Patrick J. Venta Ph.D.
Small Animal Clinical Sciences
College of Veterinary Medicine
Michigan State University
East Lansing, MI 48824-1314
We are currently continuing with the whole genome linkage scan for the craniomandibular osteopthy (CMO) gene. Previously we reported that we had tested markers that were estimated to exclude approximately 30% of the gene-rich regions of the genome as containing the CMO gene. We are currently in the process of completing analysis of an additional 20 markers, about half of which are in gene-rich regions of the genome, with the other half being in regions of the genome in which the density of genes is lower but for which gene-specific markers were available. All of these markers are contained in specific genes, so that their location is known with high accuracy with respect to the human genome. This is less important now, but will be much more important when a linkage is established and the work to identify the causative gene and mutation is begun. The human and canine genomes have a great deal of similarity that will aid in moving from the linked marker to the identification of the gene.
Computer analyses of the data are not yet complete, but simple inspection of the data indicates that none of the markers tested so far are linked to the causative gene. Once complete analysis of these genes is done, we estimate that 35% of the gene-rich portion of the genome will have been tested. We plan to test an additional 50 markers in the next few months, aiming particularly for gene-rich regions because the probability of obtaining a linkage is greater at an earlier time (about 2/3 of gene-rich regions tested at that point). If all gene-rich regions are excluded then we will move to the other regions of the genome.
What will happen once a linkage is established? As we have stated before, our ultimate goal is to identify the actual causative gene and mutation. We plan to continue to work towards this end until the gene has been found. We anticipate that, with the identification of a linked marker, other groups will join in the search for the CMO gene. This happened with the copper toxicosis gene in Bedlington terriers, with at least three groups (and probably a few more) all working to identify the disease gene once the linked marker had been published. Recently, one group identified the causative gene and mutation for CT in Bedlington terriers (MURR1 is the causative gene). From published marker (Yuzbasiyan-Gurkan et al., Am. J. Vet. Res. 1997;58:23-27) to identification of the mutation (van De Sluis et al., Hum Mol Genet. 2002;ll:165-73) took about five years. We suspect that identification of the CMO gene will be less than this, based on advances made in molecular genetics in the past two years (including some developed by us in anticipation of this phase of the work). We will welcome other groups joining us to complete this task as rapidly as possible, although we will continue to search for the gene ourselves with whatever resources we have available.