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FUNCTIONAL AND STRUCTURAL ANALYSIS OF THE MOUSE GENOME

Objective


Aspects of mouse genetics which are of strategic importance for the progress of human genome analysis were studied. This covered 3 important areas:
Detection and molecular analysis of mutations which serve as models for human genetic disease, using several mutagenesis protocols. A large number of disease genes have been detected, mapped and are being further used for study of the genetic nature and functional mechanisms of the defects. An invaluable collection of mutant mouse stocks have been created in the cryopreservation project at the MRC Radiobiology Unit.

Detection, mapping and analysis of genes controlling predisposition to multigenically controlled diseases. This is a novel area of mouse genetics, concentrating on mouse models for the most common human diseases such as cancer, cardiovascular and metabolic diseases, which form a major proportion of morbidity and mortality. Although it is recognized that the development of these diseases is under strong genetic influence, it is extremely difficult to identify the relevant genes in humans. A novel genetic tool, the recombinant congenic strains method has been developed and successfully applied to the study of the genetics of colon cancer, atherosclerosis, and immune response, indicating that this broad area of genetics is open for efficient investigation.

An increasingly important area of genome analysis uses germ line modification (transgenesis, homologous recombination) through which specific genes can be added to, or deleted from, the genome. A number of methodological and conceptual contributions has been made to this area, increasing the effectiveness of the methodology and applying it successfully to gens involved in lymphoma development. The improvement of the methods of homologous recombination is of great general value to the broad application of this technology. The use of transgenic mice in combination with retroviral induction of lymphomas paved the way to identification of several novel oncogenes and definition of complementation groups of oncogenes in lymphomagenesis, which provides new insights into the molecular alterations during lymphomagenesis. This approach can serve as a general model for a more efficient analysis of the genetic alterations during tumorigenesis.
Recent advances in mutagenesis and genetic mapping, particularly in European laboratories, now make possible detailed genome analysis of the mouse, the genetically best known vertebrate. The three Institutes propose a joint effort to this end, using advanced genetic and molecular teechniques, with emphasis on the genes relevant for tumor and disease susceptibility and development, and their human homologues, and on genetic models for human disease. The specific tools developed in individual Institutes for identification and mapping of genes, namely mutant stocks, recombinant congenic strains, and interspecific backcrosses, complement each other and will also be used to correlate physical maps with linkage maps. The identified genes will be cloned and analysed for their function using transgenic mice and mutagenesis by homologous recombination.

Coordinator

THE NETHERLANDS CANCER INSTITUTE/ANTONI VAN LEEUWENHOEK HOSPITAL
Address
121,Plesmanlaan 121
1066 CX Amsterdam
Netherlands

Participants (2)

INSTITUT PASTEUR
France
Address
Rue Du Docteur Roux 25
75724 Paris
Medical Research Council (MRC)
United Kingdom
Address
20 Park Crescent
W1N 4AL London