title: Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans.
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.
authors.affiliation: Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Jane T
authors.initials: JT
authors.lastname: Seto
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Raftery
authors.forename: Kate G
authors.initials: KG
authors.lastname: Quinlan
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Huttley
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Hook
authors.forename: Frances A
authors.initials: FA
authors.lastname: Lemckert
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kee
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
authors.forename: Yemima
authors.initials: Y
authors.lastname: Berman
authors.forename: Edna C
authors.initials: EC
authors.lastname: Hardeman
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gunning
authors.forename: Simon
authors.initials: S
authors.lastname: Easteal
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000502:physiology; D000483:Alleles; D000818:Animals; D044466:Asian People; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism*; D010807:Physical Endurance / Q000235:genetics; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D044465:White People