The goal of this project is to localize precisely genes that cause deafness or hearing loss in mice and humans. The gene that causes autosomal recessive deafness with no other known anomalies in the deafness (dn/dn) mouse will be mapped by taking advantage of intersubspecific backcrosses between the dn/dn mice and the relatively distant related Mus musculus molossinus. A set of multilocus DNA markers will be typed on 100 backcross progeny and recombination fractions will be estimated by counting the number of recombinants and non-recombinants. Comparative mapping is an extremely useful method for identifying likely locations of genes in the human genome. Thus, localizing the dn gene in the mouse genome will provide a candidate region in the human genome for a gene causing autosomal recessive deafness. The studies proposed in humans will determine the locations of genes that cause Usher syndrome type I and other clinically distinct types of hearing loss with retinitis pigmentosa. Families with these diseases have been identified in the Acadian population of southwestern Louisiana. This population is relatively inbred and is therefore ideal for genetic studies of deafness and hearing loss because it is likely that the same gene is causing a particular disease in a set of related families. Linkage analysis of a set of highly polymorphic DNA markers that span the human genome at 20-30 centimorgan intervals will be performed in order to find the approximate location of the gene causing the disease in each set of families. Tightly flanking markers will then be determined by analyzing all polymorphic loci assigned to the region in which the gene is located. Linkage disequilibrium will be examined at each of the tightly linked markers to provide additional data for physical mapping studies to isolate the gene. The linked markers will provide important information for determining the probability that an unaffected relative is a carrier of the gene. This information will be combined with that obtained from the audiological studies being performed in Project III in order to determine the posterior probability that an unaffected relative is a carrier of a recessive gene for hearing impairment.
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