Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

L'utilisation de variétés présentant des résistances quantitatives polygéniques est une pratique respectueuse de l'environnement et potentiellement durable pour lutter contre les bioagresseurs. Les résistances quantitatives sont cependant mal connues et encore peu exploitées. Via l'étude de l'interaction Capsicum spp. / Phytophthora capsici, les objectifs sont de (i) caractériser la diversité naturelle de l'hôte pour le phénotype quantitatif de résistance, (ii) décrire la diversité au QTL Pc5.1, déterminant majeur de la résistance, conservé chez les géniteurs et efficace à large spectre, et (iii) déterminer le profil d'évolution moléculaire aux gènes candidats de Pc5.1. L'évaluation du niveau de résistance de ressources génétiques de Capsicum spp. et du spectre de résistance d'un panel d'accessions a permis d'identifier de nouveaux géniteurs de forte résistance au spectre large et a fourni un set d'isolats différenciant les accessions selon leur spectre. Le polymorphisme à Pc5.1 a été révélé par séquençage haut débit. Globalement, Pc5.1 présente un polymorphisme nucléotidique plus élevé que le reste du génome. Les accessions résistantes sont très peu divergentes au QTL, signe d'une forte conservation intra- et inter-génique, alors que les accessions sensibles sont plus polymorphes. Aux gènes candidats, deux haplotypes majeurs ont été identifiés, l'un présent quasi exclusivement chez des accessions résistantes et l'autre chez des accessions sensibles, ce qui confirme la forte conservation du locus et la divergence entre résistants et sensibles. Le déséquilibre de liaison mesuré aux gènes candidats étant fort, surtout chez les C. annuum, 65% des polymorphismes sont significativement associés à la résistance. Cette étude a mis en évidence le caractère contraint de l'allèle de résistance à Pc5.1 et interroge sur l'origine et l'histoire évolutive du QTL, en relation avec sonefficacité à large spectre. Il semble qu'une localisation proche du centromère limite les recombinaisons au locus et que la divergence entre les sensibles et les résistants soit un événement ancien. La détermination de la nature moléculaire et de l'histoire évolutive de Pc5.1 sera poursuivie en approfondissant les analyses de divergence des séquences et en se focalisant sur la validation fonctionnelle des gènes candidats déjà en cours. / An environmentally friendly and potentially durable strategy to control diseases is the breeding for varieties displaying quantitative polygenic resistances. However a few is known about quantitative resistances, which are thus underexploited. Through the investigation of the Capsicum spp. / Phytophthora capsici interaction, this study aimed to (i) phenotype natural host diversity for the quantitative resistance, (ii) describe the nucleotide diversity at the QTL Pc5.1, a major determinant of resistance that is retrieved among genitors and is broad-spectrum, and (iii) explore the pattern of molecular evolution at Pc5.1 candidate genes. Through the phenotyping for level of resistance in Capsicum spp. genetic resources and spectrum of resistance in a sample of accessions, novel genitors displaying strong and broadspectrum resistance have been identified, and a set of isolates that differentiate accessions according to their resistance spectrum has been established. High-throughput sequencing has been exploited to identify polymorphisms at Pc5.1. Nucleotide diversity at Pc5.1 is higher than over the genome. Resistant accessions displayed low divergence thatindicates high intra- and inter-genic conservation, while susceptible accessions are more polymorphic than resistant ones. At the candidate genes, two major haplotypes have been identified, one being almost exclusively exhibited by resistant accessions and the other by susceptible ones, which reinforces the assessments that the QTL is highly conserved and that resistant and susceptible accessions are divergent. Linkage disequilibrium at candidate genes being high, particularly for C. annuum, 65% of polymorphisms are in significant association with resistance. By highlightingthe constraint pattern of selection at Pc5.1, this study wonders about the origin and the evolution history of the QTL, in relation to its broad-spectrum efficiency. A close proximity with the centromere region seems to restrict recombinations at the QTL, and divergence between resistant and susceptible may be an ancient event. The investigation of the molecular function and the pattern of evolution of Pc5.1 will be continued through in depth study of the acquired sequences and functional validation of candidate genes already ongoing.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Abstract Schizophrenia and other psychotic disorders are severe and disabling mental disorders that break out during early adulthood, often when a person is in his/her early 20s. Furthermore, functional decline in many cognitive areas, including the ability to communicate in social interactions and impaired facial expression recognition, is typical to patients with schizophrenia. Understanding the risk factors of psychosis is essential as these disorders may be more amenable to treatment in their early stages. However, recognition of those at the highest risk of psychosis is challenging as no definitive biomarkers are available. Functional MRI is a promising tool that can potentially identify neural signals relating to the individual’s risk of psychosis onset. Psychotic disorders are etiologically heterogeneous disorders — both environmental and genetic factors have been linked to the onset of psychotic disorders. The most influential risk factor for a psychotic disorder is familial risk with genetic loading. The present study examines whether familial risk of psychosis (FR), the polygenic risk score for schizophrenia (PRS) and early adversity associate with brain response to faces. We used fMRI to measure blood oxygen level dependent (BOLD) response to faces. Our study showed that FR associated with deviant prefrontal cortex BOLD responses. In addition, we detected that interregional BOLD signal and grey matter volume varied as a function of PRS; the lowest functional and structural covariance was detected in individuals with high PRS. We also detected that early adversities associated with brain response to faces and that this association varied as a function of glucocorticoid receptor gene expression. Our findings indicate that the above risk factors of psychosis associate with brain response to faces. / Tiivistelmä Skitsofrenia ja muut psykoosisairaudet ovat vakavia mielenterveyden häiriöitä, jotka puhkeavat usein nuorella aikuisiällä. Eräs tyypillinen piirre psykoosisairauksille on vaikeus tunnistaa muiden ihmisten kasvonilmeitä. Psykoosisairauksien riskitekijöiden ymmärtäminen on tärkeää, sillä hoito tehoaa parhaiten sairastumisen alkuvaiheessa. Suurimmassa psykoosivaarassa olevien henkilöiden tunnistaminen on kuitenkin haastavaa, sillä luotettavia tautiin liittyviä biomarkkereita ei ole saatavilla. Toiminnallinen magneettikuvaus (fMRI) on lupaava työkalu, jolla saattaa olla tulevaisuudessa käyttöarvoa psykoosivaaraan liittyvien aivomuutosten tunnistamisessa. Etiologialtaan psyykoosisairaudet ovat heterogeenisiä: sekä ympäristö että perinnölliset tekijät vaikuttavat yksilön sairastumisriskiin. Voimakkain riskitekijä on suvullinen psykoosialttius. Tässä osajulkaisuväitöskirjassa tutkitaan suvullisen psykoosialttiuden, skitsofrenian polygeenisen riskipisteen (PRS) sekä varhaisten vastoinkäymisten yhteyttä aivojen kasvonilmeitä tulkitsevaan järjestelmään. Tutkimuksessa on hyödynnetty fMRI-kuvausta kasvonilmestimuluksen aikana. Tutkimuksessamme suvullinen psykoosialttius oli yhteydessä etuotsalohkon fMRI-signaalimuutoksiin. Tämän lisäksi havaitsimme, että kasvonilmejärjestelmän fMRI-signaalin ja harmaan aineen kovarianssi oli yhteydessä PRS:ään: matalin aivoalueiden välinen korrelaatio havaittiin henkilöillä, joiden PRS oli korkea. Havaitsimme myös, että varhaiset vastoinkäymiset ovat yhteydessä kasvonilmeiden aikaansaamiin aivovasteisiin. Tämä assosiaatio oli myös yhteydessä glukokortikoidireseptorin geenin ilmentymiseen. Väitöskirjan löydökset viittaavat siihen, että edellä mainitut psykoosin riskitekijät ovat yhteydessä kasvonilmeitä tulkitsevaan järjestelmään.

Abstract Adaptation through polygenic selection is a prominent feature in nature. Still, the genetic backgrounds of polygenic adaptations are often unknown. The challenges of resolving adaptive processes are related to selection being distributed over several loci with often small effect sizes. Also, even a low level of population substructure can obstruct the inference. Further, demographic factors in the history of the species, such as population size changes and range expansions leave a confounding footprint in the background genomic variation. In this thesis, polygenic adaptation was studied with Scots pine (Pinus sylvestris L.), a widespread ecologically and economically important conifer. In this thesis, timing of bud set – an adaptive polygenic trait – was studied at the level of the phenotype in a common garden study, and at the genomic level by examining the sequence and allele frequency variation patterns in bud set timing related loci, with a sampling across a latitudinal transect in Europe. An association study, combining these two levels, was carried out with a new Bayesian multipopulation method. The congruence of allozyme and nucleotide level diversity was estimated, the level of neutral genetic population structure surveyed, and a demographic background model for statistical inference of selective signals redefined. Allozyme variation seemed to correlate well with the nucleotide level variation at the between species level, but within population, at the individual allozyme coding loci, does not describe the underlying level of nucleotide variation well. Indications of recent colonization history affecting the level of differentiation between populations were seen, and the need to control for the background effects of simultaneous range expansion and adaptation shown. Lower phenotypic and additive genetic variation in timing of bud set was found in northern compared to central European populations. Signs of heterogeneity in genetic basis of this trait were also found between these areas, which could indicate different timekeeping mechanisms due to different environmental cues in the two regions. The results in this thesis are of value to the study of adaptation, but also for breeding, conservation and prediction of responses of forest trees to future climate change. / Tiivistelmä Sopeutuminen perustuu usein polygeenisiin ominaisuuksiin. Näiden ominaisuuksien geneettiset taustat ovat silti vielä pitkälti selvittämättä. Sopeutumisominaisuuksien genetiikan selvittämistä vaikeuttaa valinnan vaikutusten jakautuminen usean, usein pienivaikutuksisen lokuksen kesken. Lisäksi vähäinenkin populaatiorakenne hankaloittaa geenien tunnistamista. Myös lajin historiassa tapahtuneet demografiset muutokset, kuten populaatiokoon vaihtelut ja kolonisaatio jättävät jälkensä genomiin. Väitöskirjassani tutkin polygeenistä sopeutumista ekologisesti ja taloudellisesti tärkeän havupuulajin, metsämännyn (Pinus sylvestris L.) avulla. Väitöskirjassani tutkin metsämännyn silmunmuodostuksen ajoitusta sekä fenotyypin että sekvenssimuuntelun tasolla. Ajoitusta mitattiin eri leveysasteilta peräisin olevista eurooppalaisista populaatioista yhteiskasvatuskokeessa, ja sekvenssimuuntelua sekä alleelifrekvenssien jakautumista tutkittiin vastaavasta näytteestä. Geenikartoituskokeessa yhdistettiin nämä kaksi muuntelun tasoa hyödyntäen uutta, usean populaation tutkimiseen soveltuvaa analyysimenetelmää. Lisäksi tutkin allotsyymimuuntelun ja nukleotidimuuntelun keskinäistä tarkkuutta geneettisen diversiteetin kuvaajina, neutraalin populaatiorakenteen tasoa, sekä demografian vaikutusta metsämännyn genomissa. Allotsyymimuuntelun todettiin kuvaavan hyvin lajien välisiä diversiteettieroja. Populaation sisällä yksittäisten allotsyymien heterosygotia ei korreloinut entsyymiä koodaavan geenin muuntelun määrän kanssa. Pohjoisten populaatioiden vähäisemmät keskinäiset erot verrattuna keskieurooppalaisiin antoivat viitteitä siitä, että viimeisimmän jääkauden jälkeiset kolonisaatiotapahtumat voivat edelleen vaikuttaa populaatioiden erilaistumisasteeseen. Assosiaatiotutkimuksessa osoitettiin, kuinka tärkeää yhtäaikaisen sopeutumisen ja kolonisaation huomioiminen on sopeutumisominaisuuksien tutkimisessa. Fenotyyppinen muuntelu silmunmuodostuksen ajoituksessa oli vähäisempää pohjoisissa populaatioissa. Lisäksi löysimme merkkejä geneettisestä heterogeenisuudesta silmunmuodostuksen taustalla pohjoisten ja keskieurooppalaisten metsämäntyjen välillä, mikä voi johtua vuodenajan vaihtelun mittaamiseen käytettävien ympäristösignaalien eriytymisestä näiden alueiden välillä. Väitöskirjassani saadut tulokset hyödyttävät paitsi sopeutumistutkimusta, myös jalostus- ja luonnonsuojelututkimusta sekä ilmastonmuutoksen vaikutusten arviointia.

Le diabète de type 2 (DT2) est une maladie chronique grave et sa prévalence ne cesse d’augmenter partout dans le monde. La complication la plus sévère et la plus courante du diabète est la néphropathie diabétique dont le premier symptôme est l’albuminurie. Notre premier objectif est d’évaluer si un dépistage précoce de l’albuminurie permet une meilleure prise en charge de cette complication dans la pratique générale des médecins. Notre deuxième objectif est de valider l’efficacité de notre score de risque polygénique (SRP) sur la prédiction du risque d’albuminurie sur une cohorte canadienne composée de patients DT2, hypertendus provenant de groupe de médecine familiale (GMF) et de family health team (FHT) au Québec et en Ontario (CLINPRADIA I). Le SRP a permis de déterminer les 30% de patients à risque élevé de développer l’albuminurie. En effet, la prévalence d’albuminurie des 30% des sujets classés à haut risque génétique par le SRP était 2,6 fois plus élevée que le reste des patients de CLINPRADIA I. Dans la même cohorte, nous avons démontré que l’introduction d’un point of care testing (POCT) a amélioré la pratique et l’adhésion des médecins aux lignes directrices du traitement de l’albuminurie. Les valeurs d’albuminurie et le nombre de patients albuminuriques ont diminué significativement en réponse à l’introduction du POCT. Nous pouvons conclure de nos résultats que l’utilisation de notre SRP permettrait d’identifier les patients à risque élevés d’albuminurie alors que le POCT permettrait un dépistage précoce et un meilleur suivi de l’albuminurie chez ces patients. / Type 2 diabetes (T2D) is a serious chronic disease and its prevalence keeps increasing all over the world. The most severe and common diabetes complication is nephropathy of which the first symptom is albuminuria. Our first objective is to evaluate if early screening of albuminuria allows for a better patient care of this condition in general practitioner practice. Our second objective is to validate the efficacy of our polygenetic risk score (PRS) on the risk prediction of albuminuria on Canadian cohort composed of hypertensive TD2 patients from groupe de médecine familiale (GMF) and family health team (FHT) in Quebec and in Ontario (CLINPRADIA I). The PRS identified the 30% of T2D patients at high risk of developing albuminuria. Indeed, the albuminuria prevalence of the 30% of subjects at high genetic risk based on the PRS was 2.6 times higher than the remaining patients of CLINPRADIA I. In the same cohort, we established that the introduction of the point of care testing (POCT) improves the practice and the adherence of physicians to the guidelines for the treatment of albuminuria. The values of albuminuria and the number of patients with albuminuria decreased significantly after the introduction of the POCT. We can conclude from our results that the use of our PRS enables the early identification of the patients at high risk of albuminuria while the POCT enables the early detection of patients with albuminuria who benefited from an early intervention.

Introduction/Background: Guidelines from the World Health Organization currently recommend targeting a body mass index (BMI) between 18.5 and 24.9 kg/m2 based on the lowest risk of mortality observed in epidemiological studies. However, these recommendations are based on population observations and do not take into account potential inter-individual differences. We hypothesized that genetic and non-genetic differences in adiposity, anthropometric, and metabolic measures result in inter-individual variation in the optimal BMI. Methods: Genetic variants associated with BMI as well as related adiposity, anthropometric, and metabolic phenotypes (e.g. triglyceride (TG)) were combined into polygenic risk scores (PRS), cumulative risk scores derived from the weighted contributions of each variant. 387,692 participants in the UK Biobank were split by quantiles of PRS or clinical biomarkers such as C-reactive protein (CRP), and alanine aminotransferase (ALT). The BMI linked with the lowest risk of all-cause and cause-specific mortality outcomes (“nadir value”) was then compared across quantiles (“Cox meta-regression model”). Our results were replicated using the non-linear mendelian randomization (NLMR) model to assess causality. Results: The nadir value for the BMI–all-cause mortality relationship differed across percentiles of BMI PRS, suggesting inter-individual variation in optimal BMI based on genetics (p = 0.005). There was a difference of 1.90 kg/m2 in predicted optimal BMI between individuals in the top and bottom 5th BMI PRS percentile. Individuals having above and below median TG (p = 1.29×10-4), CRP (p = 7.92 × 10-5), and ALT (p = 2.70 × 10-8) levels differed in nadir for this relationship. There was no difference in the computed nadir between the Cox meta-regression or NLMR models (p = 0.102). Conclusions: The impact of BMI on mortality is heterogenous due to individual genetic and clinical biomarker level differences. Although we cannot confirm that are results are causal, genetics and clinical biomarkers have potential use for making more tailored BMI recommendations for patients. / Thesis / Master of Science (MSc) / The World Health Organization (WHO) recommends targeting a body mass index (BMI) between 18.5 - 24.9 kg/m2 for optimal health. However, this recommendation does not take into account individual differences in genetics or biology. Our project aimed to determine whether the optimal BMI, or the BMI associated with the lowest risk of mortality, varies due to genetic or biological variation. Analyses were conducted across 387,692 individuals. We divided participants into groups according to genetic risk for obesity or clinical biomarker profile. Our results show that the optimal BMI varies according to genetic or biomarker profile. WHO recommendations do not account for this variation, as the optimal BMI can fall under the normal 18.5 - 24.9 kg/m2 or overweight 25.0 – 29.0 kg/m2 WHO BMI categories depending on individual genetic or biomarker profile. Thus, there is potential for using genetic and/or biomarker profiles to make more precise BMI recommendations for patients.

