Browsing by Author "Joshi, Trupti"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    A novel Synthetic phenotype association study approach reveals the landscape of association for genomic variants and phenotypes
    (Elsevier, 2022) Škrabišová, Mária; Dietz, Nicholas; Zeng, Shuai; Chan, Yen On; Wang, Juexin; Liu, Yang; Biová, Jana; Joshi, Trupti; Bilyeu, Kristin D.; Medical and Molecular Genetics, School of Medicine
    Introduction: Genome-Wide Association Studies (GWAS) identify tagging variants in the genome that are statistically associated with the phenotype because of their linkage disequilibrium (LD) relationship with the causative mutation (CM). When both low-density genotyped accession panels with phenotypes and resequenced data accession panels are available, tagging variants can assist with post-GWAS challenges in CM discovery. Objectives: Our objective was to identify additional GWAS evaluation criteria to assess correspondence between genomic variants and phenotypes, as well as enable deeper analysis of the localized landscape of association. Methods: We used genomic variant positions as Synthetic phenotypes in GWAS that we named "Synthetic phenotype association study" (SPAS). The extreme case of SPAS is what we call an "Inverse GWAS" where we used CM positions of cloned soybean genes. We developed and validated the Accuracy concept as a measure of the correspondence between variant positions and phenotypes. Results: The SPAS approach demonstrated that the genotype status of an associated variant used as a Synthetic phenotype enabled us to explore the relationships between tagging variants and CMs, and further, that utilizing CMs as Synthetic phenotypes in Inverse GWAS illuminated the landscape of association. We implemented the Accuracy calculation for a curated accession panel to an online Accuracy calculation tool (AccuTool) as a resource for gene identification in soybean. We demonstrated our concepts on three examples of soybean cloned genes. As a result of our findings, we devised an enhanced "GWAS to Genes" analysis (Synthetic phenotype to CM strategy, SP2CM). Using SP2CM, we identified a CM for a novel gene. Conclusion: The SP2CM strategy utilizing Synthetic phenotypes and the Accuracy calculation of correspondence provides crucial information to assist researchers in CM discovery. The impact of this work is a more effective evaluation of landscapes of GWAS associations.
  • Thumbnail Image
    Item
    CrossMP: Enabling Cross-Modality Translation between Single-Cell RNA-Seq and Single-Cell ATAC-Seq through Web-Based Portal
    (MDPI, 2024-07-05) Lyu, Zhen; Dahal, Sabin; Zeng, Shuai; Wang, Juexin; Xu, Dong; Joshi, Trupti; Biomedical Engineering and Informatics, Luddy School of Informatics, Computing, and Engineering
    In recent years, there has been a growing interest in profiling multiomic modalities within individual cells simultaneously. One such example is integrating combined single-cell RNA sequencing (scRNA-seq) data and single-cell transposase-accessible chromatin sequencing (scATAC-seq) data. Integrated analysis of diverse modalities has helped researchers make more accurate predictions and gain a more comprehensive understanding than with single-modality analysis. However, generating such multimodal data is technically challenging and expensive, leading to limited availability of single-cell co-assay data. Here, we propose a model for cross-modal prediction between the transcriptome and chromatin profiles in single cells. Our model is based on a deep neural network architecture that learns the latent representations from the source modality and then predicts the target modality. It demonstrates reliable performance in accurately translating between these modalities across multiple paired human scATAC-seq and scRNA-seq datasets. Additionally, we developed CrossMP, a web-based portal allowing researchers to upload their single-cell modality data through an interactive web interface and predict the other type of modality data, using high-performance computing resources plugged at the backend.
