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MICE, KNOCKOUT --- PHYSIOLOGY --- MICE, KNOCKOUT --- PHYSIOLOGY

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The problem of reverse-engineering biological networks has attracted a lot of attention in the last decades. Studying the interactions occurring inside a living organism is of great importance to understand the behavior of biological systems. The development of computer science and the abundance of new genetic data raised the question of predicting gene regulatory networks. These networks describe how some genes regulate the expression of some other genes.

Many methods have already been developed to infer these networks from gene expression data. Among them, GENIE3, a method based on Random Forests, was proposed and achieved state-of-the-art performance. However, one drawback of GENIE3 is its inability to use the specificities of some types of gene expression measurements, potentially missing useful information. In particular, datasets often include knockouts, which are measurements done after the deletion of a gene.

This thesis proposes new variants for GENIE3, based on the idea of enriched random forests, in order to integrate knockout specific information as weights guiding GENIE3 to a better prediction. First, the methods are tested on ideal cases where a knockout of every gene is available. Better predictions are indeed achieved and several ways of achieving the best results are highlighted. Realistic cases are then tested. Less convincing results are then obtained, although interesting phenomena are discovered.

The second part of the thesis studies the possibility of predicting the effect of knockouts. Differences and similarities with the GRN prediction problem are analyzed and a method of evaluation, although imperfect, is proposed. Several methods are then evaluated, showing relatively encouraging results. Some initiated reflections call for future developments.

The possibility of using the proposed weighted GENIE3 methods in other situations is also briefly explained. Important improvements are indeed achieved on several datasets without the use of knockouts.

gene regulatory network --- machine learning --- random forest --- enriched random forest --- knockout --- GRN inference --- Z-score --- Ingénierie, informatique & technologie > Sciences informatiques

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La transplantation xénogénique du porc à l'homme est une entreprise multidisciplinaire complexe qui a récemment connu des avancées majeures grâce aux progrès réalisés dans un panel très large de spécialités. Dix modifications du génome porcin : la suppression de trois gènes impliqués dans le rejet rapide, d’un quatrième empêchant la prolifération du tissu cardiaque, l’insertion de six gènes humains favorisant la reconnaissance immunitaire ainsi que de nouveaux moyens pour moduler le système immunitaire ont permis de réduire la barrière immunitaire inter-espèces responsable du rejet et d’améliorer la viabilité du greffon. La production d'organes de porcs xénotransplantables conformes aux exigences règlementaires de la médecine humaine nécessite cependant de résoudre les risques de xénozoonoses en partie responsables d'un moratoire. La suppression de gènes de rétrovirus endogènes porcins (PERV) est le moyen de surmonter le principal obstacle à la production d’organes transplantables exempts de tout germe pathogène transmissible à l'homme. La mise en œuvre de techniques spécifiques d’élevage par césarienne, par transfert d’embryons contribue également à réduire les risques infectieux. Il a été montré que la production des porcs transgéniques à grande échelle rencontre des difficultés. Pig-to-human xenotransplantation is a complex multidisciplinary challenge that has recently seen major breakthroughs thanks to advances in a very wide range of specialties. Ten modifications to the porcine genome such as the deletion of three genes involved in rapid rejection, the deletion of a fourth gene preventing detrimental cardiac growth, the insertion of six human genes promoting immune recognition and new methods of immune system modulation have reduced the inter-species immune barrier responsible for rejection and improved graft viability. The production of xenogenic transplantation products that complies with the regulatory requirements of human medicine requires resolving the risks of xenozoonosis which is partly responsible for a moratorium. The deletion of porcine endogenous retrovirus (PERV) genes is the key to overcoming the main obstacles to the production of transplantable organs free of any pathogen transmissible to humans. The implementation of specific breeding techniques by caesarean section and by embryo transfer also contributes to reducing the risks of unwanted infections. It has been shown that the production of transgenic pigs on a large scale encounters difficulties.

xénotransplantation --- zoonose --- porc --- santé publique --- transgénique --- PERV --- α-3-galactosyltransférase --- hCD46 --- Sus scrofa domesticus --- knockout --- hA20 --- hHO-1 --- GGTA1 --- CMAH --- B4GaINT2 --- hTM --- hEPCR --- GHR --- hCD55 --- Sciences du vivant > Médecine vétérinaire & santé animale --- Sciences du vivant > Génétique & processus génétiques --- Sciences du vivant > Productions animales & zootechnie --- Sciences de la santé humaine > Chirurgie --- Sciences de la santé humaine > Immunologie & maladie infectieuse --- Sciences du vivant > Biochimie, biophysique & biologie moléculaire