Canine TCOF1; cloning, chromosome assignment and genetic analysis in dogs with different head types

We describe the construction of a dog embryonic head/ neck cDNA library and the isolation of the dog homolog of the Treacher Collins Syndrome gene, TC OF1. The protein shows a similar three-domain structure to that described f or human TCOF1, but the dog gene lacks exon 10 and contains two exons not p resent in the human sequence. In addition, exon 19 is differentially splice d in the dog. How these structural differences relate to TCOF1 phosphorylat ion is discussed. Isolation of a genomic clone allowed the exon/intron boun daries to be characterized and the don TCOF1 gene to be mapped to CF Chr 4q 31, a region syntenic to human Chr 5. Genetic analysis of DNA of dogs from 13 different breeds identified nine DNA sequence variants, three of which g ave rise to amino acid substitutions. Grouping dogs according to head type showed that a C396T variant, leading to a Prol 17Ser substitution, is assoc iated with skull/face shape in our dog panel. The numbers are small, but th e association between the T allele and brachycephaly, broad skull/short fac e, was highly significant (p = 0.000024). The short period of time during w hich the domestic dog breeds have been established suggests that this mutat ion has arisen only once in the history of dog domestication.