Bermudagrass (Cynodon spp.) breeding and cultivar development is hampered by limited information regarding its genetic and phenotypic diversity. A germplasm collection of 206 bermudagrass accessions from 29 countries was genotyped with high-throughput genotyping-by-sequencing technique. Genomic diversity in this diverse germplasm panel was assessed with multifaceted approaches including population structure, phylogenetic analysis, principal component analysis, and genetic diversity parameters. This study revealed substantial genetic variation in the Cynodon accessions, demonstrating the potential of this germplasm panel for further genetic studies and cultivar development in breeding programs. Another critical issue in turfgrass breeding is the lack of information regarding the genetic architecture of traits. Four agronomic traits leaf length, leaf width, internode distance and stem diameter were evaluated in a germplasm panel of common bermudagrass accessions. Then genome-wide association study was performed to dissect the genetic basis of the traits.

Flax (Linum usitatissimum L.) is a self-pollinated crop widely cultivated for fiber and oil production. Flaxseed is renowned for its health attributes but the presence of compounds, such as the heavy metal cadmium (Cd), is undesirable. Genomic studies in flax have produced large amounts of data in the last 15 years, providing useful resources to improve the genetic of this crop using genomics-based technologies and strategies. The goal of this thesis is therefore to capitalize on these advances to address the Cd problem and to propose solutions to improve breeding efficiencies. To find genomic-based solutions to Cd content, to the currently low breeding efficiency and to abiotic stress resistance in flax, this study utilized four major strategies: (1) genomic cross prediction, (2) gene family identification, (3) genome-wide association study (GWAS) and (4) genomic selection (GS). Characterization of the ATP-binding cassette (ABC) transporter and heavy metal associated (HMA) gene families was performed using the flax genome sequence. A total of 198 ABC transporter and 12 HMA genes were identified in the flax genome, of which nine were orthologous to Cd-associated genes in Arabidopsis, rice and maize. A transcriptomic analysis of eight tissues provided some support towards the functional annotation of these genes and confirmed the expression of these ABC transporter and HMA genes in flax seeds and other tissues. A diversity panel of 168 flax accessions was grown in the field at multiple locations and years and the seed content of 24 heavy metals (HMs) was measured. The panel was also sequenced and a single nucleotide polymorphism (SNP) dataset of nearly 43,000 SNPs was defined. A GWAS was conducted using these genotypic and phenotypic data and a total of 355 non-redundant quantitative trait nucleotides (QTNs) were identified for ten of the 24 metal contents. Overall, a total of 24 major and 331 minor effect QTNs were detected, including 11 that were pleiotropic. After allelic tests, 108 non-redundant QTNs were retained for eight of the ten metals and ranging from one for copper (Cu) to 70 for strontium (Sr). A total of 20 candidate genes for HM accumulation were identified at 12 of the 24 major QTN loci, of which five belonged to the ABC transporter family. Many of the metal contents, including Cd, appeared to be controlled by many genes of small effects; hence, GS is better suited than marker-assisted selection for application in breeding. To test this, predictive ability using ten GS statistical models was evaluated using trait-specific QTN and the random genome-wide 43K SNP datasets. Significantly higher predictive abilities were observed from the GS models built with the dataset made of QTNs associated with metal contents (70-80%) compared to that of the 43K dataset (10-25%). This study showed the feasibility of using GS to improve the predictive ability of polygenic traits such as metal content in seeds. GS can be applied in early generation selection to accelerate the improvement of abiotic stress resistance and either select low-Cd lines or discard high-Cd lines. These findings validate the use of a QTL-based strategy as a highly effective method for improving the efficiency of predictive ability of GS for highly complex traits such as resistance or tolerance to HM accumulation. Identification of both large and minor effect QTNs and/or pleiotropic effects hold potential for flax breeding improvement. Candidate gene functional validation can be performed using methods such as genome editing or targeting induced local lesions in genomes (TILLING).

La drépanocytose est une maladie causée par une seule mutation dans le gène de la bêta-globine. Les complications liées à la maladie se manifestent sur le plan génétique, épigénique, transcriptionnel, et métabolique. Les approches intégratives des technologies de séquençage à haut-débit permettent de comprendre le mécanisme pathologique et de découvrir des thérapies en lien avec la maladie. Dans cette thèse, j’intègre divers jeux de données omiques et j’applique des méthodes statistiques pour élaborer de nouvelles hypothèses et analyser les données. Dans les deux premières études, je combine les résultats des études d'association pangénomique d'hémoglobine fœtale (HbF) et des globules rouges denses déshydratés (DRBC) avec l'expression génique, l'interaction chromatinienne, les bases de données relatives aux maladies et les cibles médicamenteuses sélectionnées par des experts. Cette approche intégrative a révélé trois nouveaux loci sur le chromosome 10 (BICC1), le chromosome 19 (KLF1) et le chromosome 22 (CECR2) comme régulateurs de l'HbF. Pour l’étude sur la densité de globules rouges, quatre cibles médicamenteuses (BCL6, LRRC32, KNCJ14 et LETM1) ont été identifiées comme des modulateurs potentiels de la sévérité. Dans la troisième étude, j’intégre la métabolomique à la génomique pour établir une relation causale entre la L-glutamine et les crises douleurs en utilisant la randomisation mendélienne. En outre, nous avons identifié 66 biomarqueurs pour 6 complications liées à la drépanocytose et le débit de filtration glomérulaire estimé (DFGe). Enfin, dans la dernière étude j’ai appliqué une approche de clustering aux métabolites que j’ai ensuite combiné aux données de génotype. J’ai découvert des changements métabolomiques mettant en évidence des familles de métabolites impliqués dans les dysfonctionnements rénaux et hépatiques, en plus de confirmer le rôle d'une classe d'acides gras dans la formation en faucille des globules rouges. Ce travail met en évidence l'importance des approches multi-omiques pour découvrir de nouveaux mécanismes biologiques et étudier les maladies humaines. / Sickle cell disease is a monogenic disorder caused by a point mutation in the beta-globin gene. The complications related to the disease are characterized by a broad spectrum of distinct genetic, epigenetic, transcriptional, and metabolomic states. Integrative high-throughput technologies approaches to sickle cell disease pathophysiology are crucial to understanding complications mechanisms and uncovering therapeutic interventions. In this thesis, I integrate various omics datasets and apply statistical methods to derive new hypotheses and analyze data. I combine genome-wide association studies results of fetal hemoglobin (HbF) and dehydrated dense red blood cells (DRBC) with gene expression, chromatin interaction, disease-relevant databases, and expert-curated drug targets. This integrative approach revealed three novel loci on chromosome 10 (BICC1), chromosome 19 (KLF1) and chromosome 22 (CECR2) as key modulators of HbF. For DRBC, four drug targets (BCL6, LRRC32, KNCJ14, and LETM1) were identified as potential severity modifiers. Using mendelian randomization, I integrated metabolomics with genomics in the third study to establish a potential causal relationship between L-glutamine and painful crisis. Additionally, we identified 66 biomarkers for 6 SCD-related complications and estimated glomerular filtration rate (eGFR). Finally, the last study applied a clustering framework to metabolites which I then combined with genotypes. I found specific metabolomics changes highlighting families of metabolites involved in renal and liver dysfunction and confirming the role of a class of fatty acids in red blood cell sickling. This work highlights the importance of multi-omics approaches to unearth new biology and study human diseases.

No description available.

No description available.

To leverage the extreme parallelism of emerging architectures, so that scientific applications can fulfill their high fidelity and multi-physics potential while sustaining high efficiency relative to the limiting resource, numerical algorithms must be redesigned. Algorithmic redesign is capable of shifting the limiting resource, for example from memory or communication to arithmetic capacity. The benefit of algorithmic redesign expands greatly when introducing a tunable tradeoff between accuracy and resources. Scientific applications from diverse sources rely on dense matrix operations. These operations arise in: Schur complements, integral equations, covariances in spatial statistics, ridge regression, radial basis functions from unstructured meshes, and kernel matrices from machine learning, among others. This thesis demonstrates how to extend the problem sizes that may be treated and to reduce their execution time. Two “universes” of algorithmic innovations have emerged to improve computations by orders of magnitude in capacity and runtime. Each introduces a hierarchy, of rank or precision. Tile Low-Rank approximation replaces blocks of dense operator with those of low rank. Mixed precision approximation, increasingly well supported by contemporary hardware, replaces blocks of high with low precision. Herein, we design new high-performance direct solvers based on the synergism of TLR and mixed precision. Since adapting to data sparsity leads to heterogeneous workloads, we rely on task-based runtime systems to orchestrate the scheduling of fine-grained kernels onto computational resources. We first demonstrate how TLR permits to accelerate acoustic scattering and mesh deformation simulations. Our solvers outperform the state-of-art libraries by up to an order of magnitude. Then, we demonstrate the impact of enabling mixed precision in bioinformatics context. Mixed precision enhances the performance up to three-fold speedup. To facilitate the adoption of task-based runtime systems, we introduce the AL4SAN library to provide a common API for the expression and queueing of tasks across multiple dynamic runtime systems. This library handles a variety of workloads at a low overhead, while increasing user productivity. AL4SAN enables interoperability by switching runtimes at runtime, which permits to achieve a twofold speedup on a task-based generalized symmetric eigenvalue solver.

<p>Across the tree of life, novel genes are thought to be a source of much of the unique behaviors and adaptions between the different taxa. This is especially true in the social insects where novel genes are proposed to contribute to novel social behaviors. In the honey bee (Apis mellifera L.), a group of novel genes called the major royal jelly proteins (MRJPs) are proposed to be important to the expression of novel social behaviors, particularly those related to nursing versus foraging tasks. Unfortunately, identifying the functional role of novel genes is often not possible due to a lack of functional genomic tools in non-model species such as the honey bee. Here I have developed a novel ectopic expression system in Drosophila melanogaster and used it to elucidate how the MRJPs contribute to behavioral and transcriptional changes in the insect brain. I found that the MRJPs regulated the expression of hundreds of genes in Drosophila, and these overlap with genes regulated differentially between nursing and foraging honey bees. Furthermore, I found that MRJP expression impairs or negatively regulated phototaxis. My results demonstrate the MRJPs play a role in behavioral plasticity and highlight that the MRJPs may have a much larger role in the nurse-forager transition than previously thought.</p>

<p dir="ltr">Given the relatively poor visual acuity of compound eyes, many insects have developed alternative means for navigating their environment. For example, insects often rely on chemosensation to find food, mates, and inter- and intraspecific communication. Eusocial insects in particular have developed complex systems of pheromone communication to organize their colonies, enabling them to partition labor for foraging, brood care, and colony defense tasks to different portions of the colony. A variety of genes coding for proteins are involved in detecting these chemicals, including gustatory receptors, ionotropic receptors, and odorant receptors (ORs). Eusocial insects, and especially ants, have evolved an expanded clade of ORs in their genome, likely due to an increased reliance on pheromones compared to other insects. The ability to recognize nestmates from non-nestmates is one of the vital functions performed by these ORs, which detect hydrocarbons present on the cuticle to distinguish friend from foe. However, research into the details of nestmate recognition has been stymied due to difficulties in manipulating OR genes. Despite advances in genetic sequencing and manipulation technologies, strict reproductive divisions within most ant lineages make generating transgenic ants nearly impossible, and so we have been left with limited options to further investigate these receptors. To narrow down the ORs that could be involved in nestmate recognition in the Argentine ant (Mayr, 1868), I took a multi-pronged approach of generating tissue transcriptomes to identify ORs that are selectively upregulated in the antennae, as well as conducting a phylostratigraphic analysis to identify which OR genes arose more recently in the Argentine ant genome. While conducting these analyses, it became necessary to reannotate the set of Argentine ant OR genes, due to current published annotations not containing the full breadth of <i>L. humile</i> ORs. Finally, I orally administered fluorescently-labelled dsRNA to workers, and tracked the extent to which ingested dsRNA is capable of traversing the tissues of ant workers, to investigate whether RNAi is a viable method for investigating gene function for genes showing tissue-selective expression. I discovered a subset of OR genes that are highly expressed in the antennae and confirmed that dsRNA is able to reach the antennae and knock down OR gene expression through ingestion, meaning that RNA interference is a viable method for the practical study of ant OR genes and can be used to further explore how individual ORs regulate nestmate recognition.</p>

