Evolution__3rd_Edition

184 PART 2 / Evolutionary Genetics
The McDonald–Kreitman test looks
for selection by comparing dN/dS
ratios within and between species
Nearly neutral theory makes the
test inconclusive for single genes
7.8.3 Selection can be detected by comparisons of the dN/dS ratio
within and between species
A further test between drift and selection can be devised using the ratio of nonsynonymous
to synonymous evolution. The trick is to compare the ratio within one
species and between two related species. Consider a gene like Adh, which we looked at
in Section 7.8.1. Within the Drosophila melanogaster species, Adh is polymorphic a
two alleles are present in most populations of the species. We can count the number of
non-synonymous and synonymous differences between the two alleles and express the
result as a dN/dS ratio within a species. We can also measure the number of differences
between the Adh gene in D. melanogaster and in a related fruitfly species, to give the
dN/dS ratio for evolutionary changes between the two species.
McDonald & Kreitman (1991) realized that, on Kimura’s neutral theory, the dN/dS
ratio should be the same both for polymorphism within a species and evolutionary
divergence between species. In both cases, the dN/dS ratio equals the ratio of the nonsynonymous
neutral mutation rate to the synonymous neutral mutation rate.
The reason is as follows. The dN/dS ratio between species is the ratio of nonsynonymous
to synonymous evolutionary change. The rate of neutral evolution equals
the neutral mutation rate (Section 6.3, p. 144). The ratio of non-synonymous to
synonymous evolution should therefore, on Kimura’s neutral theory, equal the ratio
of the neutral mutation rates for non-synonymous and synonymous mutations.
Within a species, the amount of neutral polymorphism is given by a more complex
formula (Section 6.6, p. 151). But if we look at the ratio of polymorphism for nonsynonymous
to synonymous sites, everything in the formula cancels except the
non-synonymous neutral mutation rate and the synonymous neutral mutation rate.
The dN/dS ratio for polymorphism within a species is again the ratio of these two
mutation rates.
If selection is at work, the dN/dS ratio is not expected to be the same within and
between species. For instance, if natural selection favors a change in an amino acid in
one species but not the other, the dN/dS ratio will be higher between than within a
species. If natural selection favors a polymorphism, because of frequency-dependent
selection or heterozygous advantage (Sections 5.12–5.13, pp. 123–8), the dN/dS ratio
will be higher within a species than between. In summary, if the dN/dS ratio is similar
for polymorphisms within a species and evolutionary change between species, that
suggests random drift. If the ratio differs within and between species, that suggests
natural selection.
The McDonald–Kreitman test was initially used with individual genes such as Adh.
The test seemed to rule out the neutral theory, at least in some cases. However, the test
is not powerful for individual genes. The test can rule out Kimura’s purely neutral
theory; but it does not work against the nearly neutral theory. Once we allow for
nearly neutral mutations as well as purely neutral mutations, the dN/dS ratios depend
on population size as well as the mutation rate. The dN/dS ratio will only be the same
within and between species if population size has been constant. In practice, population
sizes fluctuate. Suppose, for instance, that the population size goes through a
bottleneck while a new species originates. During that phase, more non-synonymous
..