Weak selection and recent mutational changes influence polymorphic synonymous mutations in humans

Abstract

Recent large-scale genomic and evolutionary studies have revealed the small but detectable signature of weak selection on synonymous mutations during mammalian evolution, likely acting at the level of translational efficacy (i.e., translational selection). To investigate whether weak selection, and translational selection in particular, plays any role in shaping the fate of synonymous mutations that are present today in human populations, we studied genetic variation at the polymorphic level and patterns of evolution in the human lineage after human-chimpanzee separation. We find evidence that neutral mechanisms are influencing the frequency of polymorphic mutations in humans. Our results suggest a recent increase in mutational tendencies toward AT, observed in all isochores, that is responsible for AT mutations segregating at lower frequencies than GC mutations. In all, however, changes in mutational tendencies and other neutral scenarios are not sufficient to explain a difference between synonymous and noncoding mutations or a difference between synonymous mutations potentially advantageous or deleterious under a translational selection model. Furthermore, several estimates of selection intensity on synonymous mutations all suggest a detectable influence of weak selection acting at the level of translational selection. Thus, random genetic drift, recent changes in mutational tendencies, and weak selection influence the fate of synonymous mutations that are present today as polymorphisms. All of these features, neutral and selective, should be taken into account in evolutionary analyses that often assume constancy of mutational tendencies and complete neutrality of synonymous mutations.

Fig. 1.

Frequency (f) and Fay–Wu's H statistic of polymorphic synonymous mutations in humans. P, U, and N mutations define changes from a nonfavored to a favored codon (26), from a favored to a nonfavored codon, and between two nonfavored codons, respectively. U-GC and U-AT describe U mutations that are GC or AT, respectively.

Fig. 2.

Frequency (f) of GC and AT derived mutations in noncoding sequences and at synonymous sites in coding sequences. Probabilities are based on the nonparametric Mann–Whitney U test.

Fig. 3.

Comparison between the frequency of GC-ending favored and GC-ending nonfavored codons in genes located in different isochores.

Fig. 4.

Estimates of the ratio of polymorphism to divergence (rpd) for P (rpd_P) and U (rpd_U) mutations (a) and selection intensity on synonymous mutations based on rpd (γ_rpd) and 95% confidence intervals (b) in different isochores. Estimates of γ_rpd and 95% confidence intervals were obtained by using the mkrpf program (85).

Fig. 5.

Observed change in the frequency of favored codons (P) and synonymous GC content (SynGC) in the human lineage after human–chimpanzee separation. Results are shown for different isochores, using only codons with a single synonymous mutation among the human–chimpanzee–mouse comparison and after removing CpG dinucleotides. Changes are assigned to the human lineage by using chimpanzee and mouse orthologous sequences.