Population Genetics of Fluctuating Selection among Individuals (FSI): a New Paradigm of Molecular Evolution

Abstract The FSI (fluctuating selection among individuals) theory of population genetics postulates that the fitness effect of a mutation may fluctuate among individuals with the same genotype (heterozygote or homozygote), whereas the wildtype fitness remains a constant. We conducted a comprehensive population genetic analysis and demonstrated profound impacts on the current wisdom of population genetics and molecular evolution. First, genetic drift induced by FSI, FSI-genetic drift for short, may play an important role in molecular evolution when the N e -genetic drift is weak, i.e., the effective population size is not very small. Second, FSI toppled the golden-standard of neutrality in molecular evolution: the substitution rate equals to the mutation rate if and only if the mutation is strictly neutral. Instead, the concept of selection-duality claims that, under FSI, slightly beneficial mutations may be subject to a negative selection, resulting in a substitution rate less than the mutations rate. Consequently, there are three types of neutrality under FSI: the fixation neutrality (substitution rate equals to mutation rate), the generic neutrality (the population mean of selection coefficient is zero), and the FSI-neutrality (the midpoint of fixation neutrality and generic neutrality). Intriguingly, our theoretical analysis shows that the null hypothesis (α = 0) of MacDonald-Kreitman (MK) test exactly corresponds to the FSI-neutrality. Rejection of the null that, say, favors the alternative α > 0, could lead to two interpretations: when the observed α is below a threshold, the selection-duality is favored; otherwise an adaptive evolution is favored. We calculated the threshold for several mammals (human, macaque, lemur and vole), and found that all those observed α values (from 3.5% to 29%) were below the threshold and so they be interpreted by the selection duality rather than adaptive evolution.