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Construction of a high resolution map of chromosome 21 integrating genetic, physical, overlap and transcriptional data

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A new molecular cytogenetic approach, termed "comparative genomic in situ hybridization" (CGH) has recently been developped by a few groups in Europe and the USA(Kallioniemi et al., 1992, Science 258:818).
In Europe, the laboratories of T.Cremer P.Lichter and M.Robert-Nicoud have pioneered this development (du Manoir et al.Hum.Genet.
1993, in press ; Joos et al.1993 Hum.Genet. in press).
CGH allows to rapidly map disease specific gains and losses of genetic material, e.g.in solid tumors or fetal cells.
In contrast to other molecular genetic techniques and conventional chromosome banding, CGH is a fast and cost-effective approach, since it requires only a single two color fluorescence in situ hybridization (FISH) experiment.
It can be applied in cases where genomic DNA from suspected cells is the only material available and appears ideally suited for automation. In this proposal, european researchers and companies leading in the fields of molecular cytogenetics, fluorescence microscopy and digital image analysis, including automated chromosome analyses, have combined their expertise to enable the further development and standardization of CGH for large scale applications.
We propose (i) to increase the sensitivity of the CGH test for the detection of small genetic changes and to make it applicable to the analysis of small numbers of cells for (e.g.
nuclei isolated from bioptic samples, body fluids, as well as nuclei from paraffinembedded tissue sections) (T.
Cremer, Heidelberg, F.R.G.) (ii) to develop image analysis procedures for improved sensitivity and automated analysis of CGH-experiments (M. RobertNicoud, Grenoble, France, in collaboration with ALCATEL-TITN-ANSWARE, Grenoble, France, and the Carl ZEISS GmbH, Oberkochen, F.R.G.) and (iii) to extensively test the potential of this new approach at each level of this development to identify specific gains and losses of genetic materials in a variety of malignant tumors and clinical specimens (P.Malet Clermont-Ferrand, France ; D.Taruscio Rome, Italy ; D.Leroux Grenoble, France). At the end of this project a dedicated instrument will have been evaluated by the laboratories partners of the project in a significant number of cancer types.
It can be already envisaged that this instrument will be subject to an industrial phase in order to make a commercial product that will be requested by potential users of CGH.
This would contribute to palliate a main weakness of the european industry with respect to economical criteria and to feedback to advanced research technology, i.e.
the lack of integration between the microscope technology and the image processing technology.
Finally, we expect that CGH will have far reaching applications in tumor research and diagnostics, as well as in clinical cytogenetics.

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