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RESEARCH ARTICLE

Divergent genotypes for fatness or residual feed intake in Angus cattle. 2. Body composition but not reproduction was affected in first-parity cows on both low and high levels of nutrition

M. Laurence A B H , J. M. Accioly A C , K. J. Copping A D , M. P. B. Deland A D , J. F. Graham A E , M. L. Hebart A F , R. M. Herd A G , F. M. Jones A C , S. J. Lee A F , E. J. Speijers A C and W. S. Pitchford A F
+ Author Affiliations
- Author Affiliations

A Cooperative Research Centre for Beef Genetic Technologies.

B College of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia.

C WA Department of Agriculture and Food, Bunbury, WA 6230, Australia.

D South Australian Research and Development Institute, Struan Agricultural Centre, Naracoorte, SA 5271, Australia.

E Department of Primary Industries, Hamilton, Vic. 3300, Australia.

F School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, SA 5371, Australia.

G NSW Department of Primary Industries, University of New England, Armidale, NSW 2351, Australia.

H Corresponding author. Email: M.Laurence@murdoch.edu.au

Animal Production Science 58(1) 43-54 https://doi.org/10.1071/AN13218
Submitted: 29 May 2013  Accepted: 24 October 2013   Published: 7 September 2016

Abstract

This paper reports a subset of results from the Beef Cooperative Research Centre-funded Maternal Productivity Project. This research aimed to describe the response of Angus cows of different and divergent genotypes to variable nutritional environments over five breeding seasons. Cows selected for a divergence in either fat depth (HFat vs LFat) or residual feed intake (RFI: HRFI vs LRFI) based on mid-parent estimated breeding values (EBV) for those traits were allocated in replicate groups to either high or low nutritional treatments at two different sites, namely the Vasse Research Centre in Western Australia and the Struan Research Centre in South Australia. The traits reported in this paper include output traits (birth and weaning weight of calves, liveweight change of cows), change traits (change in Rib Fat, P8 fat, eye muscle area and liveweight between specified time points) and reproductive traits [pregnancy rates, percentage calves born alive and days to calving at the days to calving at the second calving opportunity (DC2)]. Having had their first calf, the vulnerability of these young cows to nutritional restriction and how it may adversely affect rebreeding was examined. HFat and HRFI cows were fatter, heavier and had greater eye muscle area than LFat and LRFI, respectively, at all times during the breeding cycle on both levels of nutrition. There was no difference in either days-to-calving or pregnancy rates after the second mating between genotypes. Equally, nutritional treatment had no effect on these traits in this cohort of cows. There was evidence for an implied genetic correlation between Rib Fat EBV, DC2 and pregnancy rates of –0.38 that suggests that selection for leanness may result in reduced fertility of the herd but the effect was not significant herein. As long as producers record the phenotype for both traits and select cows with favourable DC2 as well as low fatness, these problems can be avoided, owing to only 22% of variation in pregnancy rates being explained by DC2 and Rib Fat EBV. Producers can largely be confident that selection for leanness, or increased feed efficiency, has little impact on productivity as long as cows are in adequate body condition to remain healthy and productive.


References

Adams GP, Matteri RL, Kastelic JP, Ko JC, Ginther OJ (1992) Association between surges of follicle-stimulating hormone and the emergence of follicular waves in heifers. Journal of Reproduction and Fertility 94, 177–188.
Association between surges of follicle-stimulating hormone and the emergence of follicular waves in heifers.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK38Xhs1Kltr4%3D&md5=2a279f6e1fc589373358b893183302bfCAS | 1552480PubMed |

Arthur PF, Archer JA, Herd RM, Richardson EC, Exton SC, Oswin C, Dibley KCP, Burton DA (1999) Relationship between postweaning growth, net feed intake and cow performance. Proceedings of the Association for the Advancement of Animal Breeding and Genetics 13, 484–487.

Arthur PF, Archer JA, Johnston DJ, Herd RM, Richardson EC, Parnell PF (2001) Genetic and phenotypic variance and covariance components for feed intake, feed efficiency, and other postweaning traits in Angus cattle. Journal of Animal Science 79, 2805–2811.

