Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans - PubMed (original) (raw)
. 2007 Oct;39(10):1261-5.
doi: 10.1038/ng2122. Epub 2007 Sep 9.
Jane T Seto, Joanna M Raftery, Kate G Quinlan, Gavin A Huttley, Jeff W Hook, Frances A Lemckert, Anthony J Kee, Michael R Edwards, Yemima Berman, Edna C Hardeman, Peter W Gunning, Simon Easteal, Nan Yang, Kathryn N North
Affiliations
- PMID: 17828264
- DOI: 10.1038/ng2122
Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans
Daniel G MacArthur et al. Nat Genet. 2007 Oct.
Abstract
More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism.
Similar articles
- Why is alpha-actinin-3 deficiency so common in the general population? The evolution of athletic performance.
North K. North K. Twin Res Hum Genet. 2008 Aug;11(4):384-94. doi: 10.1375/twin.11.4.384. Twin Res Hum Genet. 2008. PMID: 18637739 - Altered Ca2+ kinetics associated with α-actinin-3 deficiency may explain positive selection for ACTN3 null allele in human evolution.
Head SI, Chan S, Houweling PJ, Quinlan KG, Murphy R, Wagner S, Friedrich O, North KN. Head SI, et al. PLoS Genet. 2015 Jan 15;11(2):e1004862. doi: 10.1371/journal.pgen.1004862. eCollection 2015. PLoS Genet. 2015. PMID: 25590636 Free PMC article. - Analysis of the ACTN3 heterozygous genotype suggests that α-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion.
Hogarth MW, Garton FC, Houweling PJ, Tukiainen T, Lek M, Macarthur DG, Seto JT, Quinlan KG, Yang N, Head SI, North KN. Hogarth MW, et al. Hum Mol Genet. 2016 Mar 1;25(5):866-77. doi: 10.1093/hmg/ddv613. Epub 2015 Dec 17. Hum Mol Genet. 2016. PMID: 26681802 Free PMC article. - A gene for speed: the emerging role of alpha-actinin-3 in muscle metabolism.
Berman Y, North KN. Berman Y, et al. Physiology (Bethesda). 2010 Aug;25(4):250-9. doi: 10.1152/physiol.00008.2010. Physiology (Bethesda). 2010. PMID: 20699471 Review. - Is evolutionary loss our gain? The role of ACTN3 p.Arg577Ter (R577X) genotype in athletic performance, ageing, and disease.
Houweling PJ, Papadimitriou ID, Seto JT, Pérez LM, Coso JD, North KN, Lucia A, Eynon N. Houweling PJ, et al. Hum Mutat. 2018 Dec;39(12):1774-1787. doi: 10.1002/humu.23663. Epub 2018 Nov 8. Hum Mutat. 2018. PMID: 30281865 Review.
Cited by
- Association between Complex ACTN3 and ACE Gene Polymorphisms and Elite Endurance Sports in Koreans: A Case-Control Study.
Chae JH, Eom SH, Lee SK, Jung JH, Kim CH. Chae JH, et al. Genes (Basel). 2024 Aug 23;15(9):1110. doi: 10.3390/genes15091110. Genes (Basel). 2024. PMID: 39336701 Free PMC article. - SVhawkeye: an ultra-fast software for user-friendly visualization of targeted structural fragments from BAM files.
Xiao Y, Yu T, Liang F, Hou T. Xiao Y, et al. Front Genet. 2024 Apr 24;15:1352443. doi: 10.3389/fgene.2024.1352443. eCollection 2024. Front Genet. 2024. PMID: 38721473 Free PMC article. - A Systematic Review and Meta-analysis of the Association Between ACTN3 R577X Genotypes and Performance in Endurance Versus Power Athletes and Non-athletes.
El Ouali EM, Barthelemy B, Del Coso J, Hackney AC, Laher I, Govindasamy K, Mesfioui A, Granacher U, Zouhal H. El Ouali EM, et al. Sports Med Open. 2024 Apr 12;10(1):37. doi: 10.1186/s40798-024-00711-x. Sports Med Open. 2024. PMID: 38609671 Free PMC article. - rs67047829 genotypes of ERV3-1/ZNF117 are associated with lower body mass index in the Polish population.
Clark JSC, Podsiadło K, Sobalska-Kwapis M, Marciniak B, Rydzewska K, Ciechanowicz A, van de Wetering T, Strapagiel D. Clark JSC, et al. Sci Rep. 2023 Oct 10;13(1):17118. doi: 10.1038/s41598-023-43323-3. Sci Rep. 2023. PMID: 37816715 Free PMC article. - Genome-wide association study on coordination and agility in 461 Chinese Han males.
Wang Y, Li H, Hou L, Wang S, Kang X, Yu J, Tian F, Ni W, Deng X, Liu T, You Y, Chen W. Wang Y, et al. Heliyon. 2023 Aug 18;9(8):e19268. doi: 10.1016/j.heliyon.2023.e19268. eCollection 2023 Aug. Heliyon. 2023. PMID: 37654465 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases