Animal Reproduction (AR)
Animal Reproduction (AR)
Conference Paper

Identification of genes associated with reproductive function in dairy cattle

M. Sofia Ortega

Downloads: 1
Views: 69


The use of genomics has improved response to selection for functional traits with low heritability such as fertility traits. Much of the work on fertility traits has been performed through use of genome-wide association studies (GWAS) to identify genetic loci associated with reproductive traits. Under a GWAS approach, the assumption is that the markers on the panel are in linkage disequilibrium with causative mutations. In many cases, identification of the causative mutation is difficult because an associated genetic marker can be in intergenic regions and can be in linkage disequilibrium with variants in several nearby genes. Another approach is to identify candidate genes using knowledge of the biological pathways controlling a trait to search for single nucleotide polymorphism (SNP) in genes in those pathways. This should reveal putative causative markers responsible for genetic variation in biological function, and it is expected that the marker will be more strongly associated with a trait than one in linkage disequilibrium. An example of how a series of candidate gene studies demonstrate that identification of markers in genes involved in reproductive processes can lead to discovery of additional markers associated with genetic variation in reproductive traits is presented. In addition, the inclusion of candidate markers for fertility can improve reliability of genetic estimates for fertility traits, and the repeatability of the effects across a separate population of animals gives confidence that association elucidated by this set of markers is likely to be real. More importantly, the use of candidate genes can provide insights into the biology underpinning genetic variation in fertility, and that this understanding can lead to physiological interventions to improve reproductive function.


candidate genes, fertility, genomic selection, reproductive function


Aken BL, Achuthan P, Akanni W, Amode MR, Bernsdorff F, Bhai J, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Gil L, Girón CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Juettemann T, Keenan S, Laird MR, Lavidas I, Maurel T, McLaren W, Moore B, Murphy DN, Nag R, Newman V, Nuhn M, Ong CK, Parker A, Patricio M, Riat HS, Sheppard D, Sparrow H, Taylor K, Thormann A, Vullo A, Walts B, Wilder SP, Zadissa A, Kostadima M, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Cunningham F, Yates A, Zerbino DR, Flicek P. 2017. Ensembl 2017. Nucleic Acids Res, 45:D635-D642.

Amos W, Driscoll E, Hoffman JI. 2011. Candidate genes versus genome-wide associations: which are better for detecting genetic susceptibility to infectious disease? Proc Biol Sci, 278:1183-1188.

Basiricò L, Morera P, Primi V, Lacetera N, Nardone A, Bernabucci U. 2011. Cellular thermotolerance is associated with heat shock protein 70.1 genetic polymorphisms in Holstein lactating cows. Cell Stress Chaperones, 16:441-448.

Ben-Meir, A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, Naranian T, Chi M, Wang Y, Bentov Y, Alexis J, Meriano J, Sung H-K, Gasser DL, Moley KH, Hekimi S, Casper RF, Jurisicova A. 2015. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell, 14:887-895.

Bisinotto RS, Chebel RC, Santos JEP. 2010. Follicular wave of the ovulatory follicle and not cyclic status influences fertility of dairy cows. J Dairy Sci, 93:3578-3587.

Boichard D, Manfredi E. 1994. Genetic analysis of conception rate in French Holstein cattle. Acta Agric Scand Sect Anim Sci, 44:138-145.

Brickell JS, Pollott GE, Clempson AM, Otter N, Wathes DC. 2010. Polymorphisms in the bovine leptin gene associated with perinatal mortality in Holstein-Friesian heifers. J Dairy Sci, 93:340-347.

Butler WR. 2003. Energy balance relationships with follicular development, ovulation and fertility in postpartum dairy cows. Livest Prod Sci, 83:211-218.

Cochran SD, Cole JB, Null DJ, Hansen PJ. 2013a. Discovery of single nucleotide polymorphisms in candidate genes associated with fertility and production traits in Holstein cattle. BMC Genet, 14:49. doi: 10.1186/1471-2156-14-49.

Cochran SD, Cole JB, Null DJ, Hansen PJ. 2013b. Single nucleotide polymorphisms in candidate genes associated with fertilizing ability of sperm and subsequent embryonic development in cattle. Biol Reprod, 89:69. doi: 10.1095/biolreprod.113.111260.

Cole JB, Wiggans GR, Ma L, Sonstegard TS, Lawlor TJ Jr, Crooker BA, Van Tassell CP, Yang J, Wang S, Matukumalli LK, Da Y. 2011. Genome-wide association analysis of thirty one production, health, reproduction and body conformation traits in contemporary US Holstein cows. BMC Genomics, 12:408.

