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the rate of divergence so that divergence will show no relationship to the recombination rate. Therefore, the selective sweep hypothesis explains why polymorphism increases with the recombination rate but divergence is independent of recombination rate in the Drosophila DNA sequence data.

Levels of polymorphism and rates of divergence in human DNA sequences provide a counter-example to the uncoupling of polymorphism and divergence seen in Drosophila. Hellmann et al. (2003) used a large amount of DNA sequence data to estimate both polymorphism within humans and divergence between humans, chimps, and baboons. The recombination rates near the loci used to estimate polymorphism and divergence were also known for humans. In the human sequences polymorphism increases as the recombination rate increases. But in agreement with the neutral expectation that polymorphism and divergence are correlated, the degree of divergence increased with the recombination rate as well. Thus, in humans, correlated levels of polymorphism and divergence argue for the neutral evolution of mutations. It is possible that rates of recombination and mutation are not independent in humans because mutations increase the probability of a recombination event nearby or the recombination process produces mutations.

Genetic hitch-hiking due to background or balancing selection

While genetic hitch-hiking may sometimes involve positive selection on beneficial mutations, it is also possible that new mutations may be deleterious. Negative or purifying natural selection removes deleterious mutations from the population by driving them to loss. Negative selection against deleterious mutations is also expected to reduce polymorphism through hitch-hiking in a process called background selection (Charlesworth et al. 1995). When a new deleterious mutation appears in a population, it is in gametic disequilibrium with other neutral mutations. Negative selection will cause the deleterious allele to go to loss, bringing its associated neutral mutations to loss as well. Therefore, background selection is expected to cause a reduction in polymorphism in populations. Background selection effectively lowers the mutation rate at neutral sites because it removes some portion of the new neutral mutations that appear very briefly in the population but just happen to be associated with a deleterious mutation and so go to loss quickly.

Background selection A reduction in polymorphism caused by the combination of negative or purifying selection against deleterious mutations that also leads to the loss of neutral alleles in gametic disequilibrium with the deleterious mutation.

A third possibility is that new mutations are acted on by balancing selection, which would eventually bring new beneficial mutations at the same site to intermediate frequencies and maintain them in the population for very long periods of time. Balancing selection is also expected to impact polymorphism at neutral sites that are in gametic disequilibrium with the selected site. When a new beneficial mutation appears at a site under balancing selection, the initial increase in its frequency has a effect like a selective sweep. However, long-term balancing selection leads to an increase in polymorphism because balancing selection maintains multiple alleles that persist in the population for long periods of time. These selected alleles can then accumulate mutations at neutral sites that are in gametic disequilibrium, gathering polymorphism over time. Compared to independent neutral sites, neutral sites in gametic disequilibrium with sites under balancing selection have greatly increased segregation times and so have a greater opportunity to experience mutation that leads to the accumulation of polymorphism (reviewed by Charlesworth 2006).

Hitch-hiking can be thought of as a process that alters the time to fixation or loss in the random walk of neutral genetic drift (refer to Figs 8.2 and 8.3). Hitch-hiking with beneficial mutations under positive selection greatly speeds up the time to fixation, reducing polymorphism. Hitch-hiking with deleterious mutations under negative selection also reduces polymorphism because the time to loss is accelerated. Hitch-hiking with mutations under long-term balancing selection increases polymorphism because fixation or loss are avoided for long periods during which neutral mutations can accumulate.

Gametic disequilibrium and rates of divergence

As we have seen earlier in the chapter, when the probability of fixation of a new mutation is dictated by natural selection then divergence rates change for those sites under natural selection. Positive natural selection speeds up divergence because advantageous mutations fix faster on average than they would under genetic drift alone. Alternatively, negative natural selection slows divergence rates since deleterious mutations go to loss rapidly and fewer neutral mutations remain that might fix by genetic drift. The question that remains, then, is whether or not the rate of divergence at neutral sites will be sped up or slowed down if they are in gametic disequilibrium with nucleotides that are acted on by natural selection. This question was first answered by Birky and Walsh (1988).

Earlier in the chapter we established that the rate of divergence was a function of the rate of substitution (see equation 8.32). The expected rate of substitution within a species is determined by the scaled mutation rate

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