No description available.

Il y a consensus qu’approximativement la moitié des différences individuelles liées à l’agression physique sont héritées. Cependant, les premières manifestations comportementales et sociales de cette propension génétique demeurent inconnues. Cette étude vise à tester l’hypothèse selon laquelle, les scores polygéniques liés à l’agression (SPGAG) et au trouble du déficit de l’attention/hyperactivité (TDAH; SPGTDAH), tous deux ayant précédemment été associés à l’agression physique à l’âge scolaire, se manifesteraient d’abord par des comportements externalisés et des expériences adverses à la petite enfance. Les données génétiques de 718 participants (44,6 % garçons) de l’Étude longitudinale du développement des enfants du Québec (ELDEQ) ont été utilisées pour estimer les SPGs. L’agression physique à l’âge scolaire a été rapportée à six reprises entre 6 et 13 ans par des enseignants indépendants. Les mères ont rapporté les comportements externalisés (agression physique, hyperactivité, opposition) et les expériences adverses (difficultés avec les pairs, pratiques parentales hostiles et coercitives) à trois occasions entre l’âge de 3½ et 5 ans. Les résultats indiquent que ces deux SPGs prédisent l’agression physique à l’âge scolaire. Néanmoins, seules les difficultés avec les pairs expliquent l’association entre le SPGAG et l’agression physique. L’hyperactivité, l’opposition et les pratiques parentales hostiles et coercitives sous-tendent toutes, de façon séparée, l’association entre le SPGTDAH et l’agression physique à l’âge scolaire, bien que seule l’hyperactivité ait une contribution unique lorsque ces construits sont examinés simultanément. Ces résultats contribuent à décrire comment l’étiologie génétique liée à l’agression physique se manifeste à la petite enfance, identifiant ainsi des cibles précoces d’intervention. / There is now a consensus in the literature suggesting that approximately half of the individual differences related to physical aggression (PA) are inherited. However, the behavioral and social early manifestations of this genetic propensity remain unknown. This study aims to test the hypothesis that polygenic scores related to aggression (PGSAGG) and attention deficit hyperactivity disorder (ADHD; PGSADHD), both of which were previously shown to be associated with PA during school-age, would be first phenotypically expressed as externalized behaviors and adverse experiences in early childhood. The genetic data of 718 participants (44,6% boys) from the Quebec Longitudinal Study of Child Development (QLSCD) were used to estimate the SPGs. PA in school age was reported up to six times between 6 and 13 years old by independent teachers. Externalized behaviors (PA, hyperactivity, opposition) and adverse experiences (difficulties with peers, harsh and coercive parenting practices) were reported by mothers on three occasions between the ages of 3½ and 5 years old. Results indicate that both SPGs predicted PA in school age. However, only difficulties with peers explain the association between PGSAGG and PA. Hyperactivity, opposition, and harsh and coercive parenting practices in early childhood all separately partially mediated the association between PGSADHD and PA in school age, although only hyperactivity has a unique contribution when these constructs are examined simultaneously. These findings contribute to describing how PA measured genetic etiology ascertained by the PGS come to be first phenotypically expressed in early childhood, identifying early intervention targets for interventions.

No description available.