Not All SCID Pigs Are Created Equally: Two Natural Mutations Cause Severe Combined Immunodeficiency (SCID) in Pigs

SCID is a primary immune deficiency and spontaneous mutations causing SCID have been identified in humans, horses, dogs, and mice. We recently reported the first discovery of SCID in pigs in a selection line of Yorkshire pigs. Repeated matings producing SCID piglets showed the SCID mutation to be transmitted through recessive Mendelian inheritance. In order to map the causative mutation, 20 affected piglets, 50 unaffected littermates, 6 parents (unaffected), and 96 unaffected ancestors were genotyped using the Illumina Porcine SNP60 Beadchip. The dfam option of PLINK was used to perform a genome wide association study which identified a 5.6 Mb region associated with the disease status (P=2.7x10^-7). PHASE (2.1.1) analysis of SNPs in a 1 Mb region surrounding a strong candidate gene showed two distinct haplotypes associated with the SCID phenotype. Both haplotypes were traced back to the commercial Yorkshire founders of the selection line. Targeted genomic and transcriptomic sequencing supported PHASE results by revealing two independent causative mutations in the same candidate gene. These mutations cause SCID in pigs when present in either homozygous or compound heterozygous combinations. Genetic tests for these two mutations may be valuable to detect SCID carriers in commercial swine herds. Ongoing work focuses on establishing the effect of each mutation on gene function and phenotypic differences between the two mutations. EHW is a Fellow supported by USDA NIFA National Needs grant # 2010-38420-20328.