Response to Wyckelsma et al.: Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation

Abstract

The common loss-of-function mutation R577X in the structural muscle protein ACTN3 emerged as a potential target of positive selection from early studies and has been the focus of insightful physiological work suggesting a significant impact on muscle metabolism. Adaptation to cold climates has been proposed as a key adaptive mechanism explaining its global allele frequency patterns. Here, we re-examine this hypothesis analyzing modern (n = 3,626) and ancient (n = 1,651) genomic data by using allele-frequency as well as haplotype homozygosity-based methods. The presented results are more consistent with genetic drift rather than selection in cold climates as the main driver of the ACTN3 R577X frequency distribution in human populations across the world. This Matters Arising paper is in response to Wyckelsma et al. (2021),¹ published in The American Journal of Human Genetics. See also the response by Wyckelsma et al. (2022),² published in this issue.

Keywords: ACTN3; cold adaptation; loss of function mutations; positive selection.

Figure 1

Locations of origin for modern genetic data World map showing as circles the approximate ancestral coordinates for modern data. Please note that for the 12 macro-groups from the EGDP panel these represent the average of individual locations.

Figure 2

Relationship between ACTN3 R577X allele frequency and latitude (A–F) Dataset obtained from three global panels of human genomes,, , a dataset of Northeast African genomes, and a survey focusing on the ACTN3 R577X allele. The panels show simple linear regressions of ACTN3 LoF allele frequency and latitude globally (A), in Ethiopians and non-Africans (B), in Sub-Saharan Africans (C), in West Eurasians (D), in East Eurasians (E), and in Native Americans (F). The respective correlation coefficients and p values are displayed in the bottom right corner of each panel. In (B) and (C), Ethiopians are represented by a triangle. In (C), Bantu speakers are marked by squares and Khoisan speakers by a diamond. Abbreviations: DAF, derived allele frequency of the ACTN3 R577X allele; LAT, absolute value of latitude in degrees.