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Genes of Innate Immunity and Their Significance in Evolutionary Ecology of Free Livings Rodents Alena Fornuskova

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Genes of Innate Immunity and Their Significance in Evolutionary Ecology of Free Livings Rodents Alena Fornuskova Genes of innate immunity and their significance in evolutionary ecology of free livings rodents Alena Fornuskova To cite this version: Alena Fornuskova. Genes of innate immunity and their significance in evolutionary ecology of free livings rodents. Populations and Evolution [q-bio.PE]. Université Montpellier II - Sciences et Tech- niques du Languedoc; Masarykova univerzita (Brno, République tchèque), 2013. English. NNT : 2013MON20103. tel-01021258 HAL Id: tel-01021258 https://tel.archives-ouvertes.fr/tel-01021258 Submitted on 9 Jul 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE•MONTPELLIER•II•• SCIENCES•ET•TECHNIQUES•DU•LANGUEDOC•• FACULTE•DES•SCIENCES• • and• • MASARYK•UNIVERSITY,•BRNO• FACULTY•OF•SCIENCE• • THESIS•• • To•obtain•doctoral•degree• • Formation•doctorale :•Biologie•de•l'évolution•et•écologie• • Ecole•Doctorale :•Systèmes•Intégrés•en•Biologie,•Agronomie,•Géosciences,•Hydrosciences, • Environnement,•SIBAGHE• • • Presented•and•defended•publicly• • AUTHOR:•Alena•Fornuskova• • • GENES•OF•INNATE•IMMUNITY•AND•THEIR•SIGNIFICANCE•IN• EVOLUTIONARY•ECOLOGY•OF•FREE•LIVING•RODENTS• • Toll-like•receptor•polymorphisms•in•rodents•• • • Thesis•supervised•by• Dr.•Jean- François•Cosson /Dr.•Josef•Bryja• • Date•and•place•of•defence:•the•19•December•2013•in•CBGP• • • • • • • • • • • • • COMMITTEE:• • M.•Pierre•Boursot ,•Director•of•research•CNRS,• Université •Montpellier•2,•Montpellier,•FR• ••••••••••••••••••••••••••• Examiner •• M.• Petr•Ho ín,• Professor,•University•of•Veterinary•and•Pharmaceutical•Sciences,•Brno,•CZ••••••••••••••••••••••••••••••••• Reviewer• M.•Dirk•Werling,• Professor,•The•Royal•Veterinary•College,•University•of•London,•UK• •• •••••••••••••••••••••••••••Reviewer• M.•Jan•Zima ,•Professor,•Institute•of•Vertebrate•Biology•AS•CR,•Brno,•CZ• • • ••••••••••••••••••••••••••• Examiner • M.•Josef•Bryja ,•Assoc.•professor,•Institute•of•Vertebrate•Biology•AS•CR•and•Masaryk•University,•Brno,•CZ• •••Supervisor• 2 ABSTRACT • Appropriate recognition of parasites is crucial for effective immune response, ensuring activation of adequate defence mechanisms. In vertebrates, it has frequently been demonstrated that genes encoding proteins involved in pathogen recognition by an adaptive immune system are often subject to intense selection pressures. On the contrary, much less information has been provided on the evolution of recognition mechanisms of innate immunity. The aim of this thesis is to describe the pattern of natural variation of innate immunity genes involved in pathogen recognition in rodents and to analyze the mechanisms of their evolution. We used murine rodents (subfamily Murinae) as a principal model group because they often live in our close proximity and thus are potential reservoirs of various pathogens dangerous to humans. First, we studied the intraspecific variability of five bacterial sensing Toll-like receptors (TLR1, TLR2, TLR4, TLR5, and TLR6) in inbred strains derived from two subspecies of the house mouse ( M. m. musculus , hereafter abbreviated as Mmm and Mus musculus domesticus , Mmd). Wild-derived inbred strains are suitable tools for studying variation of immunity genes because they provide information about alleles that occur in natural populations, and at the same time they occur at homozygous state. The most significant results include the findings of a stop codon in exon 2 of the Tlr5 gene in one Mmm strain and no variability in Tlr4 of Mmd. The results also provide the set of diagnostic SNPs for each gene allowing future studies of introgression of immunity genes across the house mouse hybrid zone and their possible role in the speciation process. Following these results we decided to check whether the absence of Tlr4 polymorphism in Mmd reflects the pattern found in natural populations, or whether it is a consequence of insufficient sampling or subsequent breeding. We therefore sequenced Tlr4 in both subspecies across a large part of the Western Palaearctic region (in total 39 Mmm and 62 Mmd individuals), then we compared these results with variability on mitochondrial DNA (cytochrome b). The result confirmed our prediction that observed variability in Mmd is strongly reduced also in free-living populations (compared to Mmm), probably due to strong purifying selection by pathogens with which they met during the westward colonization. However, the influence of random evolutionary processes (e.g. drift during bottlenecks) cannot be excluded based on our data. At the intraspecific level, we could not find any sign of positive selection. Our results revealed also species specific variants of Tlr4 and an important role of recombination in Mmm during evolutionary history. 