Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
Estonian Biocentre, Institute of Genomics, University of Tartu, Riia 23B, Tartu 51010, Estonia; Department of Biology, University of Padova, 35131 Padova, Italy.
Am J Hum Genet. 2022 May 5;109(5):967-972. doi: 10.1016/j.ajhg.2022.03.014.
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), published in The American Journal of Human Genetics. See also the response by Wyckelsma et al. (2022), published in this issue.
结构肌蛋白 ACTN3 中的常见功能丧失突变 R577X 早期研究中被视为潜在的正选择靶点，相关深入的生理学研究也表明其对肌肉代谢有重大影响。适应寒冷气候被认为是解释其全球等位基因频率模式的关键适应机制。在这里，我们通过使用等位基因频率以及单倍型纯合性的方法，重新分析了现代（n=3626）和古代（n=1651）基因组数据，以检验这一假设。本研究的结果更倾向于认为，与寒冷气候选择相比，遗传漂变才是导致全世界人类群体中 ACTN3 R577X 频率分布的主要驱动因素。本文是对 Wyckelsma 等人（2021 年）发表在《美国人类遗传学杂志》上的论文的回应。也可参见 Wyckelsma 等人（2022 年）发表在本期杂志上的回应。