Arthur PF, Herd RM, Wilkins JF, Archer JA (2005) Maternal productivity of Angus cows divergently selected for post-weaning residual feed intake. Australian Journal of Experimental Agriculture 45, 985–993.
Maternal productivity of Angus cows divergently selected for post-weaning residual feed intake.Crossref | GoogleScholarGoogle Scholar |

Banta JP, Lalman DL, Wettemann RP (2005) Symposium Paper: post-calving nutrition and management programs for two-year-old beef cows. The Professional Animal Scientist 21, 151–158.

Basarab JA, McCartney D, Okine EK, Baron VS (2007) Relationships between progeny residual feed intake and dam productivity traits. Canadian Journal of Animal Science 87, 489–502.
Relationships between progeny residual feed intake and dam productivity traits.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXivFyqsLg%3D&md5=b763a4ff0ec68238912b7b23932393c9CAS |

Beam SW, Butler WR (1997) Energy balance and ovarian follicle development prior to the first ovulation postpartum in dairy cows receiving three levels of dietary fat. Biology of Reproduction 56, 133–142.
Energy balance and ovarian follicle development prior to the first ovulation postpartum in dairy cows receiving three levels of dietary fat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXis1Kguw%3D%3D&md5=6309ea0c6e4a919e52ea0f8400c7b169CAS | 9002642PubMed |

Bellows RA, Short RE (1978) Effects of precalving feed level on birth weight, calving difficulty and subsequent fertility. Journal of Animal Science 46, 1522–1528.

Bellows RA, Short RE, Richardson GV (1982) Effects of sire, age of dam and gestation feed level on dystocia and postpartum reproduction. Journal of Animal Science 55, 18–27.

Boland MP, Lonergan P, O’Callaghan D (2001) Effect of nutrition on endocrine parameters, ovarian physiology, and oocyte and embryo development. Theriogenology 55, 1323–1340.
Effect of nutrition on endocrine parameters, ovarian physiology, and oocyte and embryo development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjsFSis70%3D&md5=bb55a13575fd802469c37b4352f4b705CAS | 11327687PubMed |

Cafe LM, Hennessy DW, Hearnshaw H, Morris SG, Greenwood PL (2006) Influences of nutrition during pregnancy and lactation on birth weights and growth to weaning of calves sired by Piedmontese or Wagyu bulls. Australian Journal of Experimental Agriculture 46, 245–255.
Influences of nutrition during pregnancy and lactation on birth weights and growth to weaning of calves sired by Piedmontese or Wagyu bulls.Crossref | GoogleScholarGoogle Scholar |

Ciccioli NH, Wettemann RP, Spicer LJ, Lents CA, White FJ, Keisler DH (2003) Influence of body condition at calving and postpartum nutrition on endocrine function and reproductive performance of primiparous beef cows. Journal of Animal Science 81, 3107–3120.

Copping KJ, Accioly JM, Deland MPB, Edwards NJ, Graham JF, Hebart ML, Herd RM, Jones FM, Laurence M, Lee SJ, Speijers EJ, Pitchford WS (2016) Divergent genotypes for fatness or residual feed intake in Angus cattle. 3. Performance of mature cows. Animal Production Science
Divergent genotypes for fatness or residual feed intake in Angus cattle. 3. Performance of mature cows.Crossref | GoogleScholarGoogle Scholar |

Crews DH (2005) Genetics of efficient feed utilization and national cattle evaluation: a review. Genetics and Molecular Research 4, 152–165.

