A genetic variant makes humans to either survive cold or run fast.
Yesterday, I came across a fascinating paper, which reports that a protein truncating variant in ACTN3 in the homozygous state (i.e. complete knockout of the protein) is extremely common worldwide. It seems there are around 1.2 billion human knockouts for ACTN3 worldwide. 1.2 billion! (That is the number of humans living in India). If you’re wondering why this null variant became so common, there’s an extremely fascinating reason for that.
The gene ACTN3 codes for alpha-actinin-3, a muscle protein that is present only in the fast-twitching skeletal muscle. There are two skeletal muscle types--type 1 or slow twitching and type 2 or fast twitching. While the fast twitching muscle is used for rapid contractions that lasts for short duration (used during sprinting), the slow twitching muscle is used for sustained contraction that lasts for longer duration (used during endurance activities).
In the current paper, the authors show that individuals with the null mutation (XX) withstand cold for longer duration than individuals without the null mutation (RR). The authors immersed 15 XX and 27 RR individuals in cold water for around 2 hrs (with multiple 10 mins breaks,) and tested how many were able to maintain their core body temperature (measured from rectal temperature) above 35.5 degree Celsius. While only 30% of RR individuals maintained their core body temperature, around 70% of XX individuals did the same. That is a large difference. The authors didn’t explicitly mention any effect size estimate. But I calculated a crude estimate of OR-4.75 by making a 2x2 table from their data. That’s a large effect size, and it makes sense given that they were able to show a significant association in such an extremely small sample size.
It seems that this beneficial effect (ability to tolerate cold for long) has led to the positive selection of this null mutation. The authors speculate that the mutation must have provided the ancestral humans who migrated out of Africa a survival advantage against harsh cold climates.
Interestingly, the same mutation leads to decreased athletic ability, specifically sprinting ability (sprinting requires fast twitching muscle, which the XX individuals cannot use). A previous paper shows that the XX genotype is underrepresented in elite sprint athletes. Again, I crudely calculated the effect size by making 2x2 table comparing only XX and RR genotype individuals (to make the effect sizes comparable between the two studies,) and found that the effect size is OR-0.18 (inverse OR-5.5), which is similar but opposite in direction to the XX’s effect size for cold tolerance (OR-4.75).
Fascinating isn’t it? While the mutation gives you the ability to tolerate cold, the same mutation robs you of the ability to run fast. This is an evolutionary tradeoff. I couldn’t stop noticing that XX’s effect sizes for cold tolerance and being a sprint athlete is similarly large, but opposite in direction. While the authors discuss about the evolutionary advantage of XX genotype, they don’t talk anything about RR genotype. But XX and RR genotypes are equally common. So, there should be a reason why RR didn’t vanish in time. I wonder if RR genotype too gave our ancestors a survival advantage. Ability to run fast might have saved our ancestors from falling prey to animals, or perhaps, helped them to hunt animals effectively and escape from starvation. I can only speculate. Who knows, probably a new paper in the future will shed more light on this story.
