Categories: Mortality / aging (incl. embryonic lethal)

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 610181 (trait) , 610326 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Cross-species summary: Phenes previously called ‘Abortion due to halplotype ….. ’ or ‘Abortion (embryonic lethality)’ , have been renamed to ‘Haplotype with homozygous deficiency, …’ or a phene name that is descriptive of the phenotype observed in homozygous affected animals [14/1/2022

Mapping: By conducting a GWAS on 4,072 Holstein-Friesian, 1,177 Jersey, 894 Danish Red, 1,714 Swedish Red, and 2,242 Finnish Ayrshire progeny-tested bulls, each genotyped with the 50K bovine SNP chip (yielding 37,123 informative SNPs across the five breeds), Kadri et al. (2014) identified a QTL for fertility on chromosome BTA12 in Finnish Ayrshires and Swedish Reds. By utilising additional genotyping and whole-genome next-gen sequencing data, these authors were able to attribute the QTL to a 662,463 bp deletion between 20,100,649 to 20,763,116 bp, which "encompasses three protein-encoding genes (RNASEH2B, GUCY1B2 and 3 out of 4 exons of FAM124A), one gene with uncertain coding potential (DLEU7) and two non-coding RNA genes (DLEU7-AS1 and LINC00371)". Mesbah-Uddin et al. (2022) identified the same location: “We performed single-marker association analysis for 8 female fertility traits … in HOL [Holstein], RDC [Nordic Red Dairy cattle], and JER [Jersey] cattle using imputed WGS SNPs, indels, and deletions. … In RDC, 13 deletions reached genome-wide significance; associated phenotypes included 7 fertility traits … . The strongest association was observed for a previously known lethal deletion on chromosome 12 located between position 20,100,648 and 20,763,119 bp ….”

Molecular basis: As reported by Kadri et al. (2014), one of the genes in the deletion (see Mapping section), namely RNASEH2B, is "known to cause embryonic lethality when knocked-out in the mouse". Subsequent investigations confirmed that this deletion is a recessive embryonic lethal in cattle but "is associated with a positive effect on milk yield and composition", which results in selection favouring heterozygotes (balancing selection), thereby maintaining the lethal deletion in the population.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Prevalence: Wu et al. (2020) reported a frequency of 12.9% for the tag haplotype of this recessive lethal effect in 19,309 Nordic Red Dairy cattle.

Breed: Nordic Red (Cattle) (VBO_0016847).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: