Les cellules souches embryonnaires (cellules ES) constituent un excellent système modèle pour étudier les mécanismes épigénétiques contrôlant la transcription du génome mammifère. Un nombre important de membres de la famille des facteurs de remodelage de chromatine ATP-dépendants ont une fonction essentielle pour l’auto-renouvellement des cellules ES, ou au cours de la différentiation. On pense que ces facteurs exercent ces rôles essentiels en régulant l’accessibilité de la chromatine au niveau des éléments régulateurs de la transcription, en modulant la stabilité et le positionnement des nucléosome.Dans ce projet, nous avons conduit une étude génomique à grande échelle du rôle d’une dizaine des remodeleurs (Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Ep400, Brg1, Smarca3, Smarcad1, Smarca5, ATRX et Chd1l) dans les cellules ES. Une double stratégie expérimentale a été utilisée : Des expériences d’immunoprécipitation de la chromatine suivi par un séquençage à haute-débit (ChIP-seq) sur des cellules ES étiquetées pour les différents remodeleurs, pour étudier leur distribution sur le génome, et un approche transcriptomique sur des cellules déplétées de chaque remodeleur par traitement avec des vecteurs shRNA (knockdown). Nous avons établi les profils de liaison des remodeleurs sur des éléments régulateurs (promoteurs, enhancers et sites CTCF) sur le génome, et montré que ces facteurs occupent toutes les catégories d’éléments régulateurs du génome. La corrélation entre les données ChIP-seq et les données transcriptomiques nous a permis d’analyser le rôle des remodeleurs dans les réseaux de transcription essentiels des cellules ES. Nous avons notamment démontré l’importance particulière de certains remodeleurs comme Brg1, Chd4, Ep400 et Smarcad1 dans la régulation de la transcription chez les cellules ES. / The characteristics of embryonic stem cells (ES cells) make them one of the best models to study the epigenetic regulation exerted by different actors in order to control the transcription of the mammalian genome. Members of the Snf2 family of ATP-dependent chromatin remodeling factors were shown to be of specific importance for ES cell self-renewal and during differentiation. These factors are believed to play essential roles in modifying the chromatin landscape through their capacity to position nucleosomes and determine their occupancy throughout the genome, making the chromatin more or less accessible to DNA binding factors.In this project, a genome-wide analysis of the function of a number of ATP-dependent chromatin remodelers (Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1, Ep400, ATRX, Smarca3, Smarca5, Smarcad1 and Alc1) in mouse embryonic stem (ES) cells was conducted. This was done using a double experimental strategy. First, a ChIP-seq (Chromatin Immunoprecipitation followed by deep sequencing) strategy was done on ES cells tagged for each factor in the goal of revealing the genomic binding profiles of the remodeling factors. Second, loss-of-function studies followed by transcriptome analysis in ES cells were performed in order to understand the functional role of remodelers. Data from both studies were correlated to acquire a better understanding of the role of remodelers in the transcriptional network of ES cells. Specific binding profiles of remodelers on promoters, enhancers and CTCF binding sites were revealed by our study. Transcriptomic data analysis of the deregulated genes upon remodeler factor knockdown, revealed the essential role of Chd4, Ep400, Smarcad1 and Brg1 in the control of transcription of ES cell genes. Altogether, our data highlight how the distinct chromatin remodeling factors cooperate to control the ES cell state.

Mainland Southeast Asia (MSEA) is an area with a long history of human occupation and great ethnolinguistic diversity. The earliest anatomically modern humans arrived ~65 thousand years ago, while presently it has a population size of ~263 million people speaking ~229 languages belonging to five major language families: Austroasiatic (AA), Austronesian (AN), Tai-Kadai (TK), Hmong-Mien (HM), and Sino-Tibetan (ST). Analyses of genome-wide data can provide rich insights into reconstructing human genetic population history, but there is a paucity of genome-wide data from MSEA (mostly limited to the majority groups such as the Kinh and Thai). The goal of this thesis was to analyze newly-genotyped genome-wide data (encompassing ~600 thousand SNPs) from an extensive, detailed sample of ethnolinguistic groups from Vietnam, Thailand, and Laos, encompassing all five major MSEA language families, in order to reconstruct their genetic history and relationships with cultural variation. In Chapter I, I analyzed data from 259 individuals from the Kinh and 21 Vietnamese ethnolinguistic groups. In contrast to previous studies suggesting that genetic diversity in Vietnam largely reflects internal diversification and isolation, I found evidence for different sources of genetic diversity in different linguistic groups, extensive contact between groups, and a likely case of language shift involving AN-speaking groups. In Chapter II, I analyzed data from 463 individuals from 33 ethnolinguistic groups together with 3 published groups (including the Thai), hence in total 36 groups from Thailand and Laos. I found fine-scale genetic structure for the major TK and AA groups according to their linguistic branches, and different levels of local interaction with other linguistic groups in geographical proximity. This diverse structure was also influenced by South Asian admixture, detected in several different linguistic groups from central and southern Thailand, dated to ~600-1000 years ago. This admixture date, together with the geographical distribution of these groups, suggests that the South Asian influence corresponds to the Ayutthaya kingdom period (1350-1767 AD), when there was extensive interactions and political and trading networks between people from MSEA and South Asia.:SUMMARY p.1 ZUSAMMENFASSUNG p.10 CHAPTER I p.20 Extensive ethnolinguistic diversity in Vietnam reflects multiple sources of genetic diversity CHAPTER II p.68 Reconstructing the human genetic history of mainland Southeast Asia: insights from genome- wide data from Thailand and Laos REFERENCES p.111 ACKNOWLEDGMENTS p.114 CURRICULUM VITAE p.115 DECLARATION OF INDEPENDENCE p.117 AUTHOR CONTRIBUTION STATEMENT p.118

La détection de gènes est une étape importante dans la compréhension des effets de l'information génétique d'un individu sur ses caractères phénotypiques. Durant mon doctorat, j'ai étudié les méthodes statistiques pour conduire les analyses de génétique d'association, avec les hybrides de maïs comme modèle d'application. Je me suis tout d'abord intéressé à l'estimation des paramètres d'apparentement entre individus à partir de données de marqueurs bialléliques. Cette estimation est réalisée dans le cadre d'un modèle de mélange paramétrique. J'ai étudié l'identifiabilité de ce modèle dans un cadre général mais aussi dans un cadre plus spécifique où les individus étudiés étaient issus de croisements entre lignées, cadre représentatif des plans de croisement classiquement utilisés en génétique végétale. Je me suis ensuite intéressé à l'estimation des paramètres des modèles mixtes à plusieurs composantes de variance et plus particulièrement à la performance des algorithmes pour tester l'effet de très nombreux marqueurs. J'ai comparé pour cela des logiciels existants et optimisé un algorithme Min-Max. La pertinence des différentes méthodes développées a finalement été illustrée dans le cadre de la détection de QTL à travers une analyse d'association réalisée sur un panel d'hybrides de maïs. / The detection of genes is a first step to understand the impact of the genetic information of individuals on their phenotypes. During my PhD, I studied statistical methods to perform genome-wide association studies, with maize hybrids as an application case. Firstly, I studied the inference of relatedness coefficients between individuals from biallelic marker data. This estimation is based on a parametric mixture model. I studied the identifiability of this model in the generic case but also in the specific case of mating design where observed individuals are obtained by crossing lines, a representative case of classical mating design in plant genetics. Then I studied inference of variance component mixed model parameters and particularly the performance of algorithms to test effects of numerous markers. I compared existing programs and I optimized a Min-Max algorithm. Relevance of developed methods had been illustrated for the detection of QTLs through a genome-wide association analysis in a maize hybrids panel.

Le récent développement des méthodes de séquençage permet aujourd’hui d’identifier des variations structurales chez de nombreuses espèces. Chez le maïs, des milliers de grandes insertions et délétions (InDel) de quelques pb à plusieurs centaines de Kbp ont été découvertes entre le génome de référence B73 et de nombreux autres génomes reséquencés. Ces InDel peuvent changer la composition des gènes entre les individus et donc être impliquées dans la variation du phénotype, mais cet effet sur le phénotype reste mal connu. L’objectif de cette thèse était d'étudier la contribution des InDel à l'adaptation, aux variations phénotypiques et aux performances hybrides chez le maïs. Nous avons développé une puce de génotypage des InDel Affymetrix® Axiom® capable de génotyper 105 927 InDel de 35bp à 129,7Kbp. 79 969 de ces InDel ont leur séquences absentes du génome de référence B73 et ont été identifiées par l’assemblage 3 génomes (F2, C103, and PH207). Nous avons sélectionné 61 492 InDel polymorphiques pour génotyper 362 lignées de maïs représentant une large gamme de diversité pour étudier la contribution des InDel à la diversité génétique, l’adaptation et la variation des caractères. Nous avons également génotypé 1 million de SNP à partir de deux puces de génotypage et du génotypage par séquençage pour étudier la complémentarité entre les InDel et les SNP. Qu’ils soient calculés avec les InDel ou les SNP la structuration génétique et les valeurs d’apparentement entre les lignées sont très similaires, ce qui suggère que la plupart des InDel ont suivi la même trajectoire évolutive que les SNP. 51% des InDel ne sont pas en déséquilibre de liaison élevé (>0.8) avec aucun SNP proche donc l’effet de ces InDel n’est donc a priori pas capturé pas des SNP à cette densité. Parmi les 294 régions génomiques associées au phénotype (QTL), 13 nouveaux QTL ont été détectés grâce aux InDel par rapport aux SNP par une approche de génétique d’association (GA). Nous avons détecté un enrichissement en InDel sous sélection entre les lignées tropicales, cornées et dentées par rapport aux SNP, avec 56 sur 188 régions sous sélection détectées avec les InDel. Ces régions contiennent des gènes impliqués dans l’adaptation et/ou la tolérance aux stress. De plus, le plus grand nombre d’associations a été découvert pour la floraison, caractère adaptatif chez le maïs. Ces résultats suggèrent que les InDel sont plus souvent impliquées dans l’adaptation et la tolérance aux stress. Nous avons enfin testé l’effet des InDel sur les performances hybride en analysant un panel de 287 hybrides issus du croisement de 210 lignées tempérées du panel précédent. Nous avons décomposé la variance des performances hybrides en distinguant les effets de dominance et d’additivité pour la floraison femelle (FF), la hauteur (PH) et le rendement (GY). La plus forte part de dominance et d’interaction génotype-environnement a été observée pour le GY et la plus faible pour la FF. L’effet additif et de dominance de 51,844 InDel et 469 267 SNP a été testé pour 4 combinaisons d’environnements par une approche de GA. 78 et 133 QTL avec un effet additif et dominant respectivement ont été identifiés, dont 6 et 11 avec des InDel. 83% de ces QTL ont été identifiés dans une seule combinaison d’environnements. Un des QTL de rendement identifié avec des InDel est situé dans un large cluster d’InDel sur le chromosome 6 et colocalise avec un QTL déjà identifié avec des SNP avec un effet fort dans l’augmentation du rendement sous des températures élevées. L’ajout de l’effet de dominance en plus de l’effet additif permet d’augmenter la précision des prédictions génomiques jusqu’à 5,6% pour le rendement. Cependant, l’ajout du génotypage des InDel en plus de celui des SNP n’a pas permis d’améliorer les prédictions des phénotypes hybrides. / In the last decades, the rapid development of genome sequencing allowed to identify structural variations in many species. In maize, thousands of large insertions and deletions (InDels) from few bp to hundreds of Kbp were discovered by comparing the reference genome B73 and many other resequenced genomes. These InDel sequences can carry genes and therefore be involved in phenotypic variation by changing the gene composition between individuals, but their effect on phenotype was not well studied. The aim of this thesis was to study the contribution of InDels to adaptation, phenotypic variations and hybrid performances in maize. We developed an Affymetrix® Axiom® genotyping array that allowed to genotype 105,947 InDels sequences ranging from 35bp to 129,7Kbp of size. 79,969 out 105,947 sequences of these InDels were not present in B73 reference genome and have been discovered by assembling three genomes (F2, C103, and PH207). We selected 61,492 polymorphic InDels to genotype a 362 maize inbred lines panel representing a broad range of diversity to study the contribution of InDels to genetic diversity, adaptation and trait variation. We also assembled one million of SNPs from two genotyping arrays and genotyping by sequencing to study the complementarity between InDels and SNPs. Genetic structuration and relatedness between inbred lines displayed by SNPs or by InDels were highly similar suggesting that almost all indels and SNPs followed a similar evolutionary trajectory. 51% of InDels were not in high linkage disequilibrium (LD>0.8) with any nearby SNP suggesting that the effect of these InDels was not be well captured using this density of SNP. Thanks to InDels, we detected 13 new quantitative trait loci (QTLs) among 294 QTLs identified for 23 traits by a genome wide association studies (GWAS). Similarly, 56 out 188 regions under selection between tropical, dent and flint maize lines were identified by InDels leading to an enrichment of genomic regions under selection detected by InDels compared to SNPs. These InDels include genes involved in tolerance to biotic and abiotic stress and/or adaptive traits as flowering time. Accordingly, the highest number of associated InDels was found for flowering time. These results suggest that InDels were often involved in adaptation and stress tolerance. In order to study the effect of InDels on hybrid performances, we analyzed a panel of 287 hybrids derived from the crossing of 210 maize temperate inbred lines from the previous panel. We decomposed the variance of female flowering (FF), plant height (PH) and grain yield (GY) by distinguishing the additive and dominant genetic effects. We observed the highest dominance and genotype by environment effects for GY and the lowest for FF. We performed GWAS on this panel by testing additive and dominance effects of 51,844 InDels and 469,267 SNPs on these three traits in 4 different environment combinations. We identified 78 and 133 QTLs with an additive and dominance effect, respectively including 6 and 11 QTLs discovered only by InDels. 83% of all QTLs were found with only one environment combination. One QTL for GY detected with InDels was located in a large cluster of InDels on chromosome 6, previously identified to have a strong effect on GY in heat conditions. We finally used InDels and/or SNPs genotyping to predict hybrid performances. Whereas including a dominance effect in genomic prediction models increased by 1.5 to 5.6% predictive abilities (PA) for GY, including InDels genotyping did not increased PA.

Le virus de la panachure jaune (RYMV) est une contrainte majeure pour la riziculture en Afrique. Deux gènes contrôlant des résistances récessives ont précédemment été décrits : RYMV1, qui code pour eIF(iso)4G1, un facteur d’initiation de la traduction et RYMV2, qui code pour CPR5-1, un probable composant du pore nucléaire impliqué dans la régulation des mécanismes de défense. Cependant, la capacité du virus à contourner ces résistances justifie la caractérisation de sources de résistance originales, présentes dans les espèces de riz africain O. glaberrima et O. barthii. Trois approches complémentaires ont été mises en œuvre afin d’identifier les facteurs génétiques contrôlant ces résistances.Une approche de cartographie génétique dans des populations bi-parentales a permis l’identification du gène RYMV3, contrôlant la résistance de l’accession Tog5307 et sans doute également de l’accession Tog5672. Il s’agit de la première résistance dominante identifiée dans le pathosystème riz/RYMV. RYMV3 a été cartographié dans un intervalle de 15 kb où deux gènes sont annotés, dont un gène NB-LRR. Des comparaisons de séquences entre accessions résistantes et accessions sensibles suggèrent que le polymorphisme responsable de la résistance est une mutation ponctuelle dans le domaine LRR du gène NB-LRR.Les deux autres approches ont reposé sur l’exploitation de données de séquençage Illumina de 163 accessions O. glaberrima et 84 accessions O. barthii. Les accessions O. glaberrima ont été phénotypées à la fois pour la résistance élevée et pour la résistance partielle au RYMV, et une partie des accessions O. barthii a été évaluée pour la résistance élevée. L’analyse de la variabilité allélique aux trois gènes majeurs de résistance a permis l’identification d’un probable nouvel allèle de résistance à RYMV1 et de six à RYMV2. Ces allèles sont actuellement en cours de validation. D’autre part, une approche de génétique d’association réalisée sur 125 accessions O. glaberrima a mis en évidence deux QTL de résistance partielle sur les chromosomes 6 et 11, dont l’un colocalise, en première approche, avec le gène RYMV3.Ce travail a ainsi permis l’identification d’un gène majeur, de deux QTL et de nouveaux allèles de résistance qui contribuent à une meilleure compréhension des interactions riz/RYMV et sont utilisables en sélection pour améliorer la durabilité des variétés résistantes. / The Rice yellow mottle virus (RYMV) is a major constraint for rice production in Africa. Two genes controlling recessive resistances have been previously described : RYMV1 coding for eIF(iso)4G1, a translation initiation factor, and RYMV2, coding for CPR5-1, a probable component of the nuclear pore complex involved in the regulation of defense mechanisms. However, the virus' ability to overcome these resistances highlight the need to characterize new sources of resistance in the African rice species O. glaberrima and O. barthii. Three complementary approaches were carried out in order to identify the genetic factors controlling these resistances.A genetic mapping strategy in bi-parental populations led to the identification of the RYMV3 gene, controlling resistance in the Tog5307 accession and probably also in the Tog5672 accession. It is the first dominant resistance identified in the rice/RYMV pathosystem. RYMV3 mapped in a 15 kb interval in which two genes annotated occur, including one NB-LRR gene.The two other strategies used were based on the utilization of Illumina sequencing data of 163 O. glaberrima accessions and 84 O. barthii accessions. O. glaberrima accessions were phenotyped for both high and partial resistance to RYMV, and the high resistance of a portion of the O. barthii accessions was assessed. Analysis of allelic variability at the previously identified genes led to the identification of a probable new resistance allele at RYMV1 and of six others at RYMV2. These alleles are currently undergoing validation. Furthermore, a genome wide association study was carried out on 125 O. glaberrima accessions, revealing two partial resistance QTLs on chromosomes 6 and 11, including one colocalized with RYMV3.This work has thus allowed the identification of one major resistance gene, of two QTLs and of new resistance alleles, contributing to a better understanding of rice/RYMV interactions and creating new prospects for the breeding for resistant varieties.

No description available.

<p>  </p> <p>Aging is characterized by changes in transcriptional outputs that correlate with physiological changes observed as we age, including decreased function, and increased cell death. Importantly, many of these changes are conserved across tissues and organisms . Because one of the molecular hallmarks of aging is epigenetic dysregulation, we are interested in understanding how age-associated changes in chromatin contribute to the aging transcriptome. To accomplish this, we use the <em>Drosophila </em>visual system as a model for aging, with a particular focus on photoreceptor neurons. </p> <p>To perform cell-type specific genomic studies in <em>Drosophila, </em>we previously developed a nuclei immuno-enrichment method that was compatible with RNA-seq. However, due to low nuclei yields, this protocol was not amenable to chromatin-based studies, such as ChIP-seq and ATAC-seq. In Chapter 1, we developed an improved approach to isolate Drosophila melanogaster nuclei tagged with a GFPKASH protein that increased yields without compromising efficiency. We further demonstrate that this protocol is compatible with several chromatin profiling techniques, such as Assay of Transposable-Accessible Chromatin (ATAC)-seq, Chromatin Immunoprecipitation (ChIP-seq), and CUT&Tag. </p> <p>Chromatin accessibility is enriched for transcription factors. Thus, in Chapter 2, we profiled accessible chromatin in aging photoreceptors and integrated this data with RNA-seq to identify transcription factors that showed differential activity in aging Drosophila photoreceptors. Surprisingly, we found that 57 transcription factors had differential binding activity during aging, including two circadian regulators, Clock and Cycle, that showed sustained increased activity during aging. When we disrupted the Clock:Cycle complex by expressing a dominant negative version of Clock (ClkDN) in adult photoreceptors, we observed changes in expression of 15–20% of genes including key components of the phototransduction machinery and many eye-specific transcription factors. Using ATAC-seq, we showed that expression of ClkDN in photoreceptors leads to changes in activity of 37 transcription factors and causes a progressive decrease in global levels of chromatin accessibility in photoreceptors. Supporting a key role for Clock-dependent transcription in the eye, expression of ClkDN in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Together, our data suggests that the circadian regulators Clock and Cycle act as neuroprotective factors in the aging eye by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.</p> <p>Previous work in the Weake lab found that long, highly expressed genes were more susceptible to be downregulated with age. DNA:RNA hybrids are co-transcriptional structures that form when the nascent RNA hybridizes with the template strand, resulting in a displaced non-template ssDNA. Importantly, accumulation of R-loops is associated with transcriptional inhibition and genomic instability, both hallmarks of aging. In Chapter 3, I characterized R-loop in maintaining proper transcriptional outputs and regulating visual function during aging. Bulk assays to measure R-loop levels revealed a significant increase in nuclear R-loops with age. Further, genome-wide mapping of R-loops revealed that transcribed genes accumulated R-loops over gene bodies during aging, which correlated with decreased expression of long and highly expressed genes. Importantly, while photoreceptor-specific down-regulation of Top3β, a DNA/RNA topoisomerase associated with R-loop resolution, lead to decreased visual function, over-expression of Top3β or nuclear-localized RNase H1, which resolves R-loops, enhanced positive light response during aging. </p> <p>Together, these studies underscore the importance of understanding how age-related changes in genomic processes, such as circadian transcription and maintenance of R-loops, contribute to physiological changes observed during aging. </p>

<p>Specialized metabolites are chemical tools produced by organisms to aid in their interaction with the surrounding environment. These diverse compounds can often function as metabolic weapons (<em>e.g.</em> antibiotics), structural components (<em>e.g.</em> lignins), or even attractants (<em>e.g.</em> flavonoids). Because of their frequent utilization in niche environments, specialized metabolite production is often lineage- or even species-specific. Therefore, knowledge between specialized metabolic systems is often nontransferable, which poses a major obstacle in the characterization of these bioactive and commercially relevant compounds. Beyond resolving the chemical composition of a specialized metabolite, the identification of responsible pathway genes and the evolutionary processes responsible for their formation is an arduous task. These gaps in knowledge are further widened by the lack of genomic resources available for specialized metabolite producing species. In this work, we present the genome assemblies of two organisms, each with unique specialized metabolic pathways: the Chinese medicinal plant <em>Lithospermum erythrorhizon </em>and the toxic golden alga <em>Prymnesium parvum. </em>Leveraging the predicted