α-Actinin-3: Why Gene Loss Is an Evolutionary Gain

Large-scale sequencing of human populations has revealed many regions of the genome that have undergone positive selection during recent human evolution [1]. For most such regions, the genes and the nucleotide variants under selection are challenging to identify, and one can only guess about the cellular and physiological mechanisms. In this issue of PLOS Genetics, Head et al. [2] shed light on this question for one of the most fascinating examples of selection, in part because the variant undergoing selection is a loss-of-function, and in part because it was discovered long before the human genome sequence was completed. Originally identified during a search for muscular dystrophy defects [3], deficiency of α-actinin-3 later turned out to be surprisingly common [4]. Roughly 18% of the world population is homozygous for a nonsense mutation (R577X) in ACTN3 deficiency, and the derivative allele (ACTN3 577xx) frequency correlates with greater latitude and lower temperature [5]. There is an intriguing correlation with athletic performance—the derivative allele is overrepresented among elite marathoners and other endurance athletes, but underrepresented among elite sprinters—indeed, the ancestral allele has been referred to as “the gene for speed” [6]. The evidence for positive selection of the derivative allele in European and East Asian populations is strong, but the phenotype being selected is uncertain and the underlying cell biology is even less clear. The article by Head et al. [2] provides some clarity and, together with earlier work from our group (Bruton et al. [7]), a unifying hypothesis.