MacArthur Daniel G, Seto Jane T, Raftery Joanna M, Quinlan Kate G, Huttley Gavin A, Hook Jeff W, Lemckert Frances A, Kee Anthony J, Edwards Michael R, Berman Yemima, Hardeman Edna C, Gunning Peter W, Easteal Simon, Yang Nan, North Kathryn N
Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
Nat Genet. 2007 Oct;39(10):1261-5. doi: 10.1038/ng2122. Epub 2007 Sep 9.
More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism.
据预测，全球超过10亿人由于ACTN3基因中一个过早的终止密码子多态性R577X的纯合性，完全缺乏快肌纤维蛋白α-辅肌动蛋白-3。R577X多态性与精英运动员身份和人类肌肉表现相关，这表明α-辅肌动蛋白-3缺乏会影响快肌纤维的功能。在此我们表明，在基因敲除小鼠模型中α-辅肌动蛋白-3表达缺失会导致肌肉代谢向更高效的有氧途径转变，并提高内在耐力表现。此外，我们证明，在欧洲和东亚血统个体中，577X无效等位基因周围的基因组区域显示出低水平的遗传变异和重组，这与近期强烈的正选择一致。我们提出，577X等位基因由于其对骨骼肌代谢的影响，在一些人类群体中受到了正选择。
