Evolution__3rd_Edition

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CHAPTER 8 / Two-locus and Multilocus Population Genetics 213
Box 8.1
A Genomic Hunt for Drug-resistance Genes
Chloroquine has been, since its introduction
in 1946, one of the most effective
and widely used drugs against
malaria. Malaria is caused by the parasite
Plasmodium falciparum (Section
5.12.2, p. 124), and P. falciparum that
were resistant to chloroquine were first
observed in 1957. Since then, chloroquine
resistance has spread wherever
the drug has been used. Medically, it is
useful to know the mechanism of drug
resistance. The genetic basis of drug
resistance would classically have been
identified by crosses; but now we can
use genomic data and statistical tests
for signs of selection. One recent study
looked in the P. falciparum genome for
regions of low genetic diversity and high
local linkage disequilibrium a the signs
of a selective sweep. The underlying
idea is that any gene for drug resistance
will have been selected for recently.
Selection could have acted recently on
other genes, but a sign of selection is at
least a clue that could lead to the detection
of a drug-resistance gene.
Wootton et al. (2002) looked at
diversity at 342 marker sites in the P.
Advantageous, . ..
. . . disadvantageous, ...
falciparum genome. They found locally
reduced diversity in Asian, African, and
South American P. falciparum in a region
of chromosome 7 where a gene called
pfcrt is located. The exact allele of pfcrt
that has been selected for in each continent
differs. Indeed, the sequences
suggest that chloroquine resistance has
originated independently four times a
in Asia, Indonesia, South America, and
Africa. However, the genomic site of
lowered genetic diversity is the same in
malaria parasites from all continents.
At other regions of chromosome 7,
diversity is low or high in inconsistent
patterns between the continents. The
pfcrt gene is one of a small number of
sites where diversity is reduced in all
populations.
The pfcrt gene is also a site of locally
elevated linkage disequilibrium. A
selective sweep produces linkage disequilibrium
locally. As the frequency
of the favored allele increases, the frequency
of linked nucleotide variants will
also be dragged up, producing linkage
disequilibrium by hitch-hiking. The pfcrt
locus is the only site on chromosome 7
at which there is both high local linkage
disequilibrium and a local reduction in
genetic diversity in all populations of
P. falciparum. That locus shows a strong
sign of recent selection. The genomic
evidence alone would make us suspect
that pfcrt influences drug resistance.
As it happens, we have independent
evidence that certain alleles of pfcrt do
indeed code for drug resistance. But the
genomic evidence shows how we could
locate such genes even in the absence of
independent evidence.
A local reduction in genetic diversity
and a local high of linkage disequilibrium
are both characteristics of a selective
sweep. They can be used to find gene
loci where selection has acted recently.
Drug-resistance genes are medically
important examples of gene loci where
selection has recently acted. Any clue
that enables us to find these genes is valuable.
Selective sweeps can be used to hunt
down, if not definitively identify, genes
for drug resistance in disease organisms.
Further reading: Science October 4, 2002,
pp. 79–183.
and cases that are not. The linkage disequilibrium in Papilio memnon’s mimetic polymorphism
is advantageous. Natural selection favors individuals with genic associations
like T – W 2 F 2 E 2 B 2 , whereas it works against recombinants like T + W 2 F 2 E 2 B 2 . An individual
benefits from having the haplotypes that are in excess frequency in the population.
Whole populations of P. memnon survive better than they would if the five loci
were in linkage equilibrium.
In other cases, the opposite is true. We met an example in Section 8.9. It is where
the spread of a favored allele interferes with a linked locus at which a heterozygote is
advantageous. As the favored allele A′ increases in frequency, the frequency of one
of the alleles (such as B) at the linked polymorphic locus will also increased by hitchhiking.
Linkage disequilibrium builds up by selection on the A locus (creating an excess
of the A′B haplotype). This linkage disequilibrium is disadvantageous. The individuals