Cummins SB, Lonergan P, Evans ACO, Berry DP, Evans RD, Butler ST. 2012a. Genetic merit for fertility traits in Holstein cows: I. Production characteristics and reproductive efficiency in a pasture-based system. J Dairy Sci, 95:1310-1322.

Cummins SB, Lonergan P, Evans ACO, Butler ST. 2012b. Genetic merit for fertility traits in Holstein cows: II. Ovarian follicular and corpus luteum dynamics, reproductive hormones, and estrus behavior. J Dairy Sci, 95:3698-3710.

Daetwyler HD, Capitan A, Pausch H, Stothard P, van Binsbergen R, Brøndum RF, Liao X, Djari A, Rodriguez SC, Grohs C, Esquerré D, Bouchez O, Rossignol M-N, Klopp C, Rocha D, Fritz S, Eggen A, Bowman PJ, Coote D, Chamberlain AJ, Anderson C, VanTassell CP, Hulsegge I, Goddard ME, Guldbrandtsen B, Lund MS, Veerkamp RF, Boichard DA, Fries R, Hayes BJ. 2014. Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle. Nat Genet, 46:858-865.

Driver AM, Huang W, Gajic S, Monson RL, Rosa GJM, Khatib H. 2009. Short communication: effects of the progesterone receptor variants on fertility traits in cattle. J Dairy Sci, 92:4082-4085.

Feugang JM, Kaya A, Page GP, Chen L, Mehta T, Hirani K, Nazareth L, Topper E, Gibbs R, Memili E. 2009. Two-stage genome-wide association study identifies integrin beta 5 as having potential role in bull fertility. BMC Genomics, 10:176. doi: 10.1186/1471-2164-10-176.

Flamenbaum I, Galon N. 2010. Management of heat stress to improve fertility in dairy cows in Israel. J Reprod Dev, 56:S37-41.

Fortes MRS, DeAtley KL, Lehnert SA, Burns BM, Reverter A, Hawken RJ, Boe-Hansen G, Moore SS, Thomas MG 2013. Genomic regions associated with fertility traits in male and female cattle: Advances from microsatellites to high-density chips and beyond. Anim Reprod Sci, 141:1-19.

Frąszczak M, Szyda J. 2016. Comparison of significant single nucleotide polymorphisms selections in GWAS for complex traits. J Appl Genet, 57:207-213.

Fritz, S Capitan A, Djari A, Rodriguez SC, Barbat A, Baur A, Grohs C, Weiss B, Boussaha M, Esquerré D, Klopp C, Rocha D, Boichard D. 2013. Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2. PLoS One, 8:e65550. doi: 10.1371/journal.pone.0065550.

Garcia MD, Michal JJ, Gaskins CT, Reeves JJ, Ott TL, Liu Y, Jiang Z. 2006. Significant association of the calpastatin gene with fertility and longevity in dairy cattle. Anim Genet, 37:304-305.

García-Ruiz A, Cole JB, VanRaden PM, Wiggans GR, Ruiz-López FJ, Van Tassell CP. 2016. Changes in genetic selection differentials and generation intervals in US Holstein dairy cattle as a result of genomic selection. Proc Natl Acad Sci USA, 113:E3995-E4004.

Gwazdauskas FC, Thatcher WW, Wilcox CJ. 1973. Physiological, environmental, and hormonal factors at insemination which may affect conception. J Dairy Sci, 56:873-877.

Hansen PJ, Aréchiga CF. 1999. Strategies for managing reproduction in the heat-stressed dairy cow. J Anim Sci, 77:36-50.

Höglund JK, Sahana G, Guldbrandtsen B, Lund MS. 2014. Validation of associations for female fertility traits in Nordic Holstein, Nordic Red and Jersey dairy cattle. BMC Genet, 15:8. doi: 10.1186/1471-2156-15-8.

Ioannidis JPA Tarone R, McLaughlin JK. 2011. The false-positive to false-negative ratio in epidemiologic studies. Epidemiology, 22:450-456.

Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. 2010. Mitochondrial proton and electron leaks. Essays Biochem, 47:53-67.

Kadri NK, Sahana G, Charlier C, Iso-Touru T, Guldbrandtsen B, Karim L, Sander Nielsen U, Panitz F, Pedersen Aamand G, Schulman N, Georges M, Vilkki J, Sandø Lund M, Druet T. 2014. A 660-Kb deletion with antagonistic effects on fertility and milk production segregates at high frequency in Nordic Red cattle: additional evidence for the common occurrence of balancing selection in livestock. PLoS Genet, 10:e1004049. doi: 10.1371/journal.pgen.1004049.

