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Génétique de l’infertilité : identification de gènes impliqués dans la gamétogenèse humaine.

proposé par Stéphane Viville , IGBMC 67400 Illkirch

Projet de stage : situation du sujet, objectif du stage, approches expérimentales

Human infertility is the inability to conceive after two years of regular unprotected intercourses and is due to a male factor in approximately 50% of cases. Our goal is to identify human genes involved in human gametogenesis. A second potential consequence is the identification of genes involved in the ontogeny of human PGCs. One of the main difficulties encountered in such projects is the recruitment of informative patients. In order to solve this, we have established collaborations in Turkey, North Africa (Algeria, Tunisia, Morocco) and the Middle East (Jordan, Iran, Lebanon, Saudi Arabia), where patients often come from small communities with little or no immigration and with a high degree of consanguinity. Husband and wife are thus often related and susceptible to harbor the same rare dormant recessive mutation they have inherited from a common ancestor. They are particularly suited for this type of genetically heterogeneous pathologies, as it allows the development of intra-familial strategies based on the identification of genomic regions with common parental haplotypes (homozygosity mapping). A whole genome mapping by SNP microarrays strategy to identify genes which, when mutated are responsible for an infertility phenotype, can be applied to these patients. This approach has been used successfully twice in the laboratory and two genes, SPATA16 and DPY19L2 have been identified upon studying a Jewish and a Jordanian family, respectively (Dam, Koscinski et al. 2007 ; Koscinski, Elinati et al. 2011). Both genes are responsible for a globozoospermia phenotype. These results will contribute to a better understanding of the physiopathological process of human reproduction and spermatogenesis. In the lab, we are focusing now on meiosis defects by studying azoospermic patients with maturation arrest, and infertile women producing oocytes blocked at germinal vesicule stage. The candidate will contribute to characterize the implicated genes using multidisciplinary approaches such as linkage analysis, next generation sequencing. According to the type of mutation found different strategies can be applied to prove the deleterious effect of the mutation on the encoded protein. Functional analysis of the identified protein will be conducted. The type of analysis will depend on the putative function of the protein.

Techniques mises en œuvre par le stagiaire :

Expertise scientifique : Génétique humaine, analyse bibliographique, identifications des questions scientifiques, développement des stratégies scientifiques, mise en place des expériences, analyse critique des résultats, Formulation d’hypothèses de travail, rédaction d’articles Expertise expérimentale : Biologie Moléculaire et cellulaire, analyse génomique , Bioinformatique, Culture Cellulaire, FACS.

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