doi: 10.15389/agrobiology.2016.4.423eng

UDC 636.234.1:636.082:57.017.53:577.21

The studies were performed with financial support of the Russian Ministry of Education and Science; project  № 14.604.21.0062, unique identification № RFMEFI60414X0062



N.A. Zinovieva

L.K. Ernst All-Russian Research Institute of Animal Husbandry, Federal Agency of Scientific Organizations, pos. Dubrovitsy, Podolsk Region, Moscow Province, 142132 Russia,

Received April 30, 2016


The observed progressive increase of homozygosity in the cultural cattle breeds leads to increased negative impact of LoF-mutations (LoF — loss-of-function) in reducing cow fertility. Significant progress in the identification of LoF-mutations, which are associated with fertility, was achieved with the development of a new approach called «homozygosity mapping» (C. Charlier et al., 2008). This approach allows identifying the chromosomal regions characterized by loss of homozygosity, which are the candidate regions for location of fertility haplotypes associated with embryonic and early post-embryonic mortality. In the past few years, the fertility haplotypes were identified in almost all the major breeds of dairy cattle: Holstein (P.M. VanRaden et al., 2011; S. Fritz et al., 2013; T.A. Cooper et al., 2013), Jersey (P.M. VanRaden et al., 2011; T.S. Sonstegard et al., 2013), Brown Swiss (P.M. VanRaden et al., 2011; T.A. Cooper et al., 2013; M. McClure et al., 2013), Montbeliarde (S. Fritz et al., 2013), Ayrshire (T.A. Cooper et al., 2013), Fleckvieh (H. Pausch et al., 2015), Nordic Red cattle (N.K. Kadri et al., 2014). In presented review, it is characterized the haplotypes affecting fertility, which are segregated in Holsteins — the main dairy cattle breed worldwide (bred in 161 countries). In Russia, the ratio of Holstein and holsteinized Black-Pied cattle accounted for more than 65 % of common dairy cattle population. Currently, in the Holstein breed is registered ten fertility haplotypes (HCD, HH0, HH1, HH2, HH3, HH4, HH5, HHB, HHC, HHD), which affect the pregnancy losses and/or associated with embryonic and early post-embryonic mortality at different stages (J.B. Cole et al., 2016). Possible causes for segregation of the fertility haplotypes in cattle populations are discussed. These are intensive use of carrier bulls for artificial insemination, a considerable period from occurrence to the identification of causative mutations (18-59 years), the possible association of carrier status with productive traits. The chromosomal location of the fertility haplotypes is characterized, the haplotype frequencies in North-American Holstein population are presented and the effects of bull carrier status on cow pregnancy rate are shown. It is described the stages of pregnancy and/or the age of calves on which there is the embryonic mortality of affected fetus and/or the death of affected calves. It is characterized the genes and the causative LoF-mutations, which are associated with fertility haplotypes. It is shown that more than 5 % of sires used in Russia have had the fathers, which are the carriers of fertility haplotypes. Thus, it is necessary to screen the Russian population of Holstein and holsteinized cattle to detect the carrier status of animals. The role of DNA-diagnostics in the control and elimination of fertility haplotypes and associated genetic defects in the Russian population of breeding cattle is discussed. Survey for these latent genetic defects among domestic Holstein and holsteinized Black Pied cattle showed that they occur at a relatively high rate, reaching about 10 % for cows and about 4 % for bulls. Among the bulls more than 5 % were hidden CVM carriers, and about 3 % were latent BLAD carriers. Currently, due to genetic monitoring, these mutant alleles are not being recorded in sires of the population.

Keywords: Holstein breed, embryonic mortality, genetic defects, fertility haplotype.


Full article (Rus)

Full text (Eng)



  1. Domestic animal diversity database (DAD-IS). Available Accessed February 27, 2016.
  2. Labinov V.V. Rezul'taty i osnovnye napravleniya sovershenstvovaniya selektsionno-plemennoi raboty v molochnom skotovodstve Rossiiskoi Federatsii. Ministerstvo sel'skogo khozyaistva RF [Advances and main aspects of improved breeding in livestock husbandry in the Russian Federation]. Available Accessed May 28, 2016 (in Russ.).
  3. Barbat A., Le Mezec P., Ducrocq V., Mattalia S., Fritz S., Boichard D., Ponsart C., Humblot P. Female fertility in French dairy breeds: current situation and strategies for improvement. J. Reprod. Dev., 2010, 56: S15-S21 CrossRef
  4. Washburn S.P., Silvia W.J., Brown C.H., McDaniel B.T., McAllister A.J. Trends in reproductive performance in Southeastern Holstein and Jersey DHI herds. J. Dairy Sci., 2002, 85: 244-251 CrossRef
  5. Lucy M.C. Reproductive loss in high-producing dairy cattle: where will it end? J. Dairy Sci., 2001, 84: 1277-1293 CrossRef
  6. Silvia W. Changes in reproductive performance of Holstein dairy cows in Kentucky from 1972 to 1996. J. Dairy Sci., 1998, 81(Suppl. 1): 244.
  7. Subbotin A.D. Zhivotnovodstvo Rossii, 2011, 10: 45-46 (in Russ.).
  8. Dobson H., Smith R.F., Royal M.D., Knight C.H., Sheldon I.M. The high producing dairy cow and its reproductive performance. Reprod. Domest. Anim., 2007, 42(Suppl 2): 17-23 CrossRef
  9. Oltenacu P.A., Broom D.M. The impact of genetic selection for increased milk yield on the welfare of dairy cows. Animal Welfare, 2010, 19(S): 39-49.
  10. Durbin R.M., the 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature, 2010, 467: 1061-1073 CrossRef
  11. Pelak K., Shianna K.V., Ge D., Maia J.M., Zhu M., Smith J.P., Cirulli E.T., Fellay J., Dickson S.P., Gumbs C.E., Heinzen E.L., Need A.C., Ruzzo E.K., Singh A., Campbell C.R., Hong L.K., Lornsen K.A., McKenzie A.M., Sobreira N.L., Hoover-Fong J.E., Milner J.D., Ottman R., Haynes B.F., Goedert J.J., Goldstein D.B. The characterization of twenty sequenced human genomes. PLoS Genet., 2010, 6(9): e1001111 CrossRef
  12. MacArthur D.G., Balasubramanian S., Frankish A., Huang N., Morris J., Walter K., Jostins L., Habegger L., Pickrell J.K., Montgomery S.B., Albers C.A., Zhang Z.D., Conrad D.F., Lunter G., Zheng H., Ayub Q., De Pristo M.A., Banks E., Hu M., Handsaker R.E., Rosenfeld J.A., Fromer M., Jin M., Mu X.J., Khurana E., Ye K., Kay M., Saunders G.I., Suner M.M., Hunt T., Barnes I.H., Amid C., Carvalho-Silva D.R., Bignell A.H., Snow C., Yngvadottir B., Bumpstead S., Cooper D.N., Xue Y., Romero I.G., the 1000 Genomes Project Consortium, Wang J., Li Y., Gibbs R.A., McCarroll S.A., Dermitzakis E.T., Pritchard J.K., Barrett J.C., Harrow J., Hurles M.E., Gerstein M.B., Tyler-Smith C. A systematic survey of loss-of-function variants in human protein-coding genes. Science, 2012, 335: 823-828 CrossRef
  13. Bickhart D.M., Hou Y., Schroeder S.G., Alkan C., Cardone M.F., Matukumalli L.K., Song J., Schnabel R.D., Ventura M., Taylor J.F., Garcia J.F., Van Tassell C.P., Sonstegard T.S., Eichler E.E., Liu G.E. Copy number variation of individual cattle genomes using next-generation sequencing. Genome Res., 2012, 22(4): 778-790 CrossRef
  14. Council on dairy cattle breeding. Inbreeding trend for holstein or red & white cows. Available Accessed February 27, 2016.
  15. Kuznetsov V.M., Vakhonina N.V. Sel'skokhozyaistvennaya biologiya [Agricultural Biology], 2010, 4: 55-58 (in Russ.). Available No date.
  16. Weigel K.A. Controlling inbreeding in modern breeding programs. J. Dairy Sci., 2001, 84(Suppl. E): E177-E184.
  17. StolpovskiiYu.A. Concept and principles of genetic monitoring for the purpose of preservation in situ of domestical animals kinds. Agricultural Biology, 2010, 6: 3-8 (in Engl.). Available No date.
  18. Marzanov N.S., Devrishov D.A., Marzanova S.N., Komkova E.A., Ozerov M.Yu., Kantanen Yu. Sel'skokhozyaistvennaya biologiya [Agricultural Biology], 2011, 2: 3-14 (in Russ.). Available No date. 
  19. Shanks R.D., Dombrowski D.B., Harpestad G.W., Robinson J.L. Inheritance of UMP synthase in dairy cattle. J. Hered., 1984, 75: 337-340.
  20. Shuster D.E., Kehrli Jr. M.E., Ackermann M.R., Gilbert R.O. Identification and prevalence of a genetic defect that causes leukocyte adhesion deficiency in Holstein cattle. PNAS USA, 1992, 89: 9225-9229 CrossRef
  21. Agerholm J.S., Bendixen C., Andersen O., Arnbjerg J. Complex vertebral malformation in Holstein calves. J. Vet. Diagn. Invest., 2001, 13: 283-289 CrossRef
  22. Agerholm J.S., McEvoy F., Arnbjerg J. Brachyspina syndrome in a Holstein calf. J. Vet. Diagn. Invest., 2006, 18: 418-422 CrossRef
  23. Georges M., Dietz A.B., Mishra A., Nielsen D., Sargeant L.S., Sorensen A., Steele M.R., Zhao X., Leipold H., Womack J.E. Microsatellite mapping of the gene causing weaver disease in cattle will allow the study of an associated quantitative trait locus. PNAS USA, 1993, 90: 1058-1062 CrossRef
  24. Charlier C., Coppieters W., Rollin F., Desmecht D., Agerholm J.S., Cambisano N., Carta E., Dardano S., Dive M., Fasquelle C., Frennet J.-C., Hanset R., Hubin X., Jorgensen C., Karim L., Kent M., Harvey K., Pearce B.R., Simon P., Tama N., Nie H., Vandeputte S., Lien S., Longeri M., Fredholm M., Harvey R.J., Georges M. Highly effective SNP-based association mapping and management of recessive defects in livestock. Nat. Genet., 2008, 40: 449-454 CrossRef
  25. VanRaden P.M., Olson K.M., Null D.J., Hutchison J.L. Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J. Dairy Sci., 2011, 94: 6153-6161 CrossRef
  26. Fritz S., Capitan A., Djari A., Rodriguez S.C., Barbat A., Baur A., Grohs C., Weiss B., Boussaha M., Esquerré D., Klopp C., Rocha D., Boichard D. Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2. PLoS ONE, 2013, 8(6): e65550 CrossRef
  27. Cooper T.A., Wiggans G.R., VanRaden P.M., Hutchison J.L., Cole J.B., Null D.J. Genomic evaluation of Ayrshire dairy cattle and new haplotypes affecting fertility and stillbirth in Holstein, Brown Swiss and Ayrshire breeds. JAM, 2013, T206.
  28. Sonstegard T.S., Cole J.B., VanRaden P.M., Van Tassell C.P., Null D.J., Schroeder S.G., Bickhart D., McClure M.C. Identification of a nonsense mutation in CWC15 associated with decreased reproductive efficiency in Jersey cattle. PLoS ONE, 2013, 8: e54872 CrossRef
  29. McClure M., Kim E., Bickhart D., Null D., Cooper T., Cole J., Wiggans G., Ajmone-Marsan P., Colli L., Santus L., Liu G.E., Schroeder S., Matukumalli L., Van Tassell C., Sonstegard T. Fine mapping for Weaver syndrome in Brown Swiss cattle and the identification of 41 concordant mutations across NRCAM, PNPLA8 and CTTNBP2. PLoS ONE, 2013, 8(3): e59251 CrossRef
  30. Pausch H., Schwarzenbacher H., Burgstaller J., Flisikowski K., Wurmser C., Jansen S., Jung S., Schnieke A., Wittek T., Fries R. Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle. BMC Genomics, 2015, 16: 312 CrossRef
  31. Kadri N.K., Sahana G., Charlier C., Iso-Touru T., Guldbrandtsen B., Karim L., Nielsen U.S., Panitz F., Aamand G.P., Schulman N., Georges M., Vilkki J., Lund M.S., Druet T. 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., 2014, 10(1): e1004049 CrossRef
  32. Cole J.B., Van Raden P.M., Null D.J., Hutchison J.L., Cooper T.A., Hubbard S.M. Haplotype tests for recessive disorders that affect fertility and other traits. AIP Research Report Genomic3, 02. Feb. 2016. Available Accessed February 09, 2016.
  33. Olson T. New genes: good and bad. Available Accessed March 02, 2016.
  34. Vierhout C.N., Cassell B.G., Pearson R.E. Comparisons of cows and herds in two progeny testing programs and two corresponding states. J. Dairy Sci., 1999, 82: 822-828 CrossRef
  35. Larkin D.M., Daetwyler H.D., Hernandez A.G., Wright C.L., Hetrick L.A., Boucek L., Bachman S.L., Band M.R., Akraiko T.V., Cohen-Zinder M., Thimmapuram J., Macleod I.M., Harkins T.T., McCague J.E., Goddard M.E., Hayes B.J., Lewin H.A. Whole-genome resequencing of two elite sires for the detection of haplotypes under selection in dairy cattle. PNAS USA, 2012, 109(20): 7693-7698 CrossRef
  36. Holstein sire Jocko Besne Passes. Holstein World, 2012. Available Accessed March 02, 2016.
  37. Kuhn M., Hutchison J., Van Tassell C. Effects of complex vertebral malformation gene on production and reproduction. J. Anim. Sci., 2005, 83(Suppl. 1): 140.
  38. Kipp S., Segelke D., Schierenbeck S., Reinhardt F., Reents R., Wurmser C., Pausch H., Fries R., Thaller G., Tetens J., Pott J., Piechotta M., Grünberg W. A new Holstein haplotype affecting calf survival. Interbull Bull., 2015, 49: 49-53.
  39. Menzi F., Besuchet-Schmutz N., Fragnière M., Hofstetter S., Jagannathan V., Mock T., Raemy A., Studer E., Mehinagic K., Regenscheit N., Meylan M., Schmitz-Hsu F., Drögemüller C. A transposable element insertion in APOB causes cholesterol deficiency in Holstein cattle. Anim. Genet., 2016, 47(2): 253-257 CrossRef
  40. Charlier C. The role of mobile genetic elements in the bovine genome. Proc. Plant and Animal Genome XXIV Conf. San Diego, 2016: W636.
  41. Charlier C., Agerholm J.S., Coppieters W., Karlskov-Mortensen P., Li W., de Jong G., Fasquelle C., Karim L., Cirera S., Cambisano N., Ahariz N., Mullaart E., Georges M., Fredholm M. A deletion in the bovine FANCI gene compromises fertility by causing fetal death and brachyspina. PLoS ONE, 2012, 7(8): e43085 CrossRef
  42. Adams H.A., Sonstegard T., VanRaden P.M., Null D.J., Van Tassell C., Lewin H. Identification of a nonsense mutation in APAF1 that is causal for a decrease in reproductive efficiency in dairy cattle. Proc. Plant and Animal Genome XX Conf. San Diego, 2012: P0555.
  43. McClure M.C., Bickhart D., Null D., VanRaden P., Xu L., Wiggans G., Liu G., Schroeder S., Glasscock J., Armstrong J., Cole J.B., Van Tassell C.P., Sonstegard T.S. Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects BH1, HH2 and HH3 reveal causative mutation in SMC2 for HH3. PLoS ONE, 2014, 9: e92769 CrossRef
  44. Daetwyler H.D., Capitan A., Pausch H., Stothard P., van Binsbergen R., Brøndum R.F., Liao X., Djari A., Rodriguez S.C., Grohs C., Esquerré D., Bouchez O., Rossignol M.-N., Klopp C., Richa D., Fritz S., Eggen A., Bowman P.J., Coote D., Chamberlain A.J., Anderson C., Van Tassell C.P., Hulsegge I., Goddard M.E., Guldbrandtsen B., Lund M.S., Veerkamp R.F., Boichard D.A., Fries R., Hayes B.J. Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle. Nature Genet., 2014, 46:  858-865 (doi: 10.1038/ng.3034).
  45. Schütz E., Wehrhahn C., Wanjek M., Bortfeld R., Wemheuer W.E., Beck J., Brenig B. The Holstein Friesian lethal haplotype 5 (HH5) results from a complete deletion of TBF1M and cholesterol deficiency (CDH) from an ERV-(LTR) insertion into the coding region of APOB. PLoS ONE, 2016, 11(4): e0154602 CrossRef
