BACKGROUND: Longevity-related genes have been found in several animal species as well as in humans. The goal of this study was to perform genetic analysis of long-lived Cane corso dogs with the aim to find genes that are associated with longevity. RESULTS: SNPs with particular nucleotides were significantly overrepresented in long-lived dogs in four genes, TDRP, MC2R, FBXO25 and FBXL21. In FBXL21, the longevity-associated SNP localises to the exon. In the FBXL21 protein, tryptophan in long-lived dogs replaced arginine present in reference dogs. CONCLUSIONS: Four SNPs associated with longevity in dogs were identified using GWAS and validated by DNA sequencing. We conclude that genes TDRP, MC2R, FBXO25 and FBXL21 are associated with longevity in Cane corso dogs.

Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 142 20 Prague 4 Czech Republic

Zoologická zahrada Tábor a s Dukelských Hrdinů 19 170 00 Prague 7 Czech Republic

Zobrazit více v PubMed

Arne S, Bens M, Szafranski K, Holtze S, Groth M, Görlach M, Calkhoven C, et al. Long-lived rodents reveal signatures of positive selection in genes associated with lifespan. PLoS Genet. 2018;14(3):1–22. doi: 10.1371/journal.pgen.1007272. PubMed DOI PMC

Singh PP, Demmitt BA, Nath RD, Brunet A. The genetics of aging: a vertebrate perspective. Cell. 2019;177(1):200–220. doi: 10.1016/j.cell.2019.02.038. PubMed DOI PMC

Christensen K, Vaupel JW. Determinants of longevity: genetic, environmental and medical factors. J Intern Med. 1996;240(6):333–341. doi: 10.1046/j.1365-2796.1996.d01-2853.x. PubMed DOI

Gravina S, Vijg J. Epigenetic factors in aging and longevity. Pflugers Arch - Eur J Physiol. 2010;459(2):247–258. doi: 10.1007/s00424-009-0730-7. PubMed DOI

Shadyab AH, LaCroix AZ. Genetic factors associated with longevity: A review of recent findings. Ageing Res Rev. 2015;19:1–7. doi: 10.1016/j.arr.2014.10.005. PubMed DOI

Pilling LC, Kuo C-L, Sicinski K, Tamosauskaite J, Kuchel GA, Harries LW, Herd P, Wallace R, Ferrucci L, Melzer D. Human longevity: 25 genetic loci associated in 389,166 UK biobank participants. Aging. 2017;9(12):2504–2520. doi: 10.18632/aging.101334. PubMed DOI PMC

Liu X, Song Z, Li Y, Yao Y, Fang M, Bai C, et al. Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15,651 Chinese individuals. Aging Cell. 2021;20(3):e13323. 10.1111/acel.13323. PubMed PMC

Hédan B, Cadieu É, Rimbault M, Vaysse A, Dufaure de Citres C, et al. Identification of common predisposing loci to hematopoietic cancers in four dog breeds. PLoS Genet. 2021;17(4):e1009395. doi: 10.1371/journal.pgen.1009395. PubMed DOI PMC

Wang S, Strandberg E, Arvelius P, et al. Genome-wide association studies for canine hip dysplasia in single and multiple populations – implications and potential novel risk loci. BMC Genomics. 2021;22:636. doi: 10.1186/s12864-021-07945-z. PubMed DOI PMC

Sanz CR, Sevane N, Pérez-Alenza MD, Valero-Lorenzo M, Dunner S. Polymorphisms in canine immunoglobulin heavy chain gene cluster: a double-edged sword for diabetes mellitus in the dog. Anim Genet. 2021;52(3):333–341. doi: 10.1111/age.13047. PubMed DOI

Boyko AR. The domestic dog: man’s best friend in the genomic era. Genome Biol. 2011;12(2):216. doi: 10.1186/gb-2011-12-2-216. PubMed DOI PMC

Karlsson EK, Lindblad-Toh K. Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet. 2008;9(9):713–725. doi: 10.1038/nrg2382. PubMed DOI

Jónás D, Sándor S, Tátrai K, Egyed B, Kubinyi E. A Preliminary Study to Investigate the Genetic Background of Longevity Based on Whole-Genome Sequence Data of Two Methuselah Dogs. Front Genet. 2020;11:315. 10.3389/fgene.2020.00315. PubMed PMC

Doherty A, Lopes I, Ford CT, Monaco G, Guest P, de Magalhães JP. A scan for genes associated with cancer mortality and longevity in pedigree dog breeds. Mamm Genome. 2020;0123456789. 10.1007/s00335-020-09845-1. PubMed PMC

Korec E, Chalupa O, Hančl M, Korcová J, Bydžovská M. Longevity of Cane Corso Italiano dog breed and its relationship with hair colour. Open Vet J. 2017;7(2):170. doi: 10.4314/ovj.v7i2.15. PubMed DOI PMC

O’Neill D, Church D, McGreevy P, Thomson P, Brodbelt D. Longevity and mortality of owned dogs in England. Vet J. 2013;198(3):638–643. doi: 10.1016/j.tvjl.2013.09.020. PubMed DOI

Fleming JM, Creevy KE, Promislow DEL. Mortality in North American dogs from 1984 to 2004: an investigation into age-, size-, and breed-related causes of death. J Vet Intern Med. 2011;25(2):187–198. doi: 10.1111/j.1939-1676.2011.0695.x. PubMed DOI

Galis F, Van Der Sluijs I, Van Dooren TJM, Metz JAJ, Nussbaumer M. Do large dogs die young? J Exp Zool B Mol Dev Evol. 2007;308B(2):119–126. doi: 10.1002/jez.b.21116. PubMed DOI

