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Poster by Ikhlak Ahmed (Sidra Medicine), Mubarak Ziab (Sidra Medicine), Sahar Da’as (Sidra Medicine, Hamad Bin Khalifa University), Waseem Hasan (Sidra Medicine), Sujitha P. Jeya (Sidra Medicine), Elbay Aliyev (Sidra Medicine), Sabah Nisar (Sidra Medicine), Ajaz A. Bhat (Sidra Medicine), Khalid Fakhro (Sidra Medicine, Hamad Bin Khalifa University, Weill Cornell Medicine College - Qatar), Ammira S. Alshabeeb Akil (Sidra Medicine) Background: Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to categorize candidate genes in prominent diabetic cohorts, aiming to investigate DN pathogenesis and etiology. Objective: The objective of this study is to identify critical transcriptional factors associated with diabetic nephropathy (DN) progression and validate their role in DN development using a hyperglycemic zebrafish model. Methods: In this study, we performed a meta-analysis on the expression profiles of GSE1009, GSE30122, GSE96804, GSE99340, GSE104948, GSE104954, and GSE111154 to identify critical transcriptional factors associated with DN progression. The analysis was conducted for all individual datasets for each kidney tissue (glomerulus, tubules, and kidney cortex). Results: We identified distinct clusters of susceptibility genes that were dysregulated in a renal compartment- specific pattern. Further, we recognized a small but a closely connected set of these susceptibility genes enriched for podocyte differentiation, several of which were characterized as genes encoding critical transcriptional factors (TFs) involved in DN development and podocyte function. To validate the role of identified TFs in DN progression, we functionally validated the three main TFs (DACH1, LMX1B, and WT1) identified through differential gene expression and network analysis using the hyperglycemic zebrafish model. We report that hyperglycemia-induced altered gene expression of the key TF genes leads to morphological abnormalities in zebrafish glomeruli, pronephric tubules, proximal and distal ducts. Conclusion: This study demonstrated that altered expression of these TF genes could be associated with hyperglycemia-induced nephropathy and, thus, aids in understanding the molecular drivers, essential genes, and pathways that trigger DN initiation and development.

A critical emerging factor in the fitness of individuals is their microbiome, defined as the community of microorganisms found in and on the body of an individual. Despite the rapidly accumulating evidence of the significant role of the microbiome to host health and disease, there is a lack of studies partitioning microbiome variation into explanatory source components in fish, especially those relating to host genetics. To address this knowledge gap, this thesis made several contributions to estimate the transgenerational effects on the microbiome of an ecologically, economically and culturally important salmonid – Chinook salmon (Oncorhynchus tshawytscha). To achieve this goal, breeding designs were utilized to estimate various genetic architecture components, including additive among- population variance, additive genetic variance and maternal effects. DNA was extracted from hindgut contents of saltwater juveniles, the surface of eyed eggs, and maternally sourced gut content and ovarian fluids. Polymerase chain reactions (PCRs) were conducted to amplify and metabarcode the 16S rRNA encoding gene, and high throughput sequencing was then used to generate millions of sequences based on amplified PCR products. Taxonomic operational units (OTUs) were generated to measure microbiome diversity and allow for microbial community profiling. Using a combination of parametric and non-parametric modelling, significant hybrid-cross and sire were found on the gut microbiome at the juvenile saltwater stage, respectively indicative of population and additive genetic effects. Further, significant maternal effects were found on the surface of eyed eggs. Although no correlations were found between the ovarian fluid and the eyed eggs, a surprising and significant similarity was found between the microbiomes of the dam-sourced ovarian fluid and hindgut samples. Together, the findings presented in this thesis contribute to the characterization of the genetic architecture underlying microbiome variation in Chinook salmon and to its adaptive potential. The results presented in this thesis will have critical consequences for fisheries and conservation efforts and lead the way to exciting microbiome research with the ultimate goal of selecting for microbiomes associated with improved survivability and performance.