Biology Reference
In-Depth Information
class I genes being expressed (Cadavid
et al
., 1997). It would thus appear that class
I genes have been differentially duplicated, deleted and amplified in different pri-
mate lineages (Klein
et al
., 1998).
There is an extremely high level of polymorphism at certain MHC loci, some 20
times higher than the average level of nucleotide polymorphism found in the
human genome. New MHC sequence variants have arisen by single base-pair sub-
stitution, reciprocal recombination or gene conversion (Ohta 1997; Watkins
et al
.,
1991; Yeager and Hughes, 1999). Gene conversion at the MHC locus can occur at
relatively high frequency (10
-4
per locus per generation; Zangenberg
et al
., 1995)
but, on its own, it is insufficient to account for the level of polymorphism observed.
The polymorphisms have gradually accumulated during human evolution and
have probably been maintained at high frequency by a variety of means, one of the
most important being
overdominant selection
in which the heterozygote responds
better to challenge than either homozygote (Li, 1997; Wells and Parham, 1996).
Certain MHC alleles are very ancient. Indeed, it would appear that some of the
class I MHC allelic lineages are shared by human, chimpanzee and gorilla, imply-
ing that these polymorphisms were present in the common ancestor of the three
species (Fan
et al
., 1989; Gyllensten
et al
., 1991; Kupfermann
et al
., 1992; Lawlor
et al
., 1988; 1991; Mayer
et al
., 1988; 1992). Similar findings have been reported in
the Cercopithecinae (Castro
et al
., 1996). The long-term persistence of such
trans-
species polymorphism
is potentially explicable by overdominant selection because
neutral alleles are unlikely to survive the process of speciation (Klein
et al
., 1993).
Selection would be expected to act on MHC alleles that differed in their ability to
bind and present foreign peptides. In a population exposed to pathogens, an indi-
vidual heterozygous at many MHC loci would be able to present a larger number
of foreign peptides than a homozygote and might therefore be resistant to a wider
range of pathogens (Parham and Ohta, 1996). Support for the overdominant selec-
tion hypothesis has come from studies (Hughes and Nei, 1988, 1989a; Ohta, 1991)
that noted a significantly higher rate of nonsynonymous than synonymous
nucleotide substitution in the peptide-binding region (antigen recognition site),
strong evidence for the action of positive selection (Ayala
et al
., 1994). It should
however be noted that negative or purifying selection may also operate on the
HLA system so as to reduce diversity. One example of this is found in the peptide-
binding region of the
HLA-E
gene in New World monkeys (Knapp
et al
., 1998).
The high frequency of polymorphism has probably also been maintained by
other means such as temporal variation in selection pressure driven by changes in
pathogens. Rare allele advantage (frequency-dependent selection) may play a role
in that individuals with a rare MHC allele may respond better to challenge from
new pathogen variants that have evolved in such a way as to evade the products of
the more common MHC alleles. Population size and structure may also be impor-
tant since diversity may be promoted by high effective population size or as a
result of the agglomeration of smaller populations each bearing a few different
alleles (Wells and Parham, 1996).
A high level of polymorphism can also be maintained by a 'genetic hitch-
hiker' effect. Thus the occurrence of at least 11 olfactory receptor genes
(
OR2C1
) within the MHC complex (Fan
et al
., 1995) may potentiate the selection
of specific receptor alleles matched to a subset of MHC-determined odorants,
