Caractérisation de nouveaux gènes et polymorphismes potentiellement impliqués dans les interactions hôtes-pathogènes

Informations générales
Détails de la thèse/HDR
Crouau Roy
Directeur (pour les thèses)
Daniel Olive
Laurent Abi-Rached
Résumé en anglais
Host-pathogen co-evolution and interactions contribute in shaping the genetic diversity of both organisms. The objective of this thesis is to define the genetic basis of variability in disease resistance/susceptibility through the development of large-scale in silico screens to identify novel gene candidates implicated in host-pathogen interactions (such as tuberculosis). A pilot study was conducted on CD28, CTLA4, and ICOS to investigate their polymorphism and determine if there was a correlation between variation in their coding regions and the Single Nucleotide Polymorphism (SNP) CT60 of CTLA4 that is associated with autoimmune diseases. Our results showed that CD28 and ICOS are highly conserved, while CTLA4 has two common allotypes. Population genetics analyses indicate that balancing selection maintains this polymorphism in the leader (p=0.001), but, no coding variation correlates with the SNP CT60. As a first step in our study based on data available in the literature, we selected a set of ten genes relevant for the immune response against Mycobacterium tuberculosis: BTLA, TNFRSF14, TNFRSF1B, CCL2, TLR2, INFG, IFNGR, VDR, NRAMP1, and CISH. Seven of these genes were moderately polymorphic, while three of them (IFNG, CCL2, CISH) were highly conserved. This analysis was used to prepare and setup the large scale analysis using the same developed pipeline for polymorphism detection and allele reconstruction. For our in silico screens to identify novel candidates at a large-scale, we used sequence data from several projects and consortiums (like the 1000 Genomes Project, HGPD and others) to isolate most polymorphic human genes amongst a list of over 1760 candidates selected based on a) already established relevance for infections (tuberculosis in particular, by literature searches) and b) on evolutionary considerations (multigenic families, structural domains, etc.). A first screen of 64 individuals from eight different populations from several regions of the world (1000 Genomes project) was performed and most variable genes were selected for more further extensive analyses on a larger panel (715 individuals). 30 most polymorphic genes were thus identified. The extent of polymorphism and the allelic worldwide variants of each of these 30 genes are ready to be fully characterized. The data generated could be compared against infectious disease resistance/susceptibility data to identify potentially relevant gene variation.