ACTN3 allele frequency in humans covaries with global latitudinal gradient

Abstract

A premature stop codon in ACTN3 resulting in α-actinin-3 deficiency (the ACTN3 577XX genotype) is common in humans and reduces strength, muscle mass, and fast-twitch fiber diameter, but increases the metabolic efficiency of skeletal muscle. Linkage disequilibrium data suggest that the ACTN3 R577X allele has undergone positive selection during human evolution. The allele has been hypothesized to be adaptive in environments with scarce resources where efficient muscle metabolism would be selected. Here we test this hypothesis by using recently developed comparative methods that account for evolutionary relatedness and gene flow among populations. We find evidence that the ACTN3 577XX genotype evolved in association with the global latitudinal gradient. Our results suggest that environmental variables related to latitudinal variation, such as species richness and mean annual temperature, may have influenced the adaptive evolution of ACTN3 577XX during recent human history.

Figure 1. Human population phylogeny and relationship between ACTN3 577XX frequency and latitude.

A, The Bayesian posterior consensus tree for the human populations used in this study (inferred from whole mitochondrial sequences). The numbers on the branches indicate the proportion of trees in the posterior distribution that contain a given clade. Branch lengths are in the number of changes per site. B, The relationship between ACTN3 577XX genotype frequency and latitude. The generalized linear mixed model that accounts for both phylogenetic relatedness and migration is arcsin(ACTN3XX) = 0.035–0.003 *Latitude (p-value for slope = 0.06).