proteome of <em>L. erythrorhizon</em>, we investigated the evolutionary history of specialized metabolic genes responsible for the production of shikonin, a 1,4-naphthoquinone specialized metabolite. We identified a retrotransposition-mediated duplication event responsible for the creation of the core shikonin biosynthesis gene, <em>PGT</em>. In addition, we performed a global coexpression network analysis to identify regulatory and enzymatic gene candidates involved in the shikonin biosynthesis pathway. We also built phylogenetic trees of known and candidate shikonin genes to reveal patterns of lineage-specific gene duplication and retroduplication. Like plants, unicellular algae are known for their production of diverse, often toxic, specialized metabolites. However, these species are often enigmatic. For example, previous studies have documented large phenotypic variation in both toxin chemotypes and levels among different strains of <em>P. parvum</em>. To investigate the genetic basis of this variation, we generated near chromosome level assemblies of two <em>P. parvum </em>strains and performed a broad genome survey of thirteen additional strains. As a result, we identified a commonly studied reference strain, UTEX 2797, as a hybrid with two distinct subgenomes. We also provide evidence of significant variation in haploid genome size across the species. Collectively, these studies supply genetic resources for the future study of these organisms, as well as provide insight into the evolution of their specialized metabolic pathways.</p>

Childhood obesity and its sequelae are a major public health problem in both the USA and globally. This review will focus on a systems medicine approach to obesity. Systems medicine is an integrative approach utilizing the vast amount of data garnered from "omics" technology and integrating these data with conventional pathophysiology as well as diverse environmental factors such as diet, exercise, community dynamics and the intestinal microbiome. Omics technology includes genomics, epigenomics, metagenomics, metabolomics and proteomics. In addition to unraveling etiology, the goals of a systems medicine approach are to provide actionable and evidenced-based clinical approaches. In the case of childhood obesity, an additional goal is characterizing measureable risk factors/biomarkers for obesity at the earliest possible age and devising age-appropriate optimal intervention strategies. It is also important to establish the age at which interventions could be critical. As discussed below, it is possible that some of the pathophysiological and epigenetic changes resulting from childhood obesity could become more irreversible the longer the obesity remains untreated.

Indiana University-Purdue University Indianapolis (IUPUI) / New neurons are generated throughout adulthood in two regions of the brain, the dentate gyrus of the hippocampus, which is important for memory formation and cognitive functions, and the sub-ventricular zone of the olfactory bulb, which is important for the sense of smell, and are incorporated into hippocampal network circuitry. Disruption of this process has been postulated to contribute to neurodegenerative disorders including Alzheimer’s disease [1]. AD is the most common form of adult-onset dementia and the number of patients with AD escalates dramatically each year. The generation of new neurons in the dentate gyrus declines with age and in AD. Many of the molecular players in AD are also modulators of adult neurogenesis, but the genetic mechanisms influencing adult neurogenesis in AD are unclear. The overall goal of this project is to identify candidate genes and pathways that play a role in neurogenesis in the adult brain and to test the hypotheses that 1) hippocampal neurogenesis-related genes and pathways are significantly perturbed in AD and 2) neurogenesis-related pathways are significantly associated with hippocampal volume and other AD-related biomarker endophenotypes including brain deposition of amyloid-β and tau pathology. First, potential modulators of adult neurogenesis and their roles in neurodegenerative diseases were evaluated. Candidate genes that control the turnover process of neural stem cells/precursors to new functional neurons during adult neurogenesis were manually curated using a pathway-based systems biology approach. Second, a targeted neurogenesis pathway-based gene analysis was performed resulting in the identification of ADORA2A as associated with hippocampal volume and memory performance in mild cognitive impairment and AD. Third, a genome-wide gene-set enrichment analysis was conducted to discover associations between hippocampal volume and AD related endophenotypes and neurogenesis-related pathways. Within the discovered neurogenesis enriched pathways, a gene-based association analysis identified TESC and ACVR1 as significantly associated with hippocampal volume and APOE and PVLR2 as significantly associated with tau and amyloid beta levels in cerebrospinal fluid. This project identifies new genetic contributions to hippocampal neurogenesis with translational implications for novel therapeutic targets related to learning and memory and neuroprotection in AD.