Khatib H, Schutzkus V, Chang YM, Rosa GJM. 2007. Pattern of expression of the uterine milk protein gene and its association with productive life in dairy cattle. J Dairy Sci, 90:2427-2433.

Khatib H, Maltecca C, Monson RL, Schutzkus V, Wang X, Rutledge JJ. 2008a. The fibroblast growth factor 2 gene is associated with embryonic mortality in cattle. J Anim Sci, 86:2063-2067.

Khatib H, Monson RL, Schutzkus V, Kohl DM, Rosa GJM, Rutledge JJ. 2008b. Mutations in the STAT5A gene are associated with embryonic survival and milk composition in cattle. J Dairy Sci, 91:784-793.

Khatib H, Huang W, Wang X, Tran AH, Bindrim AB, Schutzkus V, Monson RL, Yandell BS. 2009. Single gene and gene interaction effects on fertilization and embryonic survival rates in cattle. J Dairy Sci, 92:2238-2247.

Khatib H, Monson RL, Huang W, Khatib R, Schutzkus V, Khateeb H, Parrish JJ. 2010. Short communication: validation of in vitro fertility genes in a Holstein bull population. J Dairy Sci, 93:2244-2249.

Khatkar MS, Randhawa IAS, Raadsma HW. 2014. Meta-assembly of genomic regions and variants associated with female reproductive efficiency in cattle. Livest Sci, 166:144-157.

Kirkpatrick BW, Morris CA. 2015. A major gene for bovine ovulation rate. PLoS One, 10:e0129025. doi: 10.1371/journal.pone.0129025.

Kuhn MT, Hutchison JL, Wiggans GR. 2006. Characterization of Holstein heifer fertility in the United States. J Dairy Sci, 89:4907-4920.

Li G, Khateeb K, Schaeffer E, Zhang B, Khatib H. 2012. Genes of the transforming growth factor-beta signalling pathway are associated with pre-implantation embryonic development in cattle. J Dairy Res, 79:310-317.

Littlejohn, M, Grala T, Sanders K, Walker C, Waghorn G, Macdonald K, Spelman R, Davis S, Snell R. 2012. Non-replication of genome-wide-based associations of efficient food conversion in dairy cows. Anim Genet, 43:781-784.

Liu A, Wang Y, Sahana G, Zhang Q, Liu L, Lund MS, Su G. 2017. Genome-wide association studies for female fertility traits in Chinese and Nordic Holsteins. Sci Rep, 7:8487. doi:10.1038/s41598-017-09170-9.

Lorthongpanich C, Messerschmidt DM, Chan SW, Hong W, Knowles BB, Solter D. 2013. Temporal reduction of LATS kinases in the early preimplantation embryo prevents ICM lineage differentiation. Genes Dev, 27:1441-1446.

Luna-Nevarez, P, Rincon G, Medrano JF, Riley DG, Chase CC, Coleman SW, VanLeeuwen DM, DeAtley KL, Islas-Trejo A, Silver GA, Thomas MG. 2011. Single nucleotide polymorphisms in the growth hormone-insulin-like growth factor axis in straightbred and crossbred Angus, Brahman, and Romosinuano heifers: population genetic analyses and association of genotypes with reproductive phenotypes. J Anim Sci, 89:926-934.

May-Panloup P, Chrétien MF, Jacques C, Vasseur C, Malthièry Y, Reynier P. 2005. Low oocyte mitochondrial DNA content in ovarian insufficiency. Hum Reprod, 20:593-597.

Michael DD, Alvarez IM, Ocón OM, Powell AM, Talbot NC, Johnson SE, Ealy AD. 2006. Fibroblast growth factor-2 is expressed by the bovine uterus and stimulates interferon-tau production in bovine trophectoderm. Endocrinology, 147:3571-3579.

Moore SG, Scully S, Browne JA, Fair T, Butler ST. 2014. Genetic merit for fertility traits in Holstein cows: V. Factors affecting circulating progesterone concentrations. J Dairy Sci, 97:5543-5557.

Moore SG, Pryce JE, Hayes BJ, Chamberlain AJ, Kemper KE, Berry DP, McCabe M, Cormican P, Lonergan P, Fair T, Butler ST. 2016. Differentially expressed genes in endometrium and corpus luteum of Holstein cows selected for high and low fertility are enriched for sequence variants associated with fertility. Biol Reprod, 94:19: 1-11.

Moran B, Butler ST, Moore SG, MacHugh DE, Creevey CJ. 2015. Differential gene expression in the endometrium reveals cytoskeletal and immunological genes in lactating dairy cows genetically divergent for fertility traits. Reprod Fertil Dev, 29:274-282.

