Molecular Biology Reports

, Volume 40, Issue 5, pp 3829–3834 | Cite as

Ovine forkhead box class O 3 (FOXO3) gene variation and its association with lifespan

  • Seung Ok Byun
  • Rachel H. Forrest
  • Huitong Zhou
  • Chris M. Frampton
  • Jon G. H. Hickford


FOXO3 is a member of the FOXO (forkhead box class O) transcription factor family and has roles in cell cycle control, apoptosis, neural and hematopoietic cell differentiation and DNA repair among other functions. Several human studies provide evidence for an association between aging, longevity and variation in FOXO3. Recently variation has been identified in exon 2 of ovine FOXO3. This exon encodes the C-terminus of the DNA-binding domain and a transcription activation domain that is the key regulator of transcriptional activity in target genes. The association of genetic variation in exon 2 with lifespan was investigated in 1,732 New Zealand (NZ) sheep. Of the seven haplotypes detected, the presence of the D haplotype, which codes for an amino acid substitution (a conserved methionine residue is replaced by a valine) at residue 407, is associated with a decrease of 0.39 years in mean age (P = 0.034). Significant differences in mean age were also detected between genotypes containing D (AD: 4.7 ± 0.21; BD: 4.7 ± 0.25) and genotypes that did not contain D (AA: 5.1 ± 0.14; AB: 4.9 ± 0.18; BB: 5.3 ± 0.25). Other genotypes were rare in the sheep investigated and were not analyzed. This suggests that genetic variation in ovine FOXO3 influences the lifespan of sheep either directly or indirectly by impacting on factors that lead to reduced productivity and increased likelihood of culling.


FOXO3 Variation PCR-SSCP Sheep Lifespan Fertility 



This work was supported by the Lincoln University Gene-Marker Laboratory.

Conflict of interest

None for all authors.


  1. 1.
    Kaestner KH, Knochel W, Martinez DE (2000) Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 14:142–146PubMedGoogle Scholar
  2. 2.
    Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (1998) Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 47:187–199PubMedCrossRefGoogle Scholar
  3. 3.
    Carlsson P, Mahlapuu M (2002) Forkhead transcription factors: key players in development and metabolism. Dev Biol 250:1–23PubMedCrossRefGoogle Scholar
  4. 4.
    Wang F, Marshall CB, Yammanoto K, Li GY, Plevin M, You H, Mak TW, Ikura M (2008) Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J Mol Biol 384:590–603PubMedCrossRefGoogle Scholar
  5. 5.
    Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425PubMedCrossRefGoogle Scholar
  6. 6.
    Barthel A, Schmoll D, Unterman TG (2005) FOXO proteins in insulin action and metabolism. Trends Endocrinol Metab 16:180–183Google Scholar
  7. 7.
    Daitoku H, Fukamizu A (2007) FOXO transcription factors in the regulatory networks of longevity. J Biochem 141:769–774PubMedCrossRefGoogle Scholar
  8. 8.
    Arden KC (2008) FOXO animal models reveal a variety of diverse roles for FOXO transcription factors. Oncogene 27:2345–2350PubMedCrossRefGoogle Scholar
  9. 9.
    Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3a genotype is strongly associated with human longevity. Proc Natl Acad Sci USA 105:13987–13992PubMedCrossRefGoogle Scholar
  10. 10.
    Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci USA 106:2700–2705PubMedCrossRefGoogle Scholar
  11. 11.
    Anselmi C, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, Bellazzi R, Puca AA (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res 12:95–104PubMedCrossRefGoogle Scholar
  12. 12.
    Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18:4897–4904PubMedCrossRefGoogle Scholar
  13. 13.
    Zeng Y, Cheng L, Chen H, Cao H, Hauser ER, Liu Y, Xiao Z, Tan Q, Tian XL, Vaupel JW (2010) Effects of FOXO genotypes on longevity: a biodemographic analysis. J Gerontol A Biol Sci Med Sci 65:1285–1299PubMedCrossRefGoogle Scholar
  14. 14.
    Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell 9:1010–1017PubMedCrossRefGoogle Scholar
  15. 15.
    Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ et al (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8:460–472PubMedCrossRefGoogle Scholar
  16. 16.
    Byun SO, Zhou H, Hickford JG (2011) Characterization of genetic variation in the Forkhead box class O3 gene (FOXO3) in sheep. DNA Cell Biol 30:449–452PubMedCrossRefGoogle Scholar
  17. 17.
    Zhou H, Hickford JGH, Fang Q (2006) A two-step procedure for extracting genomic DNA form dried blood spots on filter paper for polymerase chain reaction amplification. Anal Biochem 354:159–161PubMedCrossRefGoogle Scholar
  18. 18.
    Byun SO, Fang Q, Zhou H, Hickford JGH (2009) An effective method for silver-staining DNA in large numbers of polyacrylamide gels. Anal Biochem 385:174–175PubMedCrossRefGoogle Scholar
  19. 19.
    Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282:30107–30119PubMedCrossRefGoogle Scholar
  20. 20.
    Youngson NA, Vickaryous N, van der Horst A, Epp T, Harten S, Fleming JS, Khanna KK, de Kretser DM, Whitelaw E (2011) A missense mutation in the transcription factor Foxo3a causes teratomas and oocyte abnormalities in mice. Mamm Genome 22:235–248PubMedCrossRefGoogle Scholar
  21. 21.
    Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA (2003) Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301:215–218PubMedCrossRefGoogle Scholar
  22. 22.
    Parmley JL, Chamary JV, Hurst LD (2006) Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers. Mol Bio Evol 23:301–309CrossRefGoogle Scholar
  23. 23.
    Qu HQ, Lawrence SG, Guo F, Majewski J, Polychronakos C (2006) Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms. BMC Genomics 7:213–218PubMedCrossRefGoogle Scholar
  24. 24.
    Donlon TA, Curb JD, He Q, Grove JS, Masaki KH, Rodriguez B, Elliott A, Willcox DC, Willcox BJ (2012) FOXO3 gene variants and human aging: coding variants may not be key players. J Gerontol A Biol Sci Med Sci 67:1132–1139PubMedCrossRefGoogle Scholar
  25. 25.
    Flachsbart F, Möller M, Däumer C, Gentschew L, Kleindorp R, Krawczak M, Caliebe A, Schreiber S, Nebel A (2012) Genetic investigation of FOXO3A requires special attention due to sequence homology with FOXO3B. Eur J Hum Genet. doi: 10.1038/ejhg.2012.83 Google Scholar
  26. 26.
    McGregor BA (2011) Incisor development, wear and loss in sheep and their impact on ewe production, longevity and economics: a review. Small Rumin Res 95:79–87CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Seung Ok Byun
    • 1
  • Rachel H. Forrest
    • 2
  • Huitong Zhou
    • 1
  • Chris M. Frampton
    • 3
  • Jon G. H. Hickford
    • 1
  1. 1.Department of Agricultural Science, Faculty of Agriculture and Life SciencesLincoln UniversityLincolnNew Zealand
  2. 2.Faculty of Health SciencesEastern Institute of TechnologyNapierNew Zealand
  3. 3.Christchurch School of Medicine and Health SciencesChristchurchNew Zealand

Personalised recommendations