  46. De Zio D., Maiani E., Cecconi F. Apaf1 in embryonic development — shaping life by death, and more. Int. J. Dev. Biol., 2015, 59(1-3): 33-39 CrossRef
  47. Hayes B., Daetwyler H.D., Fries R., Guldbrandtsen B., Lund M.S., Boichard D.A., Stothard P., Veerkamp R.F., Hulsegge I., Rocha D., Van Tassell C., Mullaart E., Gredler B., Druet T., Bagnato A., Goddard M., Chamberlain A., 1000 Bull Genomes Consortium. The 1000 Bull Genomes project — toward genomic selection from whole genome sequence data in dairy and beef cattle. Proc. Plant and Animal Genome XXI Conf. San Diego, 2013: W150.
  48. Schmiesing J.A., Ball A.R. Jr., Gregson H.C., Alderton J.M., Zhou S., Yokomori K. Identification of two distinct human SMC protein complexes involved in mitotic chromosome dynamics. PNAS USA, 1998, 95(22): 12906-12911 CrossRef.
  49. Ng A., Uribe R.A., Yieh L., Nuckels R., Gross J.M. Zebrafish mutations in gart and paics identify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development. Development, 2009, 136(15): 2601-2611 CrossRef
  50. Nagahata H. Bovine leukocyte adhesion deficiency (BLAD): a review. J. Vet. Med. Sci., 2004, 66: 1475-1482 CrossRef
  51. Thomsen B., Horn P., Panitz F., Bendixen E., Petersen A.H., Holm L.E., Nielsen V.H., Agerholm J.S., Arnbjerg J., Bendixen C. A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acetylglucosamine transporter, causes complex vertebral malformation. Genome Res., 2006, 16: 97-105 CrossRef
  52. Nielsen U.S., Aamand G.P., Andersen O., Bendixen C., Nielsen V.H., Agerholm J.S. Effects of complex vertebral malformation on fertility traits in Holstein cattle. Livestock Production Science, 2003, 79: 233-238 CrossRef
  53. Agerholm J.S., Andersen O., Almskou M.B., Bendixen C., Arnbjerg J., Aamand G.P., Nielsen U.S., Panitz F., Petersen A.H. Evaluation of the inheritance of the complex vertebral malformation syndrome by breeding studies. Acta Vet. Scand., 2004, 45: 133-137.
  54. Schwenger B., Schöber S., Simon D. DUMPS cattle carry a point mutation in the uridine monophosphate synthase gene. Genomics, 1993, 16(1): 241-244 CrossRef
  55. Shanks R.D., Robinson J.L. Embryonic mortality attributed to inherited deficiency of uridine monophosphate synthase. J. Dairy Sci., 1989, 72(11): 3035-3039 CrossRef
  56. Shanks R.D., Popp R.G., McCoy G.C., Nelson D.R., Robinson J.L. Identification of the homozygous recessive genotype for the deficiency of uridine monophosphate synthase in 35-day bovine embryos. J. Reprod. Fertil., 1992, 94(1): 5-10 CrossRef
  57. Bulls' status for haplotypes impacting fertility on the records of Holstein Association USA. Holstein Association USA, 14.12.2015. Available Accessed March 05, 2016.
  58. Zinov'eva N.A., Gladyr' E.A., Ernst L.K., Brem G. Vvedenie v molekulyarnuyu gennuyu diagnostiku sel'skokhozyaistvennykh zhivotnykh [Introduction to molecular gene diagnosis in farm animals]. Dubrovitsy, 2002 (in Russ.).
  59. Romanenkova O.V., Gladyr' E.A., Kostyunina O.V., Zinov'eva N.A.  Dostizheniya nauki i tekhniki APK, 2015, 11: 91-94 (in Russ.).
  60. Romanenkova O.V., Gladyr' E.A., Kostyunina O.V., Zinov'eva N.A.  Dostizheniya nauki i tekhniki APK, 2016, 30(2): 94-97 (in Russ.).
  61. Zinov'eva N.A., Kostyunina O.V., Volkova V.V., Yanchukov I.N., Ermilov A.N. Molochnoe i myasnoe skotovodstvo, 2016, 2: 5-7 (in Russ.).
  62. Zinov'eva N.A., Gladyr' E.A., Kharzinova V.R., Kostyunina O.V., Pokrovskaya M.V., Drushlyak N.G., Kabitskaya Ya.A. Dostizheniya nauki i tekhniki APK, 2012, 11: 37-40 (in Russ.).
  63. Zinov'eva N.A., Strekozov N.I., Eskin G.V., Turbina I.S., Yanchu-
    kov I.N., Ermilov A.N. Zhivotnovodstvo Rossii, 2015, 6: 30-31 (in Russ.)