Evolution__3rd_Edition

..
But the test has proved illuminating
with genomic data, ...
. . . and allows an estimate of how
much non-synonymous evolution is
driven by selection
CHAPTER 7 / Natural Selection and Random Drift 185
mutations may behave as nearly neutral mutations (for much the same reason as
we met in Section 7.5.3). The ratio dN/dS will go up. The ratio for polymorphisms
in the modern species will not be affected, because population sizes have been
restored to normal. Only the dN/dS ratio for the comparison between species is
affected. It is high because of the many substitutions that occurred during the population
bottleneck.
For this reason, by the late 1990s, the McDonald–Kreitman test was thought to be
interesting but not usually decisive. The test could be used against the purely neutral
theory. However, the neutral theory had by then moved on to the nearly neutral theory,
and the McDonald–Kreitman test did not work against that.
The McDonald–Kreitman test has enjoyed a revival as whole (or almost whole)
genome sequences have become available. The dN/dS ratio could be calculated within
and between species down the whole genome, if the whole genome had been sequenced
for several individuals of two species. In practice, this kind of research has so far used
parts of a genome, rather than whole genomes and has been confined to fruitflies (Fay
et al. 2002; Smith & Eyre-Walker 2002). The dN/dS ratio is found to be larger between
species rather than within. If that were true equally for all sites in the genome, the result
could be explained either by positive selection for change or by the nearly neutral
theory (with a population bottleneck during speciation). However, the excess nonsynonymous
substitutions are confined to only some sites in the genome. For many
sites, the dN/dS ratio is equal within and between species. These sites have probably
evolved by random drift. But at other sites, the amino acid has changed between related
fruitfly species. It looks like selection has acted at those sites.
More interestingly, the fraction of sites at which the dN/dS ratio is elevated
between species can be used to estimate the fraction of evolutionary substitutions
that have been driven by selection, as opposed to drift. In this way, Smith & Eyre-
Walker (2002) estimated that 45% of non-synonymous substitutions between one
pair of fruitfly species (Dropsophila simulans and D. yakuba) were fixed by positive
selection.
The use of the McDonald–Kreitman test with genomic data avoids the problem of
population sizes. A change in population size will influence the pattern of evolution
across the whole genome. The new inferences use variation between sites within a
genome. They focus on regions of the genome where the dN/dS ratio is abnormally
high, between species. It cannot be argued that the sites with high dN/dS ratios have
experienced one history of population sizes, and other sites (with lower dN/dS ratios)
some other history of population sizes. All the sites in the genome must experience the
same population size.
The results so far are preliminary. They are based on a limited genomic sample from
one small group of species. However, the results have great interest. They suggest that
natural selection may be a major force, at least for substitutions that change amino
acids. They also show how genomic data may be used to estimate the relative importance
of selection and drift in molecular evolution. In the future, the sequences of chimp
and human genomes will become available. Evolutionary biologists can then scan
down the sequences, to find sites where the dN/dS ratio is relatively high for comparisons
between the species. Those sites may be the ones where selection has favored
changes that have made us human.