Adaptive evolution in humans revealed by the negative correlation between the polymorphism and fixation phases of evolution

Abstract

The selective forces acting on amino acid substitutions may be different in the two phases of molecular evolution: polymorphism and fixation. Negative selection and genetic drift may dominate the first phase, whereas positive selection may become much more significant in the second phase. However, the conventional dichotomy of synonymous vs. nonsynonymous changes does not offer the resolution needed to study the dynamics of these two phases. Following previously published methods, we separated amino acid changes into 75 elementary types (1-bp substitution between their respective codons). The likelihood of each type of amino acid change becoming polymorphic (PI, which stands for "polymorphic index"), relative to synonymous changes, can then be calculated. Similarly, the likelihood of fixation (FI, for "fixation index"), conditional on common polymorphisms, is also calculated. Using Perlegen and HapMap data on human polymorphisms and the chimpanzee sequences as the outgroup, we compared the evolutionary dynamics of the 75 elementary changes in the two phases. We found a strong "L-shaped" negative correlation (P < 0.001) between FI and PI. Only those changes with low PIs show FI > 1, which is often a signature of adaptive evolution. These patterns suggest that negative and positive selection operate more effectively on the same set of amino acid changes and that approximately 10-13% of amino acid substitutions between humans and chimpanzee may be adaptive.

Fig. 1.

A/S ratios partitioned by the frequency of the SNPs. The observed A and S as well as the expected S are also given. In the far right is the divergence between human and chimpanzee. The expected S for each frequency class is calculated on the assumption of neutral equilibrium, with the total being equal to the observed. In neutral equilibrium, the expected number of mutations that are observed i times in the sample is proportional to 1/i. (a) Perlegen data. (b) HapMap data.

Fig. 2.

The observed FIs for the 75 elementary amino acid changes in the Perlegen data as a function of the physicochemical distance (Grantham's distance, ref. 22) between amino acid pairs. Note the absence of any correlation.

Fig. 3.

Correlation between FI and PI among the 75 elementary amino acid changes. Points inside the dashed box have FI values that are statistically higher than the rest, which have the same FI, indicated by the horizontal dashed line. (a) Perlegen data. (b) HapMap data. Note that only changes with low PI have high FI values.