Differing evolutionary histories of the ACTN3*R577X polymorphism among the major human geographic groups

Abstract

It has been proposed that the functional ACTN3*R577X polymorphism might have evolved due to selection in Eurasian human populations. To test this possibility we surveyed all available population-based data for this polymorphism and performed a comprehensive evolutionary analysis of its genetic diversity, in order to assess the action of adaptive and random mechanisms on its variation across human geographical distribution. The derived 577X allele increases in frequency with distance from Africa, reaching the highest frequencies on the American continent. Positive selection, detected by an extended haplotype homozygosisty test, was consistent only with the Eurasian data, but simulations with neutral models could not fully explain the results found in the American continent. It is possible that particularities of Native American population structure could be responsible for the observed allele frequencies, which would have resulted from a complex interaction between selective and random factors.

Fig 1. Demographic models used for the coalescent simulations: A—population split at T₂ with two derived populations of the same size; B—population split at T₂ with two derived populations with ratio between their effective population sizes (N_EF) equal to 0.15; C—population split at T₂ with two derived populations with the ratio between their N_EFs equal to 0.06 at T₂ and 0.15 presently (T₀); D—same as model B, but with population substructure arising at T₁ in both derived populations; E—same as model C, but with population substructure arising at T₁ in both derived populations.

The number of demes depicted does not correspond to the actual simulations. For further details see methods section.

Fig 2. Relative extended haplotype homozygosity (REHH) for 30 SNPs located at a distance described in the X-axis from ACTN3 rs1815739 spanning circa 510 kb.

The orange line represents the homozygosity of the flanking SNPs relative to rs1815739 for haplotypes carrying the derived 577X allele, while the red line represents the same for haplotypes carrying the ancestral allele (i.e. for Asia, REHH indicates that extended haplotype homozygosity-EHH, considering 577X-bearing chromosomes, is about 5.5 times greater than the average EHH of the others bearing R577). A: Asian; B: European; and C: American data.