Balancing selection at a premature stop mutation in the myostatin gene underlies a recessive leg weakness syndrome in pigs.

Balancing selection provides a plausible explanation for the maintenance of deleterious alleles at moderate frequency in livestock, including lethal recessives exhibiting heterozygous advantage in carriers. In the current study, a leg weakness syndrome causing mortality of piglets in a commercial line showed monogenic recessive inheritance, and a region on chromosome 15 associated with the syndrome was identified by homozygosity mapping. Whole genome resequencing of cases and controls identified a mutation causing a premature stop codon within exon 3 of the porcine Myostatin (MSTN) gene, similar to those causing a double-muscling phenotype observed in several mammalian species. The MSTN mutation was in Hardy-Weinberg equilibrium in the population at birth, but significantly distorted amongst animals still in the herd at 110 kg, due to an absence of homozygous mutant genotypes. In heterozygous form, the MSTN mutation was associated with a major increase in muscle depth and decrease in fat depth, suggesting that the deleterious allele was maintained at moderate frequency due to heterozygous advantage (allele frequency, q = 0.22). Knockout of the porcine MSTN by gene editing has previously been linked to problems of low piglet survival and lameness. This MSTN mutation is an example of putative balancing selection in livestock, providing a plausible explanation for the lack of disrupting MSTN mutations in pigs despite many generations of selection for lean growth. Author summary Lameness is an important problem in livestock production for both animal welfare and economic reasons. A severe piglet lameness syndrome was observed in a commercial pig population. The incidence of the condition was low (6.3%), but was higher in affected families (25%), which suggested a genetic basis and a recessive mode of inheritance. We discovered a region on Chromosome 15 where cases shared the same alleles that were different to healthy piglets. In this region, we discovered a mutation that causes a premature stop codon in the myostatin gene. Myostatin causes double-muscle' phenotype in several mammalian species. Piglets with two copies of this mutant allele suffer the lameness syndrome and do not survive post 40 kg live weight. However, those that carry a single copy have higher muscle depth and lower fat depth compared to wild type. We suggest that despite the negative consequences of the mutant allele in homozygous form, the mutation was maintained in the herd due to positive selection for this allele in heterozygous form. This is an interesting example of so-called balancing selection' and may explain why naturally occurring myostatin mutations have not previously been reported in pigs despite centuries of selection for lean growth.