Moran B, Cummins SB, Creevey CJ, Butler ST. 2016. Transcriptomics of liver and muscle in Holstein cows genetically divergent for fertility highlight differences in nutrient partitioning and inflammation processes. BMC Genomics, 17:603. doi:10.1186/s12864-016-2938-1.

Murphy MP. 2009. How mitochondria produce reactive oxygen species. Biochem J, 417:1-13.

Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson R.O, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki E.M, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H. 2009. The hippo signaling pathway components lats and yap pattern tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell, 16:398-410.

Norman HD, Wright JR, Hutchison JL, Mattison JM. 2014. Selection changes in the United States due to genomics. Interbull Bull, 48:37-39.

Ortega MS, Denicol AC, Cole JB, Null DJ, Hansen PJ. 2016a. Use of single nucleotide polymorphisms in candidate genes associated with daughter pregnancy rate for prediction of genetic merit for reproduction in Holstein cows. Anim Genet, 47:288-297.

Ortega MS, Rocha-Frigoni NAS, Mingoti GZ, Roth Z, Hansen PJ. 2016b. Modification of embryonic resistance to heat shock in cattle by melatonin and genetic variation in HSPA1L. J Dairy Sci, 99:9152-9164.

Ortega MS, Denicol AC, Cole JB, Null DJ, Taylor JF, Schnabel RD, Hansen PJ. 2017a. Association of single nucleotide polymorphisms in candidate genes previously related to genetic variation in fertility with phenotypic measurements of reproductive function in Holstein cows. J Dairy Sci, 100:3725-3734.

Ortega MS, Wohlgemuth S, Tribulo P, Siqueira LGB, Null DJ, Cole JB, Silva D, Hansen PJ. 2017b. A single nucleotide polymorphism in COQ9 affects mitochondrial and ovarian function and fertility in Holstein cows. Biol Reprod, 96:652-663.

Parr MH, Mullen MP, Crowe MA, Roche JF, Lonergan P, Evans ACO, Diskin MG. 2012. Relationship between pregnancy per artificial insemination and early luteal concentrations of progesterone and establishment of repeatability estimates for these traits in Holstein-Friesian heifers. J Dairy Sci, 95:2390-2396.

Pei J, Grishin NV. 2012. Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors. Cell Signal, 24:758-769.

Petersson K-J, Strandberg E, Gustafsson H, Royal MD, Berglund B. 2008. Detection of delayed cyclicity in dairy cows based on progesterone content in monthly milk samples. Prev Vet Med, 86:153-163.

Ponsuksili S, Brunner RM, Goldammer T, Kühn C, Walz C, Chomdej S, Tesfaye D, Schellander K, Wimmers K, Schwerin M. 2006. Bovine NALP5, NALP8, and NALP9 genes: assignment to a QTL region and the expression in adult tissues, oocytes, and preimplantation embryos. Biol Reprod, 74:577-584.

Pritchard T, Coffey M, Mrode R, Wall E. 2013. Genetic parameters for production, health, fertility and longevity traits in dairy cows. Animal, 7:34-46.

Pryce JE, Royal MD, Garnsworthy PC, Mao IL. 2004. Fertility in the high-producing dairy cow. Livest Prod Sci, 86:125-135.

Reynier P, May-Panloup P, Chrétien M-F, Morgan CJ, Jean M, Savagner F, Barrière P, Malthièry Y. 2001. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod, 7:425-429.

Riancho JA. 2012. Genome-wide association studies (GWAS) in complex diseases: advantages and limitations. Reumatol Clin, 8:56-57.

Ribeiro ES, Gomes G, Greco LF, Cerri RLA, Vieira-Neto A, Monteiro Jr PLJ, Lima FS, Bisinotto RS, Thatcher WW, Santos JEP. 2016. Carryover effect of postpartum inflammatory diseases on developmental biology and fertility in lactating dairy cows. J Dairy Sci, 99:2201-2220.

Rosenkrans Jr C, Banks A, Reiter S, Looper M. 2010. Calving traits of crossbred Brahman cows are associated with Heat Shock Protein 70 genetic polymorphisms. Anim, Reprod Sci, 119:178-182.

Royal M, Mann GE, Flint AP. 2000. Strategies for reversing the trend towards subfertility in dairy cattle. Vet J, 160:53-60.

Santos JEP, Bisinotto RS, Ribeiro ES, Lima FS, Greco LF, Staples CR, Thatcher WW. 2011. Applying nutrition and physiology to improve reproduction in dairy cattle. Reprod Domest Rumin, 67:387-403.

