Frequent adaptation and the McDonald–Kreitman test

Abstract

Population genomic studies have shown that genetic draft and background selection can profoundly affect the genome-wide patterns of molecular variation. We performed forward simulations under realistic gene-structure and selection scenarios to investigate whether such linkage effects impinge on the ability of the McDonald-Kreitman (MK) test to infer the rate of positive selection (α) from polymorphism and divergence data. We find that in the presence of slightly deleterious mutations, MK estimates of α severely underestimate the true rate of adaptation even if all polymorphisms with population frequencies under 50% are excluded. Furthermore, already under intermediate rates of adaptation, genetic draft substantially distorts the site frequency spectra at neutral and functional sites from the expectations under mutation-selection-drift balance. MK-type approaches that first infer demography from synonymous sites and then use the inferred demography to correct the estimation of α obtain almost the correct α in our simulations. However, these approaches typically infer a severe past population expansion although there was no such expansion in the simulations, casting doubt on the accuracy of methods that infer demography from synonymous polymorphism data. We propose a simple asymptotic extension of the MK test that yields accurate estimates of α in our simulations and should provide a fruitful direction for future studies.T he relative importance of natural selection and random genetic drift in shaping molecular evolution is a matter of a longstanding dispute. Whereas the neo-Darwinian synthesis placed natural selection as the dominant force (1), from the late 1960s on it became popular to assume that the bulk of molecular variation is selectively neutral or at most weakly selected (2). The "neutral theory" of molecular evolution enabled development of analytical approaches, based on the diffusion approximation, for calculating the expected frequency spectra and fixation probabilities of polymorphisms of varying selective effect. Most of the currently available approaches for estimating selection and demography from population genetic data rest upon these results.Recent studies have strongly challenged key assumption of the neutral theory. First, in many species the rate of adaptation appears to be very high with, for example, in Drosophila melanogaster more than 50% of the amino acid changing substitutions, and similarly large proportions of noncoding substitutions, driven to fixation by positive selection (3). Importantly, it appears that frequent adaptation strongly affects the genome-wide patterns of polymorphism (3-6). These results imply that the dynamics of a given polymorphism is not only affected by genetic drift and purifying selection acting at its particular site, but also by the socalled genetic draft (7), which describes the stochastic effects generated by recurrent selective sweeps at closely linked sites. Second, there is accumulating evidence that many polymorphisms in natural populations are sligh...

Effects of Linked Selective Sweeps on Demographic Inference and Model Selection

“…Our results are broadly concordant with a recent examination of the ability of the McDonald-Kreitman (MK) test (McDonald and Kreitman 1991) to infer the fraction of substitutions that were adaptive (a) under a simulated recurrent hitchhiking scenario with constant population size (Messer and Petrov 2013). Their study found that Eyre-Walker and Keightley's distribution of fitness effects a (DFE-a) method (Eyre-Walker and Keightley 2009), which simultaneously estimates a, the DFE, and a two-epoch population size history, incorrectly inferred the presence of population size changes (Messer and Petrov 2013).…”

“…Positive selection may also affect estimation of multipopulation demographic scenarios: although we did not examine this here, Mathew and Jensen (2015) recently showed that selective sweeps will impair parameter estimates for a two-population isolationwith-migration model. Thus our results, combined with those of Mathew and Jenson (2015), Ewing and Jensen (2016), and Messer and Petrov (2013), strongly suggest that the problem of natural selection skewing demographic inference is a general one.…”

“…Their study found that Eyre-Walker and Keightley's distribution of fitness effects a (DFE-a) method (Eyre-Walker and Keightley 2009), which simultaneously estimates a, the DFE, and a two-epoch population size history, incorrectly inferred the presence of population size changes (Messer and Petrov 2013). It is therefore reasonable to assume that positive selection could have a substantial confounding effect on a variety of population genomic methods for demographic inference in practice, beyond those considered here.…”

Determining the factors driving selective effects of new nonsynonymous mutations

“…We infer that the population size of YRI and Drosophila expanded 2.3-fold 6,000 generations ago and 2.7-fold 500,000 generations ago, respectively (SI Appendix, Table S1). Note that demographic estimates from synonymous sites are biased by selection affecting linked neutral sites (13,14), but that this bias does not affect our ability to infer the DFE (14, 15) (SI Appendix, Text S3).…”

Estimating the parameters of background selection and selective sweeps in Drosophila in the presence of gene conversion

“…There is increasing evidence that this is also true for many other organisms (1,3). Such processes have important implications for attempts to estimate demographic parameters, which usually ignore these complications, as has been pointed out before (53)(54)(55)(56). This is especially important when selection at linked sites distorts gene genealogies and hence site frequency spectra, because these are the main basis for inferring demographic parameters.…”