Biology Reference
In-Depth Information
1997) and
CCR5
(3p21; Dean
et al
., 1996; Libert
et al
., 1998) chemokine receptor
genes and the stromal cell-derived (
SDF1
; 10q11.2; Winkler
et al
., 1998) gene.
With the advent of the HIV epidemic, these variants may become advantageous in
that they appear able to restrict HIV-1 infection and decrease the progression of
HIV-1 infection to AIDS. Genetic susceptibility to parasitic infections may be
under oligogenic control (e.g.
Leishmania
, Shaw
et al
., 1995;
Schistosoma mansoni
,
Marquet
et al
., 1996;
Mycobacterium tuberculosis
, Bellamy
et al
., 1998; 1999; Shaw
et
al
., 1997;
Plasmodium falciparum
; Rihet
et al
., 1998) implying that a number of dif-
ferent variants at different loci may be subject to selection. Infectious and parasitic
disease is currently estimated to kill up to 20 million people in the world every year
with acute respiratory infection, tuberculosis, diarrhoea, malaria, measles, hepati-
tis B, whooping cough and tetanus responsible for 3/4 of this toll. Clearly, it is
likely that selection will continue to operate on existing genetic variation at a wide
range of genetic loci that serve to determine both the host's susceptibility and
resistance to the disease in question.
Polymorphism of the human ABO blood group system (
ABO
; 9q34) may owe
its origins to balancing (overdominant) selection mediated by infectious agents
(Eder and Spitalnik, 1997). Intriguingly, the same substitutions that differenti-
ate the A and B alleles in humans are also present in the great apes and Old
World monkeys (see Chapter 1, section 1.2.2) leading to speculation that these
polymorphic antigens may have arisen early in primate evolution (Kominato
et
al
., 1992; Matinko
et al
., 1993). However, intronic sequence data point instead to
an origin for the human alleles about 3 Myrs ago (O'Huigen
et al
., 1997) which
argue for a model of convergent evolution of the blood group antigens in the
higher primates.
Whilst pathogen-driven selection may be an important factor in increasing
the frequency of certain genetic variants at specific human loci, susceptibility to
infectious disease is unlikely to be the sole means by which natural selection
influences allele frequencies. One common genetic variant not thought to be
associated with infectious disease has been found in factor VII. Plasma levels of
factor VII vary significantly in the general population (Howard
et al
., 1994) and
are known to be influenced by a number of different environmental factors
including sex, age, cholesterol, and triglyceride levels (Scarabin
et al.
, 1996). An
Arg/Gln polymorphism at residue 353 of factor VII (
F7
; 13q34) which occurs
with a frequency of about 10% in various populations, is associated with a
20-25% reduction in the level of plasma factor VII activity as a result of the
impaired secretion of the Gln variant (Cooper
et al
., 1997). This high frequency
is suggestive of a balanced polymorphism and could indicate that the Gln vari-
ant confers some benefit, for example protection against thrombosis, myocar-
dial infarction or arterial disease (Escoffre
et al
., 1995). In support of this
postulate, Silveira
et al
. (1994) have shown that the Gln allele is associated with
a reduction in the amount of activated factor VII (FVIIa) generated in response
to fat intake; individuals with the Arg/Gln genotype were found to possess
FVIIa levels 48% of that exhibited by individuals homozygous for the Arg
allele. Interestingly, a decanucleotide insertion polymorphism at -323 in the
F7
gene promoter has been shown to be associated with a 33% reduction in pro-
moter activity
in vitro
and a lower level of plasma factor VII activity and antigen
