Gene density and human nucleotide polymorphism.

Abstract

Population genetics theory indicates that natural selection will affect levels and patterns of genetic variation at closely linked loci. Background selection (Charlesworth, Morgan, and Charlesworth 1993) proposes that the removal of recurrent deleterious mutations and associated neutral variants will cause a reduction of nucleotide variation in low-recombination regions. The strength of background selection depends on the deleterious mutation rate, the magnitude of selection and dominance, and the recombination rate. Genetic hitchhiking (Maynard Smith and Haigh 1974), the fixation of advantageous alleles and the associated fixation of linked neutral alleles, can also decrease nucleotide diversity in low-recombination regions. The extent of genetic hitchhiking depends on the strength of selection and the rate of recombination. Therefore, under both background selection and genetic hitchhiking, theory predicts that genomic regions that rarely recombine may be subject to reductions in nucleotide diversity. Furthermore, if the rate of deleterious mutation or selective sweeps (or both) is sufficiently high, background selection (Hudson and Kaplan 1995) and genetic hitchhiking (Wiehe and Stephan 1993) models predict an overall positive correlation between nucleotide polymorphism and recombination rate. Empirical investigations of nucleotide variation support these predictions. In Drosophila melanogaster, regions of the genome with little recombination show reduced heterozygosity (Aguade, Miyashita, and Langley 1989; Begun and Aquadro 1991; Berry, Ajioka, and Kreitman 1991). Furthermore, there is evidence that nucleotide variation and recombination rate are positively correlated in several taxa, including fruit flies (Begun and Aquadro 1992), house mice (Nachman 1997), goatgrasses (Dvorak, Luo, and Yang 1998), sea beets (Kraft et al. 1998), tomatoes (Stephan and Langley 1998), humans (Nachman et al. 1998; Przeworski, Hudson, and Di Rienzo 2000; Nachman 2001), and maize (Tenaillon et al. 2001). The combination of theoretical and empirical results indicates that selection acting at linked sites is likely to be a major force shaping genomic patterns of nucleotide variation. The documented relationship between nucleotide variation and recombination rate raises the question of whether other measurable variables can explain additional variation in nucleotide polymorphism in the context of selection at linked sites. We predict that the effects of selection at linked sites will depend on local