<p dir="ltr">Neutrophils are critical for innate immunity, acting as the body's first line of defense. They are terminally differentiated and are short-lived white blood cells. Cyclin-dependent kinases (CDKs), traditionally associated with cell cycle progression are now known to regulate crucial neutrophil functions: CDK2 influences neutrophil migration, CDK4 and 6 regulate neutrophil extracellular traps (NETs) formation, CDK5 controls degranulation, and CDK7 and 9 are pivotal for apoptosis and inflammation resolution.</p><p dir="ltr">Despite extensive studies on CDK2 in cell cycle regulation, its role in neutrophil function remained uncharacterized until recently. Inhibiting CDK2 kinase activity significantly impairs neutrophil migration. Using phosphoproteomic methods, we identified key proteins in multiple cellular pathways affected by CDK2 inhibition, with Cyclin D3 emerging as a binding partner. Direct substrates of CDK2, including RCSD1, CCDC6, LMNB1, and STK10, were found to be essential for neutrophil motility. These findings provide insights into the molecular mechanisms underlying this process. Consequently, targeting CDK2 or its substrates presents potential therapeutic strategies for conditions involving aberrant neutrophil migration or neutrophil-mediated inflammation, offering new avenues for treating neutrophil-dominant inflammatory diseases and advancing our understanding of neutrophil regulation.</p><p dir="ltr">Emergency granulopoiesis, a response to severe inflammation, involves the increased production of neutrophils in hematopoietic tissue. Understanding the body's response to severe inflammation necessitates more precise and less invasive methods to track neutrophil development. To distinguish newly formed neutrophils from existing ones in the occurrence of emergency granulopoiesis, we developed a transgenic zebrafish line expressing a time-dependent GFP-RFP switch fluorescent protein, enabling quantification through simple GFP/RFP ratiometric imaging. This method bypasses the limitations of traditional photo-labeling, which requires strong laser lines and label subsets of existing neutrophils.</p>

Yes / Bone morphogenetic proteins (BMPs) play essential roles in the control of skin development, postnatal tissue remodelling and tumorigenesis. To explore whether some of the effects of BMP signalling are mediated by microRNAs, we performed genome-wide microRNA (miRNA) screening in primary mouse keratinocytes after BMP4 treatment. Microarray analysis revealed substantial BMP4-dependent changes in the expression of distinct miRNAs, including miR-21. Real-time PCR confirmed that BMP4 dramatically inhibits miR-21 expression in the keratinocytes. Consistently, significantly increased levels of miR-21 were observed in transgenic mice overexpressing the BMP antagonist noggin under control of the K14 promoter (K14-noggin). By in situ hybridization, miR-21 expression was observed in the epidermis and hair follicle epithelium in normal mouse skin. In K14-noggin skin, miR-21 was prominently expressed in the epidermis, as well as in the peripheral portion of trichofolliculoma-like hair follicle-derived tumours that contain proliferating and poorly differentiated cells. By transfecting keratinocytes with a miR-21 mimic, we identified the existence of two groups of the BMP target genes, which are differentially regulated by miR-21. These included selected BMP-dependent tumour-suppressor genes (Pten, Pdcd4, Timp3 and Tpm1) negatively regulated by miR-21, as well as miR-21-independent Id1, Id2, Id3 and Msx2 that predominantly mediate the effects of BMPs on cell differentiation. In primary keratinocytes and HaCaT cells, miR-21 prevented the inhibitory effects of BMP4 on cell proliferation and migration. Thus, our study establishes a novel mechanism for the regulation of BMP-induced effects in the skin and suggests miRNAs are important modulators of the effects of growth factor signalling pathways on skin development and tumorigenesis.