In a shake of a lamb's tail: using genomics to unravel a cause of chondrodysplasia in Texel sheep

Summary Chondrodysplasia in Texel sheep is a recessively inherited disorder characterized by dwarfism and angular deformities of the forelimbs. A genome-wide association study using the Illumina OvineSNP50 BeadChip on 15 sheep diagnosed as affected and eight carriers descended from three affected rams was conducted to uncover the genetic cause. A homozygous region of 25 consecutive single nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 1 Mbp on ovine chromosome 4. Seven positional candidate genes – including the solute carrier family 13 (sodium/sulphate symporters), member 1 (SLC13A1) – were identified and used to search for new SNPs for fine mapping of the causal locus. The SLC13A1 gene, encoding a sodium/sulphate transporter, was the primary candidate gene attributable to similar phenotypes observed in the Slc13a1 knockout mouse model. We discovered a 1-bp deletion of T (g.25513delT) at the 107 bp position of exon 3 in the SLC13A1 gene. Genotyping by direct sequencing and restriction fragment length polymorphism analysis for this mutation showed that all 15 affected sheep were g.25513delT/g.25513delT; the eight carriers were g.25513delT/T and 54 normal controls were T/T. The mutation g.25513delT shifts the open reading frame of SLC13A1 to introduce a stop codon and truncate C-terminal amino acids. It was concluded that the g.25513delT mutation in the SLC13A1 gene was responsible for the chondrodysplasia seen in these Texel sheep. This knowledge can be used to identify carriers with the defective g.[25513delT] allele to avoid at-risk matings to improve animal welfare and decrease economic losses.