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In light of human-mediated environmental change, a fundamental goal for biologists is to determine which phenotypic characteristics enable some individuals, populations or species to be more adept at coping with such change, while rendering others more vulnerable. Studying ongoing range expansions provide a unique opportunity to address this question by allowing documentation of how novel environments shape phenotypic variation on ecological timescales. At range-edges, individuals are exposed to strong selective pressures and population genetic challenges (e.g. bottlenecks and/or founder effects), which make genetic adaptation difficult. Nevertheless, certain species, such as the house sparrow (Passer domesticus), seem to thrive in their introduced ranges, despite genetic challenges, resulting in a genetic paradox. Increasing evidence suggests that rapid phenotypic differentiation at range-edges may be facilitated by phenotypic plasticity among individuals. Further, a role for epigenetic mechanisms as molecular drivers of such plasticity—particularly in genetically depauperate populations—has recently garnered empirical support across a broad range of taxa. For my dissertation, I investigated the role of epigenetic mechanisms (i.e. DNA methylation) as a potential mediator of range expansion success in vertebrates. Specifically, I proposed that success or failure at range-edges may be underlain by variation in the capacity for epigenetically-mediated plasticity (i.e. epigenetic potential) and used extant literature on an inherently plastic and highly integrated physiological system (i.e. the HPA-axis) to support this hypothesis (Chapter I). I then tested these ideas empirically by examining the relative contribution of genetic and epigenetic variation to immunological variation in Kenyan house sparrows (Chapter II) and explored whether mediators of neural plasticity (i.e. BDNF) and epigenetic potential (i.e. DNA methyltransferases; DNMTs) varied among populations of Senegalese house sparrows, including the potential for covariation among BDNF, DNMTs and corticosterone (CORT) within individuals (Chapter III). Flexibility in the regulation of glucocorticoids (GCs) via the HPA-axis is crucial for survival at range-edges because (i) GCs act as integrators capable of coordinating diverse physiological and/or behavioral responses and (ii) the HPA-axis contains multiple regulatory checkpoints which may help to buffer organisms from maladaptive responses (via redundancy) while simultaneously allowing for the fine-tuning of phenotypic responses to future stressors contingent on current and past experiences. GC regulatory flexibility can be influenced by (and in some cases have an effect on) variation in the capacity for epigenetic mechanisms to regulate environmentally-induced phenotypic changes (i.e. epigenetic potential). DNMTs are capacitators of epigenetic change, thus provide one such example of how variation in epigenetic potential could arise via genetic (e.g. variation in coding regions of DNMT genes) and/or environmental (e.g. developmental programming of DNMT expression) factors. For my first chapter, I conducted a literature review to explore where within the HPA-axis epigenetic potential was most likely to occur and to demonstrate how such variation could promote/constrain range expansion success via its impact on GC regulatory flexibility. Results from the literature search revealed that within the HPA-axis, evidence for epigenetic regulation was highest for receptors, suggesting that variation in epigenetic potential of these targets may be most impactful for variation in GC regulatory flexibility. Using a physiological regulatory network (PRN) framework, I showed how variation in epigenetic potential can modify plasticity of PRN states by altering the regulatory relationships (e.g. connectivity) between HPA elements (e.g. GCs as central hubs) and other physiological/behavioral traits (e.g. subnetworks). As such, I portrayed how genetic forms of epigenetic potential can dictate the upper/lower limits of an individual’s homeostatic range, while environmental forms can act to further titrate GC regulatory flexibility through plasticity of PRN states or stabilization of PRN states. The concept of epigenetic potential in the HPA-axis demonstrates how plasticity at the molecular level can influence plasticity at the whole-organism level, which is likely to be important when coping with novel challenges at range-edges. Among the strongest of selective pressures faced by range-edge populations is exposure to parasites, particularly those with which individuals have little to no evolutionary history. Previous work from our lab on house sparrows in Kenya—site of an ongoing range expansion—revealed that range-edge birds had higher expression of Toll-like receptor 4 (TLR4—a microbial surveillance gene) than birds from the range-core. Moreover, extensive inter-individual variation in genome-wide DNA methylation was found among Kenyan house sparrows, including an inverse relationship between epigenetic diversity and genetic diversity across populations. For my second chapter, I investigated whether these two observations were related, asking whether and how DNA methylation and/or genetic variation within the putative promoter of the TLR4 gene contributed to variation in TLR4 expression. I found that DNA methylation status at CpG1, which varied from only ~73-100%, was a strong predictor of TLR4 expression within individuals. Interestingly, other studies have shown that similar magnitudes of variation in DNA methylation of TLR4 can result in differences in the susceptibility/resistance to bacterial pathogens, thus, it’s plausible that the variation we observed could have functional implications for host defense. I also discovered four genetically linked polymorphisms within the TLR4 promoter that grouped into two general genotypes. We revealed a trend that suggests that genotype differences may influence TLR4 expression, confirmation of which may be possible with increased representation from individuals with the rare genotype. Given that DNA methylation did not vary systematically among populations and evidence for extensive genetic admixture at the Kenyan range-edge, it seems likely that individual-level factors (e.g. genotype, early-life experience, infection history, etc.) may be more predictive of variation in DNA methylation of TLR4 than population-level processes. Coping with novel challenges often requires coordinated adjustments to environmentally-sensitive (i.e. plastic) traits. Findings from my first dissertation chapter, as well as previous research from the Martin lab, revealed that CORT regulation, exploratory behavior and epigenetic mechanisms likely contribute to range expansion success in house sparrows. Within the hippocampus, mediators of neural plasticity such as brain-derived neurotrophic factor (BDNF), play a unique role in the bidirectional regulation of CORT and exploratory behavior, with important implications for hippocampal-dependent learning and memory. Moreover, evidence suggests that the regulatory capacity of CORT and BDNF to influence learning and memory relies heavily on the catalytic capacity of epigenetic modification enzymes—including DNA methyltransferases (DNMTs). For my third chapter, I explored whether previous CORT/behavioral/epigenetic patterns contributed to population-level differences in hippocampal BDNF expression and/or hippocampal expression of DNMTs (mediators of epigenetic potential), including potential covariation among CORT, BDNF and DNMTs within individuals. I collected house sparrows from three populations in Senegal—site of an ongoing range expansion—and measured stressor-induced CORT, hippocampal BDNF, DNMT1 and DNMT3a expression. Given the potential importance of neural plasticity and epigenetic potential for coping with novel challenges, I hypothesized that BDNF and DNMT expression would be highest at the range-edge, while positive covariation would occur between CORT, BDNF and/or DNMT expression within individuals. I found that intermediate levels of CORT resulted in the highest BDNF expression within individuals, suggesting that interactions between CORT and BDNF are likely important for balancing homeostatic and progressive (e.g. cognitive) changes within the hippocampus in response to environmental challenges. I also found that CORT positively covaried with DNMT1 expression in one, but not both, range-edge populations, while the reverse was true at the range-core. These findings suggest that in newly established population, CORT may promote epigenetic potential, allowing for rapid and fine-tuned organism-wide responses to novel stressors, while at the range-core, where stressors are presumably less novel, CORT may inhibit epigenetic potential as a means of diverting resources away from cognitive processes and towards maintaining homeostasis. Altogether, my dissertation has demonstrated how inherently plastic sub-organismal level traits (i.e. molecular, physiological, and neurological) may interact and contribute to range expansion success in an introduced bird. Specifically, my research has not only shown that epigenetic variation can influence an ecologically-relevant trait, but also that variation in the regulatory potential of epigenetic mechanisms can be mediated by intrinsic and extrinsic factors. These studies have expanded our understanding about how epigenetic mechanisms act as regulatory mediators of plasticity at the molecular level and can influence (and be influenced by) variation at multiple phenotypic levels, with implications for whole-organism performance in natural populations. I hope that my work contributes to the field of ecological epigenetics by providing the framework for epigenetic potential as an additional tool for assessing how epigenetic processes contribute to phenotypic outcomes in the face of rapid environmental change.

L'émergence de l'éco-immunologie a permis une approche intégrative de l'étude des interactions hôtes-parasites allant des mécanismes moléculaires de la réponse immunitaire au rôle de l'immunocompétence dans l'évolution des traits d'histoire de vie. Dans ce contexte, cette thèse a pour but d'étudier les variations de l'immunocompétence dans deux populations naturelles de chevreuils vivant en milieux contrastés. Cependant, les méthodes disponibles pour caractériser le système immunitaire dans les populations naturelles sont peu nombreuses et peu adaptées. Aussi les objectifs de cette thèse étaient i) d'identifier et mettre au point des méthodes permettant de caractériser le système immunitaire du chevreuil, ii) d'étudier le lien entre les différents déterminants de l'immunocompétence, et iii) d'étudier les variations de l'immunocompétence en lien avec la condition physique d'une part, et avec un caractère sexuel secondaire d'autre part. Nous avons mesuré plusieurs composantes de l'immunité prenant en compte les aspects descriptifs, comme la numération des leucocytes, et fonctionnels, avec le test d'hémagglutination-hémolyse, la prolifération lymphocytaire ou la phagocytose. Nous avons mis en évidence une corrélation négative entre les deux déterminants de l'immunité, la condition physique et le parasitisme. Nous avons également montré un déclin des paramètres hématologiques et biochimiques avec l'âge (sénescence). Ensuite, nous avons montré des relations entre l'immunocompétence et la condition physique ou la taille des bois. Ces travaux corroborent différentes hypothèses de l'écologie évolutive / Ecoimmunology focuses on an integrative approach of host-pathogens interactions from the molecular mechanics