ACTN3 has often been called “The Sprint Gene,” and for good reason. Out of the entire realm of Sports Genetics the ACTN3 variant that results in a non-functional protein has received some of the most intense research. Early studies in Olympic level sprinters showed that virtually 100% of them had at least one functional copy. It was worth a publication all its own when a genetic study discovered a single Olympic level hurdler from Spain who was homozygous for the non-functional, or null allele.
While the majority of individuals have at least one functional copy of ACTN3, which is all that is typically needed to be a sprinter, there has been some interesting research pointing to signals of positive natural selection within some populations of humans on the null allele.
So what does ACTN3 do? ACTN3, or alpha-actinin-3 is a major component of what are known as ‘fast-twitch’ muscle fibers. In all muscles, the muscle fibers are made up of long tubes called myofibrils. These fibrils are themselves composed of filaments. There are two types of filaments in muscle fibrils: actin (thin filament) and myosin (thick filament). These filaments are parallel to one another. Other proteins interacting with the filaments pull them past one another, creating muscle contractions.
Actin Filament made up of individual subunits. “Actin filament atomic model” by Thomas Splettstoesser — Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons — http://tinyurl.com/nn6vplt
Individual actin subunits, which make up the actin filament, are stabilized by actin-binding proteins (actinins). Actinin 2 (ACTN2)and Actinin 3 are the main types, with Actinin 2 expressed in all skeletal muscle types and Actinin 3 found only in fast-twitch fibers. Fast-twitch fibers fire quickly and generate more force compared to slow-twitch fibers; however, slow-twitch fibers are much more efficient in their use of oxygen to generate energy. And it is this energy-efficiency that is key in natural selection acting on the ACTN3 null mutation in some human populations.
Even as far back as the original “speed gene” studies on ACTN3, the implication of positive benefits to the loss of ACTN3 has been there. MacArthur et al (2007) initially showed that the region of the genome around the ACTN3 gene showed a low level of genetic variation in populations of European or East Asian descent, which is consistent with positive selection in those groups. They also created a mouse model completely lacking ACTN3 and showed a shift in muscle metabolism towards more efficient aerobic pathways. Mice without ACTN3 appeared basically identical to their ACTN3 wild-type counterparts, including their muscles (under the miscroscope). There was no apparent reduction in fast fibers and there was also an increase in expression of ACTN2. This matched with other observations in humans, which indicates that ACTN2 expression is increased when ACTN3 is absent, and functionally compensates by being incorporated into fast-twitch fibers where it is not normally found. Additional work showed that the loss of ACTN3 doesn’t decrease the amount of fast-twitch muscle fibers, but because these fast-twitch fibers use ACTN2 instead of ACTN3, the metabolism that happens within the fibers is altered, with a shift towards more aerobic pathways, which are better for endurance performance.
Other work has been done over the years on both the evolutionary and molecular aspects of this story. Friedman et al (2013) showed that the signal of positive selection in human populations was correlated with the latitude those populations live (or historically lived) in. Their models explained this correlation basically as a one of resource-richness and temperature. As you move from the tropics to the poles average annual temperature decreases, as does the overall food resources available. Positive selection in these circumstances would favour more energy-efficient metabolisms. Amorim et al (2015) found similar results, although they notice that the highest frequencies of the null variant are observed in the Americas. Their results were only statistically significant for those of European and Asian descent. It is likely that the existing public population data for the Americas, which contains many groups with mixed ancestry, simply created problems in the analysis for that group.
On the molecular side, recent work by Head et al (2015) ties some of this molecular favourability to how Calcium signalling occurs in these muscle fibers, in a manner similar to that seen during exposure to the cold or as a result of endurance training. This cold exposure hypothesis dovetails nicely with the observed correlations with latitude and may explain positive selection for the null variant as an adaptation to cold exposure. The increased metabolic efficiency further supports the hypothesis that the null genotype in humans may also be favourable for endurance performance, although the results of direct association analyses have been conflicting in that area.
Even for the most studied of the “sports genes” there is still plenty to learn about exactly how they work in terms of molecular biology and human physiology. This marker in ACTN3 is one of many markers reported on in the context of Sport’s Genetics at Athletigen.