Malas, Stavros; (1995) Genetics and physical mapping studies on mouse chromosome 2. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes two genetic maps of mouse chromosome 2 (MMU2), genetic maps relative to the wasted (wst) and Ragged (Ra) mutations on distal MMU2 and a physical map of the region likely to contain the latter two genes. The first two maps include 18 new PCR markers which were isolated from a subgenomic library constructed from a mouse-hamster somatic cell hybrid line whose main mouse-genome component was MMU2. Fourteen of these loci define microsatellite sequences and four represent randomly chosen DNA sequences. The maps were constructed using two interspecific backcrosses established using a laboratory mouse strain and mice from the related species Mus spretus. The inheritance pattern on MMU2 reveals loci that exhibit significant segregation distortion (SD) in males. The genes responsible for the wasted (wst) and ragged (Ra) phenotypes are very closely linked (0.2 cM) on the extreme end of MMU2. Two interspecific backcrosses segregating wst and Ra were set up in order to define the genetic position of these loci relative to currently available molecular markers. In total, 167 wst/wst and 329 Ra/+ or +/+ mice were phenotyped for 5 microsatellites and two genes which, on the basis of the consensus map, would be expected to map near wst and Ra. The gene order established is: D2Ucl1, Gnas- 1.8 cM ± 1.0, D2Mit200- 1.8 cM ± 1.0, D2Mit230 0.6 cM ± 0.6, D2Mit74- 0.6 cM ± 0.6, Acra4- 0.6 cM ± 0.6, D2Mit266, wst D2Ucl1, Gnas- 1.2 cM ± 0.6, D2Mit200- 0.6 cM ± 0.4, D2Mit230- 0.6 cM ± 0.4, D2Mit74, Acra4, D2Mit266, Ra In an attempt to isolate flanking markers for both mutations, four overlapping yeast artificial chromosomes (YACs) were isolated and analysed by way of fluorescence in situ hybridisation (FISH), Southern blot and PCR analysis. These clones span a region of at least 360 kb and encompass the markers D2Mit74, Acra4 and D2Mit266\ the contig extends at least 200 kb proximal and 160 kb distal to Acra4. In the context of this work, a framework physical map extending 200 kb proximal and 310 kb distal to this gene was also established. Two YACs were found to span the T(2;16)28H translocation breakpoint. On the basis of these results, D2Mit74 is tentatively proposed to reside proximal to the breakpoint. All the genes which map to human chromosome 20 also map to distal MMU2 and the order appears to be conserved. The human homologues of Ra and wst would be expected to map on 20q13.1→ qter. The human homologue of the rat gene for vitamin D3 24-hydroxylase (CYP24) maps to 20q13.1→ qter. In this study, the mouse homologue of this gene (Cyp24) was localised to distal MMU29 cM proximal to Ra.

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