Categories: Normal phene

Mendelian trait/disorder: unknown

Disease-related: no

History: In the course of collecting sequence data for the first pig genome assembly, Groenen et al. (2012) identified a nonsense mutation (rs81212146, c.944T>A, L315X) in the ASS1 gene, that would be expected, when homozygous, to give rise to citrullinaemia. But they reported live pigs homozygous for this variant having no signs of citrullinaemia. In a most intriguing report, Mármol-Sánchez et al. (2019) appear to have solved this mystery, by identifying a SNP (rs81212145; c.943T>C) in the first position of the same codon (315) of the porcine ASS1 gene, and showing that the C allele at the first position is in complete linkage disequilibrium with the nonsense variant c.944A that is located at the second position in the same codon 315, in a sample of Duroc pigs in which the nonsense mutation is segregating. As Mármol-Sánchez et al. (2019) report, the "wild-type" codon is TTG, encoding leucine. The nonsense mutation (c.944A, in the second position of codon 315) converts TTG to the stop codon TAG, and is thus expected to be deleterious. However, in all 323 Duroc pigs genotyped, the nonsense c.944A was in complete linkage disequilibrium with c.943C, in which case the nonsense variant is no longer nonsense, because whenever it appears, the triplet of codon 315 is CAG, which encodes glutamine. Of course, the resultant missense mutation could itself be harmful, but Mármol-Sánchez et al. (2019) report that this leucine->glutamine substitution "is predicted to be tolerated (PolyPhen‐2 score = 0.012)". The authors conclude "that the c.944T>A ASS1 mutation probably does not have pathological consequences on pigs owing to the existence of an adjacent mutation that prevents the formation of a premature stop codon." Noting that "the rs81212145 and rs81212146 SNPs are annotated as synonymous and stop gained substitutions in the Sscrofa10.2 and Sscrofa11.1 assemblies of the pig genome respectively", Mármol-Sánchez et al. (2019) suggest that "they should be jointly considered as a dinucleotide polymorphism in codon 315 with a missense effect".

Prevalence: Mármol-Sánchez et al. (2019) reported complete linkage disequilibrium between variants c.943C and c.944A (and hence also between variants c.943T and c.944T) in the genome sequences of 40 European domestic pigs, 40 Asian domestic pigs and 40 Asian wild boars.

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).