A Genetic Link to Tolerating the Cold

HGNC  · 

Photo: Wellcome Genome Campus in the snow this December, Hinxton UK

ACTN3 Variants and Tolerance to Cold Temperatures

Although some of us may be dreaming of a white Christmas, others are piling on the blankets to keep warm as energy prices continue to skyrocket. We all know someone who seems to not feel the cold as much as the rest of us - those who wear shorts whatever the weather! Do some people have superior cold resilience? A psychological effect has been suggested for the apparent ability of minimally dressed clubbers to resist the cold. But are there also additional genetic factors at play?

The gene ACTN3 (actinin alpha 3) has become pseudogenized in at least 1.5 billion people worldwide, (~16% of the global population and 18% of Caucasians). The functioning copy of this gene encodes for a protein that is only expressed in “fast-twitch” type II muscle fibers.

Human ACTN3 is an example of a segregating pseudogene, also known as a polymorphic pseudogene. This is a gene that is protein coding in some of the population, but is no longer coding in other individuals. In the case of this nonsense polymorphism, a C to T base substitution transforms an arginine (R) into a premature stop codon (X). There are three commonly known genotypes at this locus - individuals can be homozygous (RR or XX) or heterozygous (RX). Individuals with an XX genotype do not have a functioning protein coding copy of ACTN3 and therefore completely lack alpha-actinin 3.

An interesting paper published in 2021 by Wyckelsma et al suggests that as modern humans moved into colder climates, the prevalence of the R577X allele in the population increased. They showed that humans that lack the alpha-actinin 3 protein are better at maintaining their core body temperature when immersed in cold water. The lack of alpha-actinin 3 changes skeletal muscle thermogenesis in the human body. The study found that individuals with a pseudogenised ACTN3 gene displayed an increase in the presence of slow-twitch muscle fiber isoforms of the proteins encoded by MYH2 (myosin heavy chain 2), ATP2 family proteins (alias SERCAs) and the SR calcium storage protein encoded by CASQ2 (calsequestrin 2) (alias CSQ2) in their muscles.

However, a group responding to the Wyckelsma et al paper suggests caution over their hypothesis of there being a strong positive selection for this allele in populations living in colder environments. They state that “Although Wyckelsma et al. provide insightful new physiological evidence on the relationship between R577X and skeletal muscle thermogenesis and core body temperature maintenance, multiple lines of population genetic evidence are more consistent with drift rather than selection behind its global frequency distribution”.

ACTN3 and Athletic Performance

The loss of function mutation in ACTN3 has also been shown to have an effect on muscle performance in top athletes. Elite sprinters appear to have a higher frequency of the protein coding 577R ACTN3 allele when compared to groups of control subjects. There is currently some controversy as to whether the effect is additive, with some studies showing an intermediate phenotype in 577RX individuals but other studies showing no difference between the 577RR and 577RX genotypes.

What about endurance athletes? Well, while Actn3 knockout mice display a reduction in muscle mass and strength, they recover better from fatigue, which might be good for endurance events.

Duchenne muscular dystrophy is linked to a variant of the gene DMD (dystrophin). Interestingly, the ACTN3 R577X polymorphism appears to have some modifying effect on the pathology of patients with Duchenne muscular dystrophy (DMD, OMIM:310200).

Disease onset and progression can be very variable between patients with DMD. Those with the ACTN3 R577X allele show reduced muscle strength earlier, and it takes them longer to walk 10m in a particular clinical test. However, a double knockout mouse model with the alpha-actinin-3 deficiency appeared to experience slower dystrophic progression. Hogarth et al suggest that this protective effect comes from an increase in oxidative muscle metabolism through increased calcineurin activation (PMID:28139640).

Other studies link ACTN3 variants to cardiac health in DMD patients. The 577XX null genotype is associated with a higher risk for left ventricular (LV) dilation in the heart. LV remodeling can be a precursor of clinical heart failure, so the authors suggest that a DMD patient’s ACTN3 genotype should be determined at the time of diagnosis to allow appropriate monitoring and hopefully improve patients’ cardiac outcomes.

Other Polymorphic/Segregating Pseudogenes

As well as ACTN3, there are also many other examples of human polymorphic/segregating pseudogenes. We currently have 41 genes approved with the term “(gene/pseudogene)” included in their gene names to reflect this.

Olfactory receptors (ORs), responsible for our sense of smell are particularly heavily represented as part of this gene set, and are the the largest multigene family in mammals. While differences between individuals in their ability to smell odors can be due to the presence or absence of a protein coding copy of a particular OR, they may also be determined by the particular variant copy of these genes that a person may have. The situation becomes more complex in that several different ORs may determine an individual’s ability to detect a particular scent.

For more about the work of the VGNC in naming ORs together with our specialist advisors, you can read our previous guest post here.

Conclusion

While your ACTN3 gene variant may have an effect on your tolerance of the cold weather, we recommend warm woolly jumpers and hot water bottles for all this winter regardless of your genotype.