R577X polymorphism of alpha-actinin-3 in human populations of North-Eastern Asia

Cover Page

Abstract


Background. In polymorphism rs1815739, a C → T transition converts arginine to a premature stop-codon at residue 577 of the alpha-actinin-3 (ACTN3) protein (R577X polymorphism). This polymorphism may affect muscle performance, and the derived 577X allele has been found to be under-represented in sprint/power athletes. In addition, loss of alpha-actinin-3 results in a shift in muscle metabolism toward the more efficient aerobic pathway, thus pointing that this polymorphism may have been involved in enhancing the capability for hunting and for cold adaptation. Here, we study rs1815739 polymorphism in native populations (Chukchi, Koryaks and Evens) and newcomers (Russians) of North-Eastern Asia.

Materials and methods. Genomic DNA was isolated from peripheral blood. ACTN3 genotypes for rs1815739 locus were established by enzymatic digestion of amplicons with DdeI. Heterozygotes TT were confirmed by DNA sequencing. In addition, data on exome variation in Siberian populations were analyzed.

Results. Lowered frequencies (less than 40%) of “mutant” allele rs1815739-T were found in studied populations of North-Eastern Asia. Analysis of exome data has shown that haplotype comprising the rs1815739-T allele reaches the highest frequencies in populations of Southern and Central Siberia, while it is rather rare in the north-east of Siberia.

Conclusion. The results obtained contradict the hypothesis that the rs1815739 polymorphism may have been involved in cold adaptation of North-East Siberians.


Boris A Malyarchuk

Author for correspondence.
malyarchuk@ibpn.ru
Institute of Biological Problems of the North FEB RAS
Russian Federation, Magadan, Russia

Doctor Biol Sci, Laboratory Head, Genetics Laboratory

Miroslava V Derenko

mderenko@mail.ru
Institute of Biological Problems of the North FEB RAS
Russian Federation, Magadan, Russia

Doctor Biol Sci, Principal Researcher, Genetics Laboratory

Galina A Denisova

gad@ibpn.ru
Institute of Biological Problems of the North FEB RAS
Russian Federation, Magadan, Russia

Candidate Biol Sci, Senior Researcher, Genetics Laboratory

  • Mills M, Yang N, Weinberger R, et al. Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Human Molecular Genetics. 2001;10:1335-1346. doi: 10.1093/hmg/10.13.1335.
  • North KN, Yang N, Wattanasirichaigoon D, et al. A common nonsense mutation results in alpha-actinin-3 deficiency in the general population. Nature Genetics. 1999;21:353-354. doi: 10.1038/7675.
  • Alfred T, Ben-Shlomo Y, Cooper R, et al. ACTN3 genotype, athletic status, and life course physical capability: meta-analysis of the published literature and findings from nine studies. Human Mutation. 2011;9:1008-1018. doi: 10.1002/humu.21526.
  • Yang N, MacArthur DG, Gulbin JP, et al. ACTN3 genotype is associated with human elite athletic performance. American Journal of Human Genetics. 2003;73:627-631. doi: 10.1086/377590.
  • MacArthur DG, Seto JT, Raftery JM, et al. Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nature Genetics. 2007;39:1261-1265. doi: 10.1038/ng2122.
  • Bramble DM, Lieberman DE. Endurance running and the evolution of HomO. Nature. 2004;432:345-352. doi: 10.1038/nature03052.
  • MacArthur DG, North KN. A gene for speed? The evolution and function of alpha-actinin-3. Bioessays. 2004;26:786-795. doi: 10.1002/bies.20061.
  • Schlebusch CM, Skoglund P, Sjödin P, et al. Genomic variation in seven Khoe-San groups reveals adaptation and complex African history. Science. 2012;338:374-379. doi: 10.1126/science.1227721.
  • Amorim CE, Acuña-Alonzo V, Salzano FM, et al. Differing evolutionary histories of the ACTN3_R577X polymorphism among the major human geographic groups. PLoS ONE. 2015;10(2): e0115449. doi: 10.1371/journal.pone.0115449.
  • Wang S, Lewis CM, Jakobsson M, et al. Genetic variation and population structure in native Americans. PLoS Genetics. 2007;3(11): e185. doi: 10.1371/journal.pgen.0030185.
  • Hofer T, Ray N, Wegmann D, Excoffier L. Large allele frequency differences between human continental groups are more likely to have occurred by drift during range expansions than by selection. Annals of Human Genetics. 2009;73:95-108. doi: 10.1111/j.1469-1809.2008.00489.x.
  • Rasmussen M, Anzick SL, Waters MR, et al. The genome of a Late Pleistocene human from a Clovis burial site in western Montana. Nature. 2014;506:225-229. doi: 10.1038/nature13025.
  • Reich D, Patterson N, Campbell D, et al. Reconstructing Native American population history. Nature. 2012;488:370-374. doi: 10.1038/nature11258.
  • Eynon N, Ruiz JR, Femia P, et al. The ACTN3 R577X polymorphism across three groups of elite male European athletes. PLoS ONE. 2012;7(8):e43132. doi: 10.1371/journal.pone.0043132.
  • Untergasser A, Cutcutache I, Koressaar T, et al. Primer3 – new capabilities and interfaces. Nucleic Acids Research. 2012;40:e115. doi: 10.1093/nar/gks596.
  • Clemente FJ, Cardona A, Inchley CE, et al. A selective sweep on a deleterious mutation in the CPT1A gene in Arctic populations. American Journal of Human Genetics. 2014;95(5):584-589. doi: 10.1016/j.ajhg.2014.09.016.
  • Pagani L, Lawson DJ, Jagoda E, et al. Genomic analyses inform on migration events during the peopling of Eurasia. Nature. 2016;538:238-242. doi: 10.1038/nature19792.
  • Tamura K, Peterson D, Peterson N, et al. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Molecular Biology and Evolution. 2011;28:2731-2739. doi: 10.1093/molbev/msr121.
  • Excoffier L, Laval G, Schneider S. Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evolutionary Bioinformatics Online. 2007;1:47-50. PMCID: PMC2658868.
  • Excoffier L, Laval G, Balding D. Gametic phase estimation over large genomic regions using an adaptive window approach. Hum Genomics. 2003;1:7-19. PMCID: PMC3525008.
  • Pasqua LA, Bueno S, Matsuda M, et al. The genetics of human running: ACTN3 polymorphism as an evolutionary tool improving the energy economy during locomotion. Annals of Human Biology. 2016;43(3):255-260. doi: 10.3109/03014460.2015.1050065.

Views

Abstract - 36

PDF (Russian) - 31


Copyright (c) 2017 Malyarchuk B.A., Derenko M.V., Denisova G.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.