Kinase Insert Domain Receptor - A Candidate for the Hereford “spotted” Gene

The “spotted” locus is responsible for several unique coat color phenotypes in cattle including the Hereford pattern which is characterized by a white face, underbelly, legs, and tail switch.  Since the breed is fixed for this phenotype, we postulated that a historic selective sweep occurred during breed formation to fix the spotted allele while simultaneously fixing alleles at nearby hitchhiking loci. The spotted locus in Hereford cattle was linkage mapped by Grosz and McNeil (1999) between BM4528 at 64,727,183 bp and ELO3 at 85,504,512 bp (UMD3.1) on BTA6. We examined this region in 476 registered Hereford steers genotyped with the Illumina HD assay and found a single 25,100 bp region of homozygosity containing 15 consecutive SNP markers between 72,246,623 and 72,271,723 bp. The only gene in this region is Bos taurus kinase insert domain receptor (KDR, a type III receptor tyrosine kinase) mRNA, which encodes vascular endothelial growth factor receptor 2 (VEGF-2).  Since tyrosine kinase loci including KIT1 and KITLG are known to be associated with coat color variants in cattle, KDR is strongly suggested as the candidate locus. However, we found no fixed point mutations or small indels between 11 sequenced Angus bulls (putatively homozygous for the non-spotted allele) and the Hereford reference assembly, suggesting that the causal mutation may be a large insertion or deletion.