Haplotype with homozygous deficiency HH3, SMC2-related

Phene ID

3555

Name

Haplotype with homozygous deficiency HH3, SMC2-related

Phene Name

Haplotype HH3

OMIA ID

1824

Species ID

9913

Characterised

Yes

Characterised Year

2013

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".

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.