Crowe MA (2008) Resumption of ovarian cyclicity in post-partum beef and dairy cows. Reproduction in Domestic Animals 43, 20–28.
Resumption of ovarian cyclicity in post-partum beef and dairy cows.Crossref | GoogleScholarGoogle Scholar | 19068029PubMed |

Crowe MA, Padmanabhan V, Mihm M, Beitins IZ, Roche JF (1998) Resumption of follicular waves in beef cows is not associated with periparturient changes in follicle-stimulating hormone heterogeneity despite major changes in steroid and luteinizing hormone concentrations. Biology of Reproduction 58, 1445–1450.
Resumption of follicular waves in beef cows is not associated with periparturient changes in follicle-stimulating hormone heterogeneity despite major changes in steroid and luteinizing hormone concentrations.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXjsFShtLc%3D&md5=7a5184a3ea3f368d62e3b84418b50b36CAS | 9623604PubMed |

CSIRO (2013) Grazfeed. Available at http://www.grazplan.csiro.au/?q=node/2 [Verified 18 November 2013]

Davis ME, Simmen RC (2000) Genetic parameter estimates for serum insulin-like growth factor-I concentration and carcass traits in Angus beef cattle. Journal of Animal Science 78, 2305–2313.

Davis ME, Rutledge JJ, Cundiff LV, Hauser ER (1983) Life cycle efficiency of beef production: I. Cow efficiency ratios for progeny weaned. Journal of Animal Science 57, 832–851.

DiCostanzo A, Meiske JC, Plegge SD, Peters TM, Goodrich RD (1990) Within-herd variation in energy utilization for maintenance and gain in beef cows. Journal of Animal Science 68, 2156–2165.

DiCostanzo A, Meiske JC, Plegge SD (1991) Characterization of energetically efficient and inefficient beef cows. Journal of Animal Science 69, 1337–1348.

Diskin MG, Mackey DR, Roche JF, Sreenan JM (2003) Effects of nutrition and metabolic status on circulating hormones and ovarian follicle development in cattle. Animal Reproduction Science 78, 345–370.
Effects of nutrition and metabolic status on circulating hormones and ovarian follicle development in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXksF2gt74%3D&md5=0fc7099f150183ccc5bcf1c8da20cd2fCAS | 12818653PubMed |

Donoghue KA, Arthur PF, Wilkins JF, Herd RM (2011) Onset of puberty and early-life reproduction in Angus females divergently selected for post-weaning residual feed intake. Animal Production Science 51, 183–190.
Onset of puberty and early-life reproduction in Angus females divergently selected for post-weaning residual feed intake.Crossref | GoogleScholarGoogle Scholar |

Egan AF, Ferguson DM, Thompson JM (2001) Consumer sensory requirements for beef and their implications for the Australian beef industry. Australian Journal of Experimental Agriculture 41, 855–859.
Consumer sensory requirements for beef and their implications for the Australian beef industry.Crossref | GoogleScholarGoogle Scholar |

Ginther OJ, Wiltbank MC, Fricke PM, Gibbons JR, Kot K (1996) Selection of the dominant follicle in cattle. Biology of Reproduction 55, 1187–1194.
Selection of the dominant follicle in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXkvV2gtA%3D%3D&md5=668b56a495280cac2c45918eb43d4bd0CAS | 8949873PubMed |

Graham J (2006) ‘Condition scoring of beef cattle.’ Agriculture Notes. (Department of Primary Industries Victoria: Hamilton)

Gutierrez CG, Oldham J, Bramley TA, Gong JG, Campbell BK, Webb R (1997) The recruitment of ovarian follicles is enhanced by increased dietary intake in heifers. Journal of Animal Science 75, 1876–1884.

Hebart ML, Accioly JM, Copping KJ, Deland MPB, Herd RM, Jones FM, Laurence M, Lee SJ, Lines DS, Speijers EJ, Walmsley BJ, Pitchford WS (2016) Divergent breeding values for fatness or residual feed intake in Angus cattle. 5. Cow genotype affects feed efficiency and maternal productivity. Animal Production Science
Divergent breeding values for fatness or residual feed intake in Angus cattle. 5. Cow genotype affects feed efficiency and maternal productivity.Crossref | GoogleScholarGoogle Scholar |

Herd RM, Bishop SC (2000) Genetic variation in residual feed intake and its association with other production traits in British Hereford cattle. Livestock Production Science 63, 111–119.
Genetic variation in residual feed intake and its association with other production traits in British Hereford cattle.Crossref | GoogleScholarGoogle Scholar |

Herd RM, Richardson EC, Hegarty RS, Woodgate R, Archer JA, Arthur PF (1998) Pasture intake by high versus low feed efficient Angus cows. Animal Production in Australia 22, 137–140.

Hess BW, Lake SL, Scholljegerdes EJ, Weston TR, Nayigihugu V, Molle JDC, Moss GE (2005) Nutritional controls of beef cow reproduction. Journal of Animal Science 83, E90–E106.

Johnston DJ, Bunter KL (1996) Days to calving in Angus cattle: genetic and environmental effects, and covariances with other traits. Livestock Production Science 45, 13–22.
Days to calving in Angus cattle: genetic and environmental effects, and covariances with other traits.Crossref | GoogleScholarGoogle Scholar |

Johnston DJ, Herd RM, Kadel MJ, Graser HU, Arthur PF, Archer JA (2002) Evidence of IGF-1 as a genetic predictor of feed efficiency in beef cattle. In ‘7th World Congress on genetics applied to livestock production’. (Ed. F Minvielle) pp. 0–4. (Quae Editions: Montpellier, France)

Jones FM, Accioly JM, Copping KJ, Deland MPB, Graham JF, Hebar ML, Herd RM, Laurence M, Lee SJ, Speijers EJ, Pitchford WS (2016) Divergent breeding values for fatness or residual feed intake in Angus cattle. 1. Pregnancy rates of heifers differed between fat lines and were more affected by weight and fat. Animal Production Science
Divergent breeding values for fatness or residual feed intake in Angus cattle. 1. Pregnancy rates of heifers differed between fat lines and were more affected by weight and fat.Crossref | GoogleScholarGoogle Scholar | in press.

Kadarmideen HN, Thompson R, Coffey MP, Kossaibati MA (2003) Genetic parameters and evaluations from single- and multiple-trait analysis of dairy cow fertility and milk production. Livestock Production Science 81, 183–195.
Genetic parameters and evaluations from single- and multiple-trait analysis of dairy cow fertility and milk production.Crossref | GoogleScholarGoogle Scholar |

Kerr JC, Cameron ND (1995) Reproductive performance of pigs selected for components of efficient lean growth. Animal Science 60, 281–290.
Reproductive performance of pigs selected for components of efficient lean growth.Crossref | GoogleScholarGoogle Scholar |

Koch RM, Swiger LA, Chambers D, Gregory KE (1963) Efficiency of feed use in beef cattle. Journal of Animal Science 22, 486–494.

Lake SL, Scholljegerdes EJ, Atkinson RL, Nayigihugu V, Paisley SI, Rule DC, Moss GE, Robinson TJ, Hess BW (2005) Body condition score at parturition and postpartum supplemental fat effects on cow and calf performance. Journal of Animal Science 83, 2908–2917.

Lake SL, Scholljegerdes EJ, Hallford DM, Moss GE, Rule DC, Hess BW (2006) Effects of body condition score at parturition and postpartum supplemental fat on metabolite and hormone concentrations of beef cows and their suckling calves. Journal of Animal Science 84, 1038–1047.

Lucy MC (2004) New tools for managing reproduction. Animal Production in Australia 25, 363–372.

Lucy MC, Staples CR, Michel FM, Thatcher WW (1991) Energy balance and size and number of ovarian follicles detected by ultrasonography in early postpartum dairy cows. Journal of Dairy Science 74, 473–482.
Energy balance and size and number of ovarian follicles detected by ultrasonography in early postpartum dairy cows.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3M3lvVKntQ%3D%3D&md5=550964c3d278e23b31a84d7bd92baed4CAS | 2045556PubMed |

Mackey DR, Wylie AR, Sreenan JM, Roche JF, Diskin MG (2000) The effect of acute nutritional change on follicle wave turnover, gonadotropin, and steroid concentration in beef heifers. Journal of Animal Science 78, 429–442.

Meikle A, Kulcsar M, Chilliard Y, Febel H, Delavaud C, Cavestany D, Chilibroste P (2004) Effects of parity and body condition at parturition on endocrine and reproductive parameters of the cow. Reproduction (Cambridge, England) 127, 727–737.
Effects of parity and body condition at parturition on endocrine and reproductive parameters of the cow.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXlt1Ohu7Y%3D&md5=12e90899f0dfe1583a57db6db6b2514eCAS |

Miller V, Ungerfeld R (2008) Weekly bull exchange shortens postpartum anestrus in suckled beef cows. Theriogenology 69, 913–917.
Weekly bull exchange shortens postpartum anestrus in suckled beef cows.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD1c3ksFaltw%3D%3D&md5=11c9611165989a96dceb23e997500598CAS | 18295874PubMed |

Nkrumah JD, Basarab JA, Price MA, Okine EK, Ammoura A, Guercio S, Hansen C, Li C, Benkel B, Murdoch B, Moore SS (2004) Different measures of energetic efficiency and their phenotypic relationships with growth, feed intake, and ultrasound and carcass merit in hybrid cattle. Journal of Animal Science 82, 2451–2459.

NRC (1996) ‘Nutrient requirements of beef cattle.’ (National Academy Press: Washington, DC)

O’Dowd S, Hoste S, Mercer JT, Fowler VR, Edwards SA (1997) Nutritional modification of body composition and the consequences for reproductive performance and longevity in genetically lean sows. Livestock Production Science 52, 155–165.
Nutritional modification of body composition and the consequences for reproductive performance and longevity in genetically lean sows.Crossref | GoogleScholarGoogle Scholar |

Pitchford WS, Accioly JM, Banks RG, Barnes AL, Barwick SA, Copping KJ, Deland MPB, Donoghue KA, Edwards N, Hebart ML, Herd RM, Jones FM, Laurence M, Lee SJ, McKiernan WA, Parnell PF, Speijers EJ, Tudor GD, Graham JF (2016) Genesis, design and methods of the Beef CRC Maternal Productivity Project. Animal Production Science
Genesis, design and methods of the Beef CRC Maternal Productivity Project.Crossref | GoogleScholarGoogle Scholar | in press.

Pleasants AB, Barton RA (1992) Precalving nutrition of heavy two year old Angus heifers weighing 415 kg at calving. In ‘Proceedings of the New Zealand Society of Animal Production’. pp. 303–305.

Randel RD (1990) Nutrition and postpartum rebreeding in cattle. Journal of Animal Science 68, 853–862.

Randel RD, Welsh TH (2013) Joint Alpharma-Beef species symposium: interactions of feed efficiency with beef heifer reproductive development. Journal of Animal Science 91, 1323–1328.
Joint Alpharma-Beef species symposium: interactions of feed efficiency with beef heifer reproductive development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXmsFKnurw%3D&md5=e9d839c6cb947c98ccbce3b20d785f8eCAS | 23048157PubMed |

Reist M, Koller A, Busato A, Kupfer U, Blum JW (2000) First ovulation and ketone body status in the early postpartum period of dairy cows. Theriogenology 54, 685–701.
First ovulation and ketone body status in the early postpartum period of dairy cows.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3M%2FovVGrsA%3D%3D&md5=275c2b4d582f869fb39723b7429c88bdCAS | 11101031PubMed |

Rhodes FM, McDougall S, Burke CR, Verkerk GA, Macmillan KL (2003) Invited Review: treatment of cows with an extended postpartum anestrous interval. Journal of Dairy Science 86, 1876–1894.
Invited Review: treatment of cows with an extended postpartum anestrous interval.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXks1Git74%3D&md5=88c3872f5ca2a956b906a984716b12a3CAS | 12836922PubMed |

Richards MW, Wettemann RP, Spitzer JC, Warner MB (1986) Effect of varying levels of postpartum nutrition and body condition at calving on subsequent reproductive performance in beef cattle. Journal of Animal Science 62, 300–306.

