degrees of variability. More typical loci (outside the HLA) might
have one to five alleles, many less than the number found in the HLA. The reason for
the high variability is uncertain: but it would allow the HLA genotype of an individual,
even in a large population, to be unique, which is presumably important in the distinction
of self from foreign cell types.
Particular HLA alleles are associated with particular diseases, and resistance to them.
The strongest association found so far is between ankylosing spondylitis and the allele
B27; 90% of people with the disease have the B27 allele, against only 7% in the population
at large. On the other hand, allele B27 confers better than average resistance to