Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 613621 (gene) , 618242 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific description: Häfliger et al. (2021) “report the result of a large-scale reverse genetic screen in the Swiss Simmental population …. We used 115,000 phased SNP data of almost 10 thousand cattle with pedigree data. This revealed evidence for 11 genomic regions … with haplotypes (SH1 to SH11) showing a significant depletion in homozygosity and an allele frequency between 3.2 and 10.6%. For the proposed haplotypes, it was unfortunately not possible to evaluate associations with fertility traits as no corresponding data were available. …. Subsequent mining of single-nucleotide variants and short indels in the genomes of 23 sequenced haplotype carriers allowed us to identify three perfectly linked candidate causative protein-changing variants … [for haplotypes SH5, SH8 and SH9]. … Four selected haplotypes (SH5, SH7, SH8, and SH10) presented a complete deficit of observed homozygous animals, whereas the others showed a partial deficiency ranging from 85 to 96% of the expected homozygotes….”

Mapping: Häfliger et al. (2021): “Due to the application of several routinely available SNP arrays ranging from 9000 to 150,000 SNPs, the [genotyping] data had to be imputed …. haplotypes showing a deviation from the HWE, indicated by depletion of homozygosity, were identified. The first subset of data analyzed included only fully genotyped trios where the complete trio (sire, dam, and offspring) were genotyped (n = 2626), further called “trio” approach. The second dataset analyzed included genotyped trios where an offspring and two paternal animals (sire and maternal grandfather) were genotyped (n = 3969), subsequently called parent–grandparent “pgp” approach.” The SH9 haplotype was mapped to ARS-UCD1.2 Chr21: 41.855–42.851 MB (depletion in homozygosity = 96%, allele frequency = 0.043) using the trio and pgp approach.

Molecular basis: Häfliger et al. (2021): “With the selected haplotypes, we predicted individual diplotypes that represent if an animal carries one, two, or no copies of the haplotype. Based on these diplotypes, we selected three carrier animals for whole-genome sequencing (WGS) for each haplotype region. … For three deficient homozygous haplotypes (SH5, SH8, and SH9), by linkage disequilibrium analysis, we found perfectly linked (r2 = 1) candidate causal variants. … None of these variants occurred in homozygous state in any of more than 5200 sequenced cattle of various breeds. Selection against these alleles in order to reduce reproductive failure and animal loss is recommended.” SH9: NUBPL c.428C > A p.Ser143Tyr (NM_001193042.1)

Breed: Simmental (Cattle) (VBO_0000380).
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: