Hitchhiking effects of recurrent beneficial amino acid substitutions in the Drosophila melanogaster genome

Rates of evolution vary considerably among proteins (Li 1997), and the causes of this variation are the topic of continuing controversy. In the view of the neutral or nearly neutral theories, the rate of protein evolution largely reflects a balance between the level of selective constraint on a protein (i.e., negative or purifying selection) and the efficacy of selection (Kimura 1983; Ohta 2002). An opposing view posits that rates of protein evolution depend primarily on the rate at which new advantageous amino acid substitutions arise and how efficiently they can become incorporated (Gillespie 1991). Several recent studies have used a population genetic approach based on the McDonald-Kreitman (hereafter, MK) test to distinguish between these two models (McDonald and Kreitman 1991). The MK approach is based on comparing levels of polymorphism and divergence of a putatively neutral class of sites (often synonymous sites) with a putatively selected class (e.g., amino acids). The general conclusion has been that a large fraction of the protein divergence between Drosophila species is driven by positive selection (Fay et al. 2002; Smith and Eyre-Walker 2002; Sawyer et al. 2003; Bierne and Eyre-Walker 2004; Andolfatto 2005; Welch 2006). However, little is known about the associated selection coefficients (s) of beneficial amino acid mutations. This is an important quantity in population genetics, as the magnitude of s determines the efficacy of natural selection relative to genetic drift in incorporating beneficial mutations and our ability to detect positive selection in genome scans using closely linked neutral sites (Andolfatto 2001; Eyre-Walker 2006). Models of genetic hitchhiking predict that regions closely linked to sites experiencing positive selection should harbor reduced levels of neutral polymorphism (Maynard Smith and Haigh 1974; Kaplan et al. 1989; Wiehe and Stephan 1993). In Drosophila melanogaster, levels of diversity are reduced in regions of the genome with low rates of crossing-over, suggesting an interaction between selection and linkage (Aguade et al. 1989; Berry et al. 1991; Begun and Aquadro 1992). The correlation between levels of diversity and recombination rate has been used to estimate the frequency and strength of positive selection under a recurrent hitchhiking model (Wiehe and Stephan 1993; Stephan 1995; Kim and Stephan 2000; Andolfatto 2001; Innan and Stephan 2003; Eyre-Walker 2006; Kim 2006). However, as pointed out by Charlesworth et al. (1993), a similar relationship between levels of diversity and recombination rates is predicted by the effects of recurrent deleterious mutations—the so called “background selection” effect. The relative importance of recurrent hitchhiking and background selection has been vigorously debated (for review, see Andolfatto 2001), and attempts to distinguish between these models continue to prove difficult (Braverman et al. 1995, 2005; Zurovcova and Eanes 1999; Kim and Stephan 2000; Langley et al. 2000; Andolfatto and Przeworski 2001; Carr et al. 2001; Jensen et al. 2002; Innan and Stephan 2003; but see Bachtrog 2004). This difficulty largely arises from the fact that the predictions of two models can be quite similar (Charlesworth et al. 1995; Gordo et al. 2002), depending on the precise values of parameters (such as recombination rates and the distribution of selection coefficients) that are generally not known. A further difficulty arises from the recent finding that a large fraction of noncoding sites in the Drosophila genome shows evidence for being under direct selection (Andolfatto 2005; Bachtrog and Andolfatto 2006), calling into question the suitability of noncoding DNA as neutral sites from which to estimate selection parameters at linked sites. If adaptive turnover of amino acids is common, more rapidly evolving genes are expected to harbor lower levels of linked synonymous site diversity due to hitchhiking effects associated with linked beneficial amino acid substitutions. I document such a pattern in D. melanogaster, and I use a maximum likelihood approach to estimate parameters of adaptive protein evolution under a recurrent hitchhiking model. I then discuss several alternative linkage-selection models that may predict a similar correlation between levels of synonymous diversity and rates of amino acid evolution.