Richards MW, Wettermann RP, Schoenemann HM (1989) Nutritional anestrus in beef cows: body weight change, body condition, luteinising hormone in serum and ovarian activity. Journal of Animal Science 67, 1520–1526.

Roche JF, Mackey D, Diskin MD (2000) Reproductive management of postpartum cows. Animal Reproduction Science 60–61, 703–712.
Reproductive management of postpartum cows.Crossref | GoogleScholarGoogle Scholar | 10844236PubMed |

Rutter LM, Randel RD (1984) Postpartum nutrient intake and body condition: effect on pituitary function and onset of estrus in beef cattle. Journal of Animal Science 58, 265–274.

Spitzer JC, Morrison DG, Wettemann RP, Faulkner LC (1995) Reproductive responses and calf birth and weaning weights as affected by body condition at parturition and postpartum weight gain in primiparous beef cows. Journal of Animal Science 73, 1251–1257.

Stagg K, Spicer LJ, Sreenan JM, Roche JF, Diskin MG (1998) Effect of calf isolation on follicular wave dynamics, gonadotropin and metabolic hormone changes, and interval to first ovulation in beef cows fed either of two energy levels postpartum. Biology of Reproduction 59, 777–783.
Effect of calf isolation on follicular wave dynamics, gonadotropin and metabolic hormone changes, and interval to first ovulation in beef cows fed either of two energy levels postpartum.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXmsVGrsLo%3D&md5=f2001143a634ceee4bd55bcaac54b983CAS | 9746725PubMed |

Veerkamp RF, Beerda B, van der Lende T (2003) Effects of genetic selection for milk yield on energy balance, levels of hormones, and metabolites in lactating cattle, and possible links to reduced fertility. Livestock Production Science 83, 257–275.
Effects of genetic selection for milk yield on energy balance, levels of hormones, and metabolites in lactating cattle, and possible links to reduced fertility.Crossref | GoogleScholarGoogle Scholar |

Vizcarra JA, Wettemann RP, Spitzer JC, Morrison DG (1998) Body condition at parturition and postpartum weight gain influence luteal activity and concentrations of glucose, insulin, and nonesterified fatty acids in plasma of primiparous beef cows. Journal of Animal Science 76, 927–936.

Walmsley BJ, Lee SJ, Parnell PF, Pitchford WS (2016) A review of factors influencing key biological components of maternal productivity in temperate beef cattle. Animal Production Science
A review of factors influencing key biological components of maternal productivity in temperate beef cattle.Crossref | GoogleScholarGoogle Scholar |

Webb R, Garnsworthy PC, Gong JG, Armstrong DG (2004) Control of follicular growth: local interactions and nutritional influences. Journal of Animal Science 82, E63–E74.

Wiltbank JN, Remmenga EE (1982) Calving difficulty and calf survival in beef cows fed two energy levels. Theriogenology 17, 587–602.
Calving difficulty and calf survival in beef cows fed two energy levels.Crossref | GoogleScholarGoogle Scholar |

Wiltbank JN, Rowdon WW, Ingalls JE, Gregory KE, Koch RM (1962) Effect of energy level on reproductive phenomena of mature Hereford cows. Journal of Animal Science 21, 219–225.

Wright IA, Rhind SM, Smith AJ, Whyte TK (1992) Effects of body condition and estradiol on luteinizing hormone secretion in post-partum beef cows. Domestic Animal Endocrinology 9, 305–312.
Effects of body condition and estradiol on luteinizing hormone secretion in post-partum beef cows.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3sXhvVeksLg%3D&md5=be6802c858c243cc9d6e7ecc0b2133f4CAS | 1473349PubMed |

Zulu VC, Nakao T, Sawamukai Y (2002) Insulin-like growth factor-I as a possible mediator of nutritional regulation of reproduction in cattle. The Journal of Veterinary Medical Science 64, 657–665.
Insulin-like growth factor-I as a possible mediator of nutritional regulation of reproduction in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XnsFOiurk%3D&md5=e2234d167bf2b1fd6573be197b883434CAS | 12237508PubMed |