of immune responses to the role of immunity in shaping the evolution of life history traits. Here, we proposed to study the variation of immunocompetence in two natural contrasted populations of roe deer. However, available methods to characterize immune system in wild populations are still limited. Consequently, in this context, the goals of this work were i) to identify methods to investigate the roe deer immune system and to adapt these methods developed for other species to roe deer, ii) to study the relationships between potential drivers of immunocomptence, including body condition and parasitism, and iii) to study variation of immunocompetence with body condition on one hand, and in the context of sexual selection, with secondary sexual characters on the other hand. We measured simultaneously several components of immunity including descriptive measures, as numeration of leucocytes subsets, and functional measures with hemagglutination-hemolysis, lymphocyte proliferation by mitogens stimulation or phagocytosis. We found a negative correlation between body condition and parasitism and senescence patterns in haematological and biochemical parameters. Moreover, we showed variations of immunocompetence with body condition and secondary sexual characters. This work corroborates some hypotheses of evolutionary biology

Il existe dans le règne animal une diversité incroyable de durées de vie allant de quelques jours pour les petits vers gastrotriches à plusieurs centaines d’années pour certains bivalves ou tortues terrestres. Cette étonnante diversité a depuis longtemps questionné les chercheurs en biologie. L’intérêt croissant pour le phénomène de vieillissement, notamment dû à l’augmentation de l’espérance de vie chez l’Homme, a conduit les chercheurs à essayer de comprendre les processus qui déterminent les patrons de longévité et de vieillissement. D’une part, les études biomédicales et biogérontologiques ont contribué à décrire nombres de mécanismes physiologiques et cellulaires à l’origine du vieillissement. Parmi ces mécanismes, le stress oxydant a été identifié comme jouant un rôle majeur, à travers l’accumulation au cours de la vie des dégâts générés par la production de radicaux libres lors d’activités métaboliques aérobies. D’autre part, le développement de théories évolutives du vieillissement a contribué à comprendre l’origine ultime du vieillissement et l’évolution de la diversité des traits d’histoire de vie. Cependant, ces approches, bien que complémentaires, sont longtemps restées imperméables et les travaux intégrant les mécanismes physiologiques tels que le stress oxydant dans une perspective évolutive n’ont connu que de récents développements. Dans cette thèse, nous avons étudié comment des mécanismes tels que le stress oxydant et ses coûts associés lors d’évènements comme la reproduction ou la réponse immunitaire pouvaient jouer un rôle dans l’évolution des patrons de vieillissement chez les oiseaux et les mammifères (i) en étudiant le rôle des antioxydants comme ressources clés dans les compromis adaptatifs entre reproduction et survie en fonction de l’âge, (ii) en étudiant les conséquences à long terme de l’environnement périnatal, (iii) en étudiant le lien entre réponse inflammatoire et patrons de vieillissement et de longévité contrastée entre oiseaux et mammifères, (iv) en s’intéressant plus particulièrement aux mécanismes de régulation immunitaire, soulignant leur rôle crucial pour la fitness des hôtes, et notamment tard dans la vie. Nos résultats soulignent l’importance des contraintes physiologiques liées à la limitation en ressources clés (antioxydants) ou aux dégâts engendrés lors d’activités coûteuses et destructrices et sur les patrons de vieillissements à l’échelle intra et inter-spécifique. / There is an incredible diversity of lifespan in the animal kingdom ranging from a few days for small gastrotrichs worms to several hundred of years for some bivalves or tortoises. This amazing diversity has long questioned biology researchers. The growing interest in the phenomenon of aging, mainly due to the increase in life expectancy in humans, has questioned researchers on processes that determine patterns of longevity and ageing. On the one hand, biomedical and biogerontological studies helped describe numerous cellular and physiological mechanisms related to aging. Among these mechanisms, oxidative stress has been identified as playing a major role, through life-time accumulation of damage generated by production of metabolic free radicals. On the other hand, the development of evolutionary theories of aging has contributed to understanding ultimate origins of ageing and of the diversity of life history traits. However, these approaches, although complementary, have long remained separated and works that integrate physiological mechanisms such as oxidative stress in an evolutionary perspective have known only recent developments. In this thesis, we studied how mechanisms such as oxidative stress and its associated costs produced during reproduction or immune response could play a role in the evolution of patterns of ageing in birds and mammals by (i) studying the role of antioxidants as key resources involved in adaptive trade-offs between reproduction and survival through age, (ii) studying the long-term effects of the early environment, (iii) studying the relationship between inflammatory response and contrasted patterns of ageing and longevity between birds and mammals, (iv) focusing particularly on immune regulatory mechanisms, emphasizing their crucial role in fitness of hosts, especially late in life. Overall, our results highlight the importance of physiological constraints in terms of key resources limitation (i.e. antioxidants) or damage caused during costly and destructive activities and on intra-and inter-specific patterns of ageing.