Kraus C, Pavard S, Promislow DEL. The Size–Life Span Trade-Off Decomposed: Why Large Dogs Die Young. Am Nat. 2013;181(4):492–505. doi: 10.1086/669665. PubMed DOI

Adams V, Watson P, Carmichael S, Gerry S, Penell J, Morgan D. Exceptional longevity and potential determinants of successful ageing in a cohort of 39 Labrador retrievers: results of a prospective longitudinal study. Acta Vet Scand. 2015;58(1):29. 10.1186/s13028-016-0206-7. PubMed PMC

King MD. Etiopathogenesis of Canine Hip Dysplasia, Prevalence, and Genetics. Vet Clin N Am Small Anim Pract. 2017;47(4):753–767. doi: 10.1016/j.cvsm.2017.03.001. PubMed DOI

Korec E, Hančl M, Bydžovská M, Chalupa O, Korcová J. Segregation Analysis of Canine Hip Dysplasia in Cane Corso Italiano Dogs. Appro Poult Dairy Vet Sci. 2018;2(3) APDV.000539.2018. DOI

Bartolomé N, Segarra S, Artieda M, Francino O, Sánchez E, Szczypiorska M, Casellas J, Tejedor D, Cerdeira J, Martínez A, Velasco A, Sánchez A. A genetic predictive model for canine hip dysplasia: integration of Genome Wide Association Study (GWAS) and candidate gene approaches. PLoS One. 2015;10(4):e0122558. doi: 10.1371/journal.pone.0122558. PubMed DOI PMC

Korec E, Hančl M, Bydžovská M, Chalupa O, Korcová J. Inheritance of coat colour in the cane Corso Italiano dog. BMC Genet. 2019;20:24. doi: 10.1186/s12863-019-0731-2. PubMed DOI PMC

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–575. doi: 10.1086/519795. PubMed DOI PMC

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.

RStudio Team . RStudio: Integrated Development for R. PBC, Boston, MA: RStudio; 2020.

Wickham H. ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2016.

Turner S. qqman: an R package for visualizing GWAS results using Q-Q and manhattan plots. J Open Source Softw. 2018. 10.21105/joss.00731.

Sarkar D. Lattice: Multivariate Data Visualization with R. New York: Springer; 2008.

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna; 2022. https://www.R-project.org/

Fisher RA. Statistical methods for research workers. 5. Edinburgh; 1934. Statistical methods for research workers.

Rangwala SH, Kuznetsov A, Ananiev V, Asztalos A, Borodin E, Evgeniev V, Joukov V, Lotov V, Pannu R, Rudnev D, Shkeda A, Weitz EM, Schneider VA. Accessing NCBI data using the NCBI Sequence Viewer and Genome Data Viewer (GDV) Genome Res. 2021;31:159–169. doi: 10.1101/gr.266932. PubMed DOI PMC

Mao S, Wu F, Cao X, He M, Liu N, Wu H, Yang Z, Ding Q, Wang X. TDRP deficiency contributes to low sperm motility and is a potential risk factor for male infertility. Am J Transl Res. 2016;8(1):177–187. PubMed PMC

Kuersten S, Goodwin E. The power of the 3′ UTR: translational control and development. Nat Rev Genet. 2003;4:626–637. doi: 10.1038/nrg1125. PubMed DOI

Crocco P, Montesanto A, Passarino G, Rose G. Polymorphisms Falling Within Putative miRNA Target Sites in the 3′UTR Region of SIRT2 and DRD2 Genes Are Correlated With Human Longevity. J Gerontol Ser A. 2016;71(5):586–592. doi: 10.1093/gerona/glv058. PubMed DOI

Jiang GY, Zhang XP, Wang L, et al. FBXO25 promotes cell proliferation, invasion, and migration of NSCLC. Tumor Biol. 2016;37:14311–14319. doi: 10.1007/s13277-016-5298-1. PubMed DOI

Kuzmanov A, Johansen P, Hofbauer G. FBXO25 promotes cutaneous squamous cell carcinoma growth and metastasis through cyclin D1. J Investig Dermatol. 2020;140(12):2496–2504. doi: 10.1016/j.jid.2020.04.003. PubMed DOI

Hoffman JM, Lourenço BN, Promislow DEL, Creevy KE. Canine hyperadrenocorticism associations with signalment, selected comorbidities and mortality within North American veterinary teaching hospitals. J Small Anim Pract. 2018;59(11):681–690. doi: 10.1111/jsap.12904. PubMed DOI PMC

Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka-Hata H, Nakagawa T, Lanjakornsiripan D, Nakayama KI, Fukada Y. FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell. 2013;152(5):1106–1118. doi: 10.1016/j.cell.2013.01.054. PubMed DOI

Liu F, Chang HC. Physiological links of circadian clock and biological clock of aging. Protein Cell. 2017;8(7):477–488. doi: 10.1007/s13238-016-0366-2. PubMed DOI PMC

Refinetti R, Piccione G. Intra-and inter-individual variability in the circadian rhythm of body temperature of rats, squirrels, dogs, and horses. J Therm Biol. 2005;30(2):139–146. doi: 10.1016/j.jtherbio.2004.09.003. DOI

Piccione G, Giudice E, Fazio F, Mortola JP. The daily rhythm of body temperature, heart and respiratory rate in newborn dogs. J Comp Physiol B. 2010;180(6):895–904. doi: 10.1007/s00360-010-0462-1. PubMed DOI

Identification of genes associated with longevity in dogs: 9 candidate genes described in Cavalier King Charles Spaniel

Three new genes associated with longevity in the European Bison