Unit: Mammalian Genetics - URA 2578

Director: Montagutelli Xavier

The interest of the Unité de Génétique des Mammifères is in the mouse as a model organism for studying several human diseases with genetic determinism. Specific mutations, with deleterious effects on the neuromuscular system, the integument and its derivatives or the bone tissue have been investigated over the last years. The Unit has also aims at a better understanding of the genetic determinism of susceptibility/ resistance to infectious diseases, with special emphasis on the innate mechanisms of defence. Finally, the Unité has developed a series of tools to help with the analysis of traits with a complex determinism (interspecific recombinant congenic and consomic strains).

The Unité de Génétique des Mammifères focuses its scientific activity on four main topics:

1. Positional cloning of four mouse mutations with deleterious effects:

- digitation anormale and malformed digits (dan mdig - Mrs Dominique Simon), two recessive mutations that impair the normal process of digit development;- paralysé and frissonnant (par and fri - MM Asadollah Aghaie, Jean Jaubert and Marek Szatanik) two mutations with severe effects on the motoneurons.- fragilitas ossium (fro - Miss Isabelle Aubin) a mutation that leads to a severe form of juvenile osteogenesis imperfecta.

These projects have been completed (articles already published or in preparation) and this scientific topic will be terminated.

2. Analysis of the genetic determinism of susceptibility/resistance of mice to experimental infections with several pathogens. A gene with a major effect on the susceptibility to the West Nile flavivirus has been identified and is being analysed (2'-5' OAS). Mrs Dominique Simon is currently preparing a series of transgenic mice with the aim to analyze the function of individual Oas genes. Susceptibility of mice to Yersinia pestis and Rift Valley fever virus is also being considered (M. Marek Szatanik). These investigations are conducted in collaboration with other research teams at the Institut Pasteur.

3. Identification of modifying genes which modulate the phenotypic expression of a mutation with a deleterious phenotype. A mouse model of erythropoietic protoporphyria is being investigated as an example (mutation Ferrochelatase deficiency - Ms Abitbol and M. Xavier Montagutelli). The identification of modifying genes with major phenotypic effect is in progress.

4. Development of interspecific recombinant congenic (IRCS) or consomic (ICS) strains as tools for the analysis of the determinism of complex or multigenic traits. The genome of these strains results from a very unequal contribution of two parental strains belonging to two different species of the genus Mus: 2 to 4% of the genome originating from Mus spretus (strain SEG/Pas) is interspersed into an otherwise C57BL/6 genetic background. Several quantitative traits are currently under study using these tools (MM. Xavier Montagutelli, Gaëtan Burgio and Marek Szatanik).

Keywords: mice, mutations, models, quantitative genetics, susceptibility to experimental infections

Activity Reports 2005 - Institut Pasteur

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