Gillett, Godfrey Tregelles; (1999) Use of irradiation hybrids in gene mapping on human chromosome 11. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The original objective of the work described in this thesis was the development of genetic and physical mapping resources on human chromosome 11q23 in order to facilitate the positional cloning of a putative locus for Tuberous Sclerosis in that region of the chromosome. To this end I constructed a panel of high dose irradiation hybrids using as a starting point a human-hamster somatic cell hybrid retaining chromosome 11 as its only human material. Forty-seven of the hybrids were characterised in detail by molecular methods and also in some cases by fluorescent in situ hybridisation. A promising hybrid (Jol2) was subcloned further to derive a hybrid containing only 11q23 as its human component. By this time it had become clear that most cases of Tuberous Sclerosis can be accounted for either by mutations at TSCl (9q34) or TSC2 (16p13) and that a locus on chromosome 11, if it exists, must account for very few cases of the disease, making an attempt at positional cloning impractical. The hybrids were therefore used in collaboration with others for the development of region specific probes, some of which were directly useful in the mapping and ultimately the cloning of genes causing ataxia telangiectasia (11q23) and multiple endocrine neoplasia type 1 (11q13). In particular I was able to show that Alu-PCR products from well-characterised hybrids could be used in a rapid and reliable way to obtain regionally defined cosmid clones from the gridded chromosome 11 library available from ICRF. In the course of this work I made use of these and other hybrids to provide new chromosomal localisations for several other genes including those coding for cofilins (CFL1 and CFL2), a fucosyl transferase (FUT4), a retinoic receptor (RXRB) and a mitochondrial NAD-dependent malic enzyme.

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