3 The last part of my dissertation is devoted to interspecific comparison of two receptors, TLR4 and TLR7. These two TLRs differ in the exposure and the ligands detection. TLR4 is an extracellular receptor detecting mainly bacterial ligands (especially lipopolysaccharides), while TLR7 is located inside the cell and detects ssRNA viruses. The aim of this part of the thesis was to describe variability of both receptors at the interspecific level and to reveal selection forces acting on TLRs in longer evolutionary time scale. In total we analyzed 23 rodent species of the subfamily Murinae in Europe, Asia and Africa. Our results suggest that purifying selection has been a dominant force in evolution of the Tlr4 and Tlr 7 genes, but we also demonstrated that episodic diversifying selection has shaped the present species-specific variation in rodent Tlr s. Sites under positive selection were concentrated mainly in the extracellular domain of both receptors, which is responsible for ligand binding. The comparison between two TLRs lead us to the conclusion that the intracellular TLR7 is under much stronger negative selection pressure, presumably due to its interaction with viral nucleic acids, which are similar to those of the host and even small changes in TLR7 conformation could cause autoimmunity. Key words: Toll-like receptors, receptors of innate immunity, Pattern Recognition Receptors, selection, evolution, natural selection, genetic polymorphism, phylogeny, host-parasite coevolution, genetic diversity. 4 RÉSUMÉ Une reconnaissance appropriée des parasites est essentielle pour une réponse immunitaire efficace, a ssurant l'activation adéquate des mécanismes de défense immunitaire. Chez les vertébrés , il a été fréquemment démontré que les gènes codant pour les récepteurs de l'immunité adaptative impliqués dans la reconnaissance des agents pathogènes sont souvent sou mis à une intense pression sélective. En revanche, beaucoup moins d’études se sont intéressées à la sélection agissant sur les récepteurs de l'immunité innée. Le but de cette thèse est de décrire la variabilité naturelle des gènes de l'immunité innée impliqués dans la détection des agents pathogènes chez les rongeurs et d’analyser les mécanismes responsables de leur évolution. Ce travail s’ est focalis é principalement sur les rongeurs de la sousfamille des Murinae de part leur présence fréquente à proximité des populations humaines et de leur rôle potentiel en tant que réservoirs d’agents pathogènes dangereux pour l’Homme . Tout d ´abord nous avons étudié la variabilité intraspécifique de cinq Toll-like récepteurs ciblant les bactéries (TLR1, TLR2, TLR4, TLR5 et TLR6) pour des lignées consanguines de souris domestiques issues d’une population sauvage de deux sous -espèces : Mus musculus domesticus (Mmd) et Mus musculus musculus (Mmm). Les souches consanguines constituent un outil adapté à l'étude de la variabilité des gènes immunitaires car elles confèrent une information sur l es allèles présents dans les populations naturelles tout en bénéficiant de génotypes homozygotes. Les résultats les plus significa tifs concernent la découverte d'un codon stop dans l'exon 2 du Tlr5 chez une lignée de Mmm et l’absence de variabilité d u Tlr4 chez Mmd. Ces résultats ont également permis de constituer un jeu de SNPs diagnostics utilisable pour de futures études afin de mieux comprendre le rôle de l’introgression de ces gènes immunitaires dans les mécanismes de spéciation de la zone hybride de la souris domestique. A la suite de ces résultats, nous avons décidé de vérifier si l‘absence de polymorphisme du Tlr4 chez Mmd reflète une absence de variabilité dans les populations naturelles, ou si il s’agit plutôt d’un effet de l'échantillonnage ou de s croisements ultérieur s. Nous avons donc séquencé le gène Tlr4 pour les deux sous- espèces provenant de la région du Paléarctique Occidental e (au total 39 Mmm et 62 Mmd) puis nous avons c omparé ces résultats avec la variabilité génétique d’ un g ène mitochondrial (cytochrome b). Nous avons confirmé notre prédiction : la variabilité de Tlr4 chez Mmd est fortement réduite par rapport à Mmm, probablement à cause d ’agents pathogènes ayant exercé une sélection purifiante chez 5 Mmd durant la colonisation vers l’ouest . Cependant, l'influence de mécanismes évolutifs neutres, tel que la dérive consécutive à un goulot d’étranglement démographique,
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