  • Thumbnail Image
    Item
    Mapping Genetic Variation in Arabidopsis in Response to Plant Growth-Promoting Bacterium Azoarcus olearius DQS-4T
    (MDPI, 2023-01-28) Plucani do Amaral, Fernanda; Wang, Juexin; Williams, Jacob; Tuleski, Thalita R.; Joshi, Trupti; Ferreira, Marco A. R.; Stacey, Gary; BioHealth Informatics, School of Informatics and Computing
    Plant growth-promoting bacteria (PGPB) can enhance plant health by facilitating nutrient uptake, nitrogen fixation, protection from pathogens, stress tolerance and/or boosting plant productivity. The genetic determinants that drive the plant–bacteria association remain understudied. To identify genetic loci highly correlated with traits responsive to PGPB, we performed a genome-wide association study (GWAS) using an Arabidopsis thaliana population treated with Azoarcus olearius DQS-4T. Phenotypically, the 305 Arabidopsis accessions tested responded differently to bacterial treatment by improving, inhibiting, or not affecting root system or shoot traits. GWA mapping analysis identified several predicted loci associated with primary root length or root fresh weight. Two statistical analyses were performed to narrow down potential gene candidates followed by haplotype block analysis, resulting in the identification of 11 loci associated with the responsiveness of Arabidopsis root fresh weight to bacterial inoculation. Our results showed considerable variation in the ability of plants to respond to inoculation by A. olearius DQS-4T while revealing considerable complexity regarding statistically associated loci with the growth traits measured. This investigation is a promising starting point for sustainable breeding strategies for future cropping practices that may employ beneficial microbes and/or modifications of the root microbiome.
  • Thumbnail Image
    Item
    Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome
    (American Society for Clinical Investigation, 2024-02-08) Srivastava, Tarak; Garola, Robert E.; Zhou, Jianping; Boinpelly, Varun C.; Rezaiekhaligh, Mohammad H.; Joshi, Trupti; Jiang, Yuexu; Ebadi, Diba; Sharma, Siddarth; Sethna, Christine; Staggs, Vincent S.; Sharma, Ram; Gipson, Debbie S.; Hao, Wei; Wang, Yujie; Mariani, Laura H.; Hodgin, Jeffrey B.; Rottapel, Robert; Yoshitaka, Teruhito; Ueki, Yasuyoshi; Sharma, Mukut; Biomedical and Applied Sciences, School of Dentistry
    Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in FSGS. Lower SH3BP2 signalosome score was associated with MCD, higher estimated glomerular filtration rate, and remission. Further work using Sh3bp2KI/KI transgenic mice with a gain-in-function mutation showed ~6-fold and ~25-fold increases in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin and unchanged serum creatinine were observed at 12 weeks. Sh3bp2KI/KI kidney morphology appeared normal except for increased mesangial cellularity and patchy foot process fusion without electron-dense deposits. SH3BP2 co-immunoprecipitated with PLCγ2 and VAV2 in human podocytes, underscoring the importance of SH3BP2 in immune activation. SH3BP2 and its binding partners may determine the immune activation pathways resulting in podocyte injury leading to loss of the glomerular filtration barrier.
  • Thumbnail Image
    Item
    The adeno-associated virus 2 genome and Rep 68/78 proteins interact with cellular sites of DNA damage
    (Oxford University Press, 2022) Boftsi, Maria; Whittle, Fawn B.; Wang, Juexin; Shepherd, Phoenix; Burger, Lisa R.; Kaifer, Kevin A.; Lorson, Christian L.; Joshi, Trupti; Pintel, David J.; Majumder, Kinjal; Biomedical Engineering and Informatics, Luddy School of Informatics, Computing, and Engineering
    Nuclear DNA viruses simultaneously access cellular factors that aid their life cycle while evading inhibitory factors by localizing to distinct nuclear sites. Adeno-associated viruses (AAVs), which are Dependoviruses in the family Parvovirinae, are non-enveloped icosahedral viruses, which have been developed as recombinant AAV vectors to express transgenes. AAV2 expression and replication occur in nuclear viral replication centers (VRCs), which relies on cellular replication machinery as well as coinfection by helper viruses such as adenoviruses or herpesviruses, or exogenous DNA damage to host cells. AAV2 infection induces a complex cellular DNA damage response (DDR), in response to either viral DNA or viral proteins expressed in the host nucleus during infection, where VRCs co-localized with DDR proteins. We have previously developed a modified iteration of a viral chromosome conformation capture (V3C-seq) assay to show that the autonomous parvovirus minute virus of mice localizes to cellular sites of DNA damage to establish and amplify its replication. Similar V3C-seq assays to map AAV2 show that the AAV2 genome co-localized with cellular sites of DNA damage under both non-replicating and replicating conditions. The AAV2 non-structural protein Rep 68/78, also localized to cellular DDR sites during both non-replicating and replicating infections, and also when ectopically expressed. Ectopically expressed Rep could be efficiently re-localized to DDR sites induced by micro-irradiation. Recombinant AAV2 gene therapy vector genomes derived from AAV2 localized to sites of cellular DNA damage to a lesser degree, suggesting that the inverted terminal repeat origins of replication were insufficient for targeting.