The primary interest of the Unité de Génétique des Mammifères is in the mouse as a model organism for studying some genetically determined human diseases. Specific mutations with deleterious effects on the neuromuscular system, the integument and its derivatives or the bone tissue are under investigation at the molecular level and experiments have been undertaken to clone the relevant genes. The Unit has also undertaken investigations aimed at a better understanding of the genetic determinism of susceptibility/resistance to infectious diseases and has developed a series of new tools to help in the analysis of genetically complex traits (interspecific recombinant congenic and consomic strains).

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

1. Positional cloning of mouse mutations with deleterious effects.

Three mutations have been or are in the process of being cloned in our Group:

- digitation anormale (dan - Mrs Dominique Simon), a recessive mutation that impairs the normal process of digit development;

- progressive motor neuronopathy (pmn - Mrs Natalia Martin and Mr Jean Jaubert) a mutation with dramatic deleterious effects on the maintenance of motor-neuron integrity and

- fragilitas ossium (fro — Miss Isabelle Aubin) a mutation that is responsible for a severe syndrome of osteogenesis imperfecta.

2. The unité de Génétique des Mammifères is also interested in the analysis of the genetic determinism of susceptibility/resistance of mice to experimental infections with several pathogens. This year, a gene with a major effect on the susceptibility of mice to the flavivirus West Nile has been identified and is being cloned. Investigations in this matter are conducted in cooperation with several other research teams at the Institut Pasteur in the frame of Transverse Research Program (TRP 21 - Mr P. Després). In the unité de Génétique des Mammifères this subject is dealt with by Mr Tomoji Mashimo and Mrs Dominique Simon.

3. The unité de Génétique des Mammifères has developed inbred strains of a new kind that represent powerful tools for the analysis of the genetic 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: Mus spretus (strain SEG/Pas) on the one hand (2-4%) and C57BL/6, the background strain (96-98%) on the other. Analyzing the phenotype of these strains for any trait that is different in the parental strains may help in the localization of the relevant genes (MM. Xavier Montagutelli, Marek Szatanik and Jean-Louis Guénet).

4. The unité de Génétique des Mammifères is also interested in the identification of genes whose action is either to alleviate or to worsen the phenotypic expression of a mutation with a deleterious phenotype. A mouse model of erythropoietic protoporphyria (mutation Ferrochelatase deficiency - Ms Abitbol and M. Xavier Montagutelli) is being investigated as an example for the action of modifier genes.

In addition to its scientific activity the unité de Génétique des Mammifères performs, as a service, genetic mapping of cloned DNA sequences for scientists requesting this information.

FLEURANCE Isabelle, ifleur@pasteur.fr

MONTAGUTELLI Xavier, IP (Scientist, xmonta@pasteur.fr)

MASHIMO Tomoji, Postdoc

SZATANIK Marek (Technician, szamar@pasteur.fr)