Santos JEP, Bisinotto RS, Ribeiro ES. 2016. Mechanisms underlying reduced fertility in anovular dairy cows. Theriogenology, 86:254-262.

Sonstegard, TS, Cole JB, VanRaden PM, Tassell CPV, Null DJ, Schroeder SG, Bickhart D, McClure MC. 2013. Identification of a nonsense mutation in CWC15 associated with decreased reproductive efficiency in Jersey cattle. PLoS One, 8:e54872. doi:10.1371/journal.pone.0054872.

Stringer S, Wray NR, Kahn RS, Derks EM. 2011. Underestimated effect sizes in gwas: fundamental limitations of single snp analysis for dichotomous phenotypes. PLoS One, 6:e27964. doi:10.1371/journal.pone.0027964.

Thompson-Crispi KA, Hine B, Quinton M, Miglior F, Mallard BA. 2012. Short communication: association of disease incidence and adaptive immune response in Holstein dairy cows. J Dairy Sci, 95:3888-3893.

Tran UC, Clarke CF. 2007. Endogenous synthesis of coenzyme Q in eukaryotes. Mitochondrion, 7(suppl):S62-S71.

Tsai T, St John JC. 2016. The role of mitochondrial DNA copy number, variants, and haplotypes in farm animal developmental outcome. Domest Anim Endocrinol, 56(suppl):S133-S146.

VanRaden PM, Sanders AH, Tooker ME, Miller RH, Norman HD. 2003. Daughter pregnancy rate evaluation. Available on: Accessed on: November 3, 2016.

VanRaden PM, Sanders AH, Tooker ME, Miller RH, Norman HD, Kuhn MT, Wiggans GR. 2004. Development of a national genetic evaluation for cow fertility. J Dairy Sci, 87:2285-2292.

VanRaden PM, Van Tassell CP, Wiggans GR, Sonstegard TS, Schnabel RD, Taylor JF, Schenkel FS. 2008. Invited review: reliability of genomic predictions for North American Holstein bulls. J Dairy Sci, 92:16-24.

VanRaden PM, Olson KM, Null DJ, Hutchison JL. 2011. Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J Dairy Sci, 94:6153-6161.

VanRaden PM, Null DJ, Sargolzaei M, Wiggans GR, Tooker ME, Cole JB, Sonstegard TS, Connor EE, Winters M, van Kaam JBCHM, Valentini A, Van Doormaal BJ, Faust MA, Doak GA. 2013. Genomic imputation and evaluation using high-density Holstein genotypes. J Dairy Sci, 96:668-678.

Waters SM, McCabe MS, Howard DJ, Giblin L, Magee DA, MacHugh DE, Berry DP. 2011. Associations between newly discovered polymorphisms in the Bos Taurus growth hormone receptor gene and performance traits in Holstein–Friesian dairy cattle. Anim Genet, 42:39-49.

Weller JI, Ron M. 2011. Invited review: quantitative trait nucleotide determination in the era of genomic selection. J Dairy Sci, 94:1082-1090.

Wiggans GR, VanRaden PM, Cooper TA. 2011. The genomic evaluation system in the United States: past, present, future. J Dairy Sci, 94:3202-3211.

Wiltbank M, Lopez H, Sartori R, Sangsritavong S, Gümen A. 2006. Changes in reproductive physiology of lactating dairy cows due to elevated steroid metabolism. Theriogenology, 65:17-29.

Wiltbank MC, Souza AH, Carvalho PD, Cunha AP, Giordano JO, Fricke PM, Baez GM, MG Diskin. 2014. Physiological and practical effects of progesterone on reproduction in dairy cattle. Animal, 8:70-81.

Yang W-C, Li S-J, Tang K-Q, Hua G-H, Zhang C-Y, Yu J-N, Han L, Yang L-G. 2010. Polymorphisms in the 5’ upstream region of the FSH receptor gene, and their association with superovulation traits in Chinese Holstein cows. Anim Reprod Sci, 119:172-177.

Zhao B, Li L, Lei Q, Guan K-L. 2010. The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev, 24:862-874.

Zhu M, Zhao S. 2007. Candidate gene identification approach: progress and challenges. Int J Biol Sci, 3:420-427.

Zondervan KT, Rahmioglu N, Morris AP, Nyholt DR, Montgomery GW, Becker CM, Missmer SA. 2016. Beyond endometriosis genome-wide association study: from genomics to phenomics to the patient. Semin Reprod Med, 34:242-254.

5b8fc9190e88251f7e59a5ed animreprod Articles
Links & Downloads

Anim Reprod

Share this page
Page Sections