Canine polydactyl mutation associated with C7orf2/Lmbr1 gene

Abstract

The canine species including wolf and jackal have four digits on the hindlimb. It was thought that an extra first digit on the hindlimb, named dewclaw, is a hereditary defect. For genetically related canine pedigrees with seventy-three members of dewclaws, we carried out a genome-wide scan for linkage with microsatellites. With an assumption of autosomal dominant mode of inheritance, significant linkages were detected for the markers on the canine chromosome 16 (CFA 16). The maximum two-point LOD score of 20.76 was obtained for the REN85M08/REN85N14 markers at a recombination fraction of 0.00. A chromosome-wide haplotype analysis revealed the location of dewclaw locus within a few centimorgan intervals delimited by the UCMCF12 and CXX876 markers. Thus, the results indicate that the affected gene to dewclaw in the Korean breed is located on the CFA16. The chromosome is known to have syntenic relationships with the human chromosomes of 4q, 7q, and 8p. Using a synteny with the HSA 7, appropriate single-nucleotide polymorphism (SNP) markers with overlapping BAC libraries were screened and exploited to further narrow down the candidate locus into approximately two hundred kilobases. This was based on linkage disequilibrium (LD) mapping with affected individuals from the Korean breed as well as from other breeds showing allele association for the candidate locus. The affected chromosomal region contains a single C7orf2 gene. C7orf2 intron S containing the region called ZRS (ZPA regulatory sequence) has been implicated in mouse and human polydactyly. SNP typings on two thirds of the C7orfl gene including ZRS led us to define intensive LD block with more than 100 Kbs. Analysis of the haplotypes within the LD Block for individuals from 14 and 6 breeds of western and Asian origins, respectively, revealed that only a subset of five haplotypes are attributed to the western breeds among the total of nine haplotypes. The haplotype analysis with pedigree or its associations b...