A nonsense mutation in the porcine myostatin gene is a candidate causative variant for a recessive leg weakness syndrome and affects muscle depth

Lameness in piglets is a major animal welfare and economic problem in pig production. Following observation of a high incidence of a leg weakness syndrome in a commercial pig lines, a variance components approach was used to assess the genetic basis of the condition. The results suggested a monogenic recessive mode of inheritance, and homozygosity mapping was used to identify a region associated with the leg weakness syndrome on SSC15. Whole genome resequencing of cases and controls identified an outstanding candidate mutation in this region which results in a premature stop codon within exon 3 of the porcine MSTN locus. Myostatin (MSTN) is a transforming growth factor-β family member that is a critical regulator of skeletal muscle development. Mutations in the MSTN gene lead to muscle hypertrophy and are responsible for the ‘double muscling’ phenotype observed in several mammalian species, and is a common target for gene editing experiments in farm animals. The candidate causal mutation in MSTN was in Hardy-Weinberg equilibrium at birth, but significantly distorted amongst animals still in the herd at 110 kg weight. In heterozygous form, the MSTN mutation was associated with a major increase in muscle depth and decrease in fat depth, explaining 31 and 18 % of the genetic variation respectively. MSTN ablation by gene editing in pigs is associated with problems of low piglet survival and lameness. Thus, in the current population, it is likely that this MSTN mutation was deleterious for piglet survival, but was maintained due to selection for increased muscle associated with heterozygous animals. The association between this MSTN mutation and fitness traits (leg weakness, survival) has clear implications for the potential use of gene editing of the porcine MSTN locus for increased meat production, and provide a plausible explanation for the lack of disrupting MSTN mutations in pigs despite intense selection for lean growth and their relatively high frequency in other species.