OMIA 001824-9913 : Abortion due to haplotype HH3 in Bos taurus

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive Lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific name: Haplotype HH3

Species-specific symbol: HH3

Mapping: Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. Three of these haplotypes occur in Holsteins only, and (following a convention proposed by breed-association staff) VanRaden et al. (2011) named them HH1, HH2 and HH3, where the first H stands for Holstein and the second H for haplotype. The disorder described in this OMIA entry is HH3, which maps to chromosome BTA8, at 90-95Mb (UMD 3.0 genome assembly). Fritz et al. (2013) confirmed the existence and location of this deleterious haplotype.

By genotyping each of 7,937 Nordic Holstein bulls with the BovineSNP50 BeadChip, yielding 36,387 informative autosomal SNPs, and then searching for 25-marker haplotypes that never occur as a homozygote where the minimum expectation is 6 occurrences, Sahana et al. (2013) "identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions harboring possible recessive lethal alleles". One of the eight regions (marked by haplotypes 08-1276, 08-1301, 08-1326 and 08-1351) seems to coincide with HH3.

McClure et al. (2014) refined the map location of haplotype HH3 on chromosome BTA8 to 95,057,877 to 95,468,310 (UMD3.1).

Molecular basis: Using inferred haplotypes from the 1000-bull-genomes project, Hayes et al. (2013) announced the discovery of the likely HH3 causal mutation.

Using exome capture and next-gen sequencing, McClure et al. (2014) confirmed and validated Hayes et al. (2013)'s causal mutation mutation as "a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the NTPase domain of the encoded protein. . . . Given the essential role of SMC2 in DNA repair, chromosome condensation and segregation during cell division, our findings strongly support the non-synonymous SNP (T/C) in SMC2 as the likely causative mutation."

Full details of the Hayes et al. (2013) discovery were provided by Daetwyler et al. (2014). In summary: "There was a single bull identified as a carrier of the derived HH3 region in the 1000 bull genomes project data set on the basis of the inferred haplotype. After filtering for mutations that were (i) carried in the heterozygous state by the HH3 carrier bull, (ii) absent in the 63 predicted non-carrier Holstein bulls, (iii) absent in the homozygous state in the Holstein bulls with unknown status and (iv) absent in the other breeds (assuming that the deleterious mutation is recent), only 1 candidate mutation was retained in the HH3 region: a thymine-to-cytosine transition at position 95,410,507 (g.95410507T>C) [UMD3.1]." For validation, the mutation "was genotyped by PCR and Sanger sequencing in a panel of 10 known HH3 carriers; all were heterozygous for the mutation, supporting the association between the HH3 region and the g.95410507C allele. As an additional test, 5,606 Holstein individuals were each genotyped in duplicate for the g.95410507T>C mutation using a custom Illumina BeadChip (all duplicate pairs were concordant). In agreement with the hypothesis that this mutation causes embryonic lethality, no individual with a CC genotype was detected (P < 0.06), whereas 2,476 individuals with the TT genotype and 171 individuals with the TC genotype were identified. In addition, 2,344 Montbeliarde individuals and 615 Normandy individuals were homozygous for the wild-type allele."

Breed: Holstein.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
SMC2 structural maintenance of chromosomes 2 Bos taurus 8 NC_037335.1 (93705340..93755402) SMC2 Homologene, Ensembl, NCBI gene


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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Friesian Holstein Abortion due to haplotype HH3 SMC2 missense UMD3.1 8 g.95410507T>C c.3404T>C p.F1135S rs456206907 2014 24667746 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2016 Cole, J.B., Null, D.J., VanRaden, P.M. :
Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility. J Dairy Sci 99:7274-88, 2016. Pubmed reference: 27394947. DOI: 10.3168/jds.2015-10777.
Segelke, D., Täubert, H., Reinhardt, F., Thaller, G. :
Considering genetic characteristics in German Holstein breeding programs. J Dairy Sci 99:458-67, 2016. Pubmed reference: 26601581. DOI: 10.3168/jds.2015-9764.
2014 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., Rocha, D., Fritz, S., Eggen, A., Bowman, P.J., Coote, D., Chamberlain, A.J., Anderson, C., VanTassell, 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. Nat Genet 46:858-65, 2014. Pubmed reference: 25017103. DOI: 10.1038/ng.3034.
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 a putative causative mutation in SMC2 for HH3. PLoS One 9:e92769, 2014. Pubmed reference: 24667746. DOI: 10.1371/journal.pone.0092769.
2013 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 8:e65550, 2013. Pubmed reference: 23762392. DOI: 10.1371/journal.pone.0065550.
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 Plant Anim Genome XXI Conf. San Diego, CA :Abstr W150, 2013.
Sahana, G., Nielsen, U.S., Aamand, G.P., Lund, M.S., Guldbrandtsen, B. :
Novel harmful recessive haplotypes identified for fertility traits in nordic holstein cattle. PLoS One 8:e82909, 2013. Pubmed reference: 24376603. DOI: 10.1371/journal.pone.0082909.
2011 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 94:6153-61, 2011. Pubmed reference: 22118103. DOI: 10.3168/jds.2011-4624.

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  • Created by Frank Nicholas on 12 Jun 2013
  • Changed by Frank Nicholas on 12 Jun 2013
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