Detection of homozygous genotypes for a putatively lethal recessive mutation in the porcine argininosuccinate synthase 1 (ASS1) gene

Abstract

The sequencing of the pig genome revealed the existence of homozygous individuals for a nonsense mutation in the argininosuccinate synthase 1 (ASS1) gene (rs81212146, c.944T>A, L315X). Paradoxically, an AA homozygous genotype for this polymorphism is expected to abolish the function of the ASS1 enzyme that participates in the urea cycle, leading to citrullinemia, hyperammonemia, coma and death. Sequencing of five Duroc boars that sired a population of 350 Duroc barrows revealed the segregation of the c.944T>A polymorphism, so we aimed to investigate its phenotypic consequences. Genotyping of this mutation in the 350 Duroc barrows revealed the existence of seven individuals homozygous (AA) for the nonsense mutation. These AA pigs had a normal weight despite the fact that mild citrullinemia often involves impaired growth. Sequencing of the region surrounding the mutation in TT, TA and AA individuals revealed that the A substitution in the second position of the codon (c.944T>A) is in complete linkage disequilibrium with a C replacement (c.943T>C) in the first position of the codon. This second mutation would compensate for the potentially damaging effect of the c.944T>A replacement. In fact, this is the most probable reason why pigs with homozygous AA genotypes at the 944 site of the ASS1 coding region are alive. Our results illustrate the complexities of predicting the consequences of nonsense mutations on gene function and phenotypes, not only because of annotation issues but also owing to the existence of genetic mechanisms that sometimes limit the penetrance of highly harmful mutations.