Genetic and Physical Mapping of the Rat agu Locus

Craig, Nicola Jane (1998) Genetic and Physical Mapping of the Rat agu Locus. PhD thesis, University of Glasgow.

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Rats homozygous for a mutation in the agu gene display reduced ability to initiate movement and slow movement. The phenotype of these rats is of particular interest as they display the closest available non-human phenotype to Parkinson's Disease and other neurodegenerative diseases. The rats show rigidity of the hindlimbs resulting in a staggering gait and a tendency to fall over every few steps. The major characteristic of the disorder, which is progressive, is difficulty in initiating movement. The mutation leading to this phenotype is a recessive mutation in single autosomal gene, and displays full penetrance in backcross progeny. AS/AGU rats have a 30-35% reduction of neostriatal dopamine when compared to control AS rats. These animals respond well to L-Dopa treatment. This thesis presents progress towards the positional cloning of the agu gene. Since few informative markers were available in the region where agu is found to map in rat, new microsatellite markers were isolated from P1 clones identified to contain rat genes from the interval or from regions of synteny in mouse and man. These novel microsatellite markers were used to refine the genetic interval containing agu. The 3' UTR of rat genes mapped to the interval containing the agu locus were also investigated for SSCPs. Microsatellite markers from the region of synteny in mouse were also investigated for strain differences between the rat strains used, to allow mapping. Novel markers identified from the P1 clones were used in conjunction with published markers to position the agu gene within a region of approximately 10 cM. A marker was identified which maps less than 0.1 cM from the agu locus. This marker was identified within the 3' UTR of a rat gene and was used in a screen of rat genomic PI and YAC libraries. Another probe designed to the 5' UTR of this gene was also used in a screen of a rat PAC library. One PI clone, seven YAC and three PAC clones were isolated in this initial screen using the closest marker. The cloned end sequences of one of these PACs were then used in a further screen of the PAC library, resulting in seven PAC clones. All of these clones have been used to establish a genomic contig spanning at least 750 kb, thought to contain the agu gene.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Genetics
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-74477
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 18:10
Last Modified: 27 Sep 2019 18:10

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