Pilz, Alison Julie; (1995) Comparative mapping of loci from human chromosome 9 in the laboratory mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The construction of molecular genetic linkage maps is a crucial first stage in the structural and functional characterisation of mammalian and non-mammalian genomes. In the past the mouse has been the mammal chosen for genetic analysis because of its short gestation period and large litter sizes, the availability of inbred strains, and the ability to perform controlled matings. Linkage mapping in the mouse, with its greater capacity for resolution of closely linked genes, can be a useful tool for predicting map positions of homologous genes in human and give insights into genome evolution. I have set out to produce a comprehensive comparative map for human chromosome 9 and homologous mouse chromosomes. In areas where gene order is conserved between human and mouse then the mouse map can be used to predict gene order in man. In addition, comparative mapping information for certain markers may suggest them as candidate genes for disease loci mapping to HSA9, or human mapping information may suggest particular genes as candidates for mouse mutations. In this study the construction of the mouse genetic linkage maps was achieved by interspecific backcross linkage analysis using a backcross between a laboratory inbred strain and Mus spretus. In addition, as very little recombination was seen in the MMU2/HSA9q region of conserved synteny, the Jackson BSB and BSS interspecific backcrosses involving C57BL/6J and Mus spretus (Rowe et al., 1994), and the European Interspecific backcrosses (EUCIB; European Backcross Collaborative Group, 1994) were used to give higher resolution in order markers in this particular region further. The comparative maps were constructed using 55 markers spanning the entire length of HSA9, from the genes for the high-affinity glutamate receptor and very low density lipoprotein receptor (SLC1A1 and VLDLR) on 9p24 (Smith et al., 1994; Oka et al., 1994; Sakai et al., 1994) to N-methyl-D-aspartate receptor (GRIN1) on 9q34.3 (Karp et al, 1993; Brett et al., 1994). In areas where there are differences in gene order between the human and mouse maps I have attempted to resolve the discrepancies between the maps to determine whether the differences in gene order are due to artefacts or real rearrangements. In addition linkage maps of different strains and species of mice were compared in order to identify any variation in recombination rate due to the genetic background of the F1 animals of the backcross. In regions of the mouse genome where genes have been shown to be closely linked genetically pulsed field gel electrophoresis (PFGE) was used in order to determine whether those genes are also closely linked physically.

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