Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602276 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: TADA2A is a protein involved in general transcription machinery.

Species-specific name: Haplotype DU1

Species-specific description: Derks et al. (2019) identified five relatively frequent haplotypes for which there was either a deficit or a complete lack of homozygotes in large populations of Landrace (28,085) and Duroc (11,255). One such haplotype (DU1) was found in the Duroc population and is the subject of this entry. Derks et al. (2019) identified that a "splice donor mutation in the TADA2A gene results in embryonic lethality in the Duroc breed". (Edited by Emmi Payten 17/8/2021)

History: This haplotype was first identified in a 2019 study from two commercial pig populations in Norway (Derks et al., 2019). (Edited by Emmi Payten 17/8/2021)

Mapping: Derks et al. (2019): "To identify lethal alleles segregating in the pig populations we examined genotype data from 28,085 (Landrace), and 11,255 (Duroc) animals. All animals were genotyped or imputed to a medium-density 50K SNPchip ... . The genotypes were phased to build haplotypes, and then we applied an overlapping sliding window approach to identify haplotypes that show a deficit in homozygosity ... . The analysis yielded one strong candidate haplotype (DU1) harbouring a lethal recessive allele in the Duroc population, and four candidates in the Landrace population (LA1-4), respectively." (Edited by Emmi Payten 17/8/2021)

Molecular basis: Derks et al. (2019): "Whole genome sequence data from nine DU1 carrier animals revealed 20 variants in high LD .... with the DU1 haplotype ...., of which only one variant is predicted to have high impact. ... [The] splice-donor mutation (12:g.38922102G>A) in the Transcriptional adapter-Ada2 (TADA2A) gene is in complete LD with the DU1 haplotype ... . The mutation affects a conserved GT splice dinucleotide site at the 5’ end of the intron between exons 13 and 14 ... . Carriers display either retention of intron 13 between exon 13-14… or "exon skipping of exon 13, resulting in a frameshift, the addition of a novel methionine, and a premature stop codon in the first codon of exon 14. The mutant mRNA codes for a truncated TADA2A protein lacking the terminal 101 amino acids that includes the conserved SWIRM domain" for DNA binding (Derks et al. 2019). (Edited by Emmi Payten 17/8/2021)

Clinical features: Derks et al. (2019): "analysed the effect of the haplotypes on fertility phenotypes including total number born (TNB), number born alive (NBA), number of stillborn (NSB), and number of mummified piglets (MUM)." The reduction in litter size (total number born) in carrier x carrier matings, compared with carrier x non-carrier matings, was 21.6%. "No significant increase in number of stillborn (NSB) or mummified piglets (MUM) was found, suggesting that homozygotes die very early in pregnancy." (Edited by Emmi Payten 17/8/2021)

Prevalence: Derks et al. (2019) reported the carrier frequency of haplotype DU1 as 9.6%, with zero observed homozygotes.

Breed: Duroc (Pig) (VBO_0001127).
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: