International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F44 Towards the Positional Cloning of the Mouse Deafness Mutant Quivering

N. J. Parkinson, J. McKee-Johnson, V. A. Street, C. Olsen, B. L. Tempel. Virginia Merrill Hearing Research Centre, University of Washington Medical School, Seattle, Washington

The quivering mouse is the only documented model of a deafness disorder caused by central nervous dysfunction. In addition affected mice display progressive hind-limb ataxia and pronounced whole body tremors. Seven alleles of quivering have been described with varying degrees of severity.

A fine scale genetic map has been produced by analyzing over 2000 meisoses from both intersubspecific back cross and inter cross breeding strategies. Upon localization of the qv locus to a 0.12cM genetic region, a physical map was initiated. Screening BAC libraries with non-recombinant and flanking recombinant polymorphic markers identified 14 clones which create two distinct non-overlapping contigs. Sequencing of one of the largest clones within the region identified two gene candidates and a single polymorphic microsatellite. Two further coding sequences have been highlighted as candidates on the basis of function and genetic map position. All candidates have been analyzed and shown to be unaltered with respect to wild-type in at least three of the seven quivering alleles by both Northern blot hybridization and direct sequence analysis.

Further physical mapping techniques such as BAC end capture and direct sequencing are being employed to complete the contig across the qv critical region. In addition, parallel studies such as cDNA hybrid selection, exon trapping and EST mapping are being used to isolate further candidate coding sequences from within this region. Once identified, the wealth of information offered by analyzing the genotype/phenotype relationship of all seven qv alleles should provide considerable insights into the biological function of the qv protein and the underlying biology of central nervous conductance and distribution of signals from the inner ear.

 


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