Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 605576 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific name: Haplotype HH3

Species-specific symbol: HH3

Inheritance: Häfliger et al. (2022) reported that "no single homozygous carrier of the SMC2 . . . [variant] was observed neither in the current population of more than 14 thousand Swiss dairy cattle nor in any other breed of cattle included in the 1000 Bull Genomes project".

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." Häfliger et al. (2022) confirmed the effect of the SMC2 variant (OMIA variant 211) in Swiss Holsteins.

Breed: Holstein (black and white) (Cattle) (VBO_0000237).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: