Browsing by Author "Lu, Qing"

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    HapCNV: A Comprehensive Framework for CNV Detection in Low-input DNA Sequencing Data
    (bioRxiv, 2025-01-07) Yu, Xuanxuan; Qin, Fei; Liu, Shiwei; Brown, Noah J.; Lu, Qing; Cai, Guoshuai; Guler, Jennifer L.; Xiao, Feifei; Radiology and Imaging Sciences, School of Medicine
    Copy number variants (CNVs) are prevalent in both diploid and haploid genomes, with the latter containing a single copy of each gene. Studying CNVs in genomes from single or few cells is significantly advancing our knowledge in human disorders and disease susceptibility. Low-input including low-cell and single-cell sequencing data for haploid and diploid organisms generally displays shallow and highly non-uniform read counts resulting from the whole genome amplification steps that introduce amplification biases. In addition, haploid organisms typically possess relatively short genomes and require a higher degree of DNA amplification compared to diploid organisms. However, most CNV detection methods are specifically developed for diploid genomes without specific consideration of effects on haploid genomes. Challenges also reside in reference samples or normal controls which are used to provide baseline signals for defining copy number losses or gains. In traditional methods, references are usually pre-specified from cells that are assumed to be normal or disease-free. However, the use of pre-defined reference cells can bias results if common CNVs are present. Here, we present the development of a comprehensive statistical framework for data normalization and CNV detection in haploid single- or low-cell DNA sequencing data called HapCNV. The prominent advancement is the construction of a novel genomic location specific pseudo-reference that selects unbiased references using a preliminary cell clustering method. This approach effectively preserves common CNVs. Using simulations, we demonstrated that HapCNV outperformed existing methods by generating more accurate CNV detection, especially for short CNVs. Superior performance of HapCNV was also validated in detecting known CNVs in a real P. falciparum parasite dataset. In conclusion, HapCNV provides a novel and useful approach for CNV detection in haploid low-input sequencing datasets, with easy applicability to diploids.
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    Integration of evidence across human and model organism studies: A meeting report
    (Wiley, 2021-04-23) Palmer, Rohan H.C.; Johnson, Emma C.; Won, Hyejung; Polimanti, Renato; Kapoor, Manav; Chitre, Apurva; Bogue, Molly A.; Benca-Bachman, Chelsie E.; Parker, Clarissa C.; Verm, Anurag; Reynolds, Timothy; Ernst, Jason; Bray, Michael; Kwon, Soo Bin; Lai, Dongbing; Quach, Bryan C.; Gaddis, Nathan C.; Saba, Laura; Chen, Hao; Hawrylycz, Michael; Zhang, Shan; Zhou, Yuan; Mahaffey, Spencer; Fischer, Christian; Sanchez-Roige, Sandra; Bandrowski, Anita; Lu, Qing; Shen, Li; Philip, Vivek; Gelernter, Joel; Bierut, Laura J.; Hancock, Dana B.; Edenberg, Howard J.; Johnson, Eric O.; Nestler, Eric J.; Barr, Peter B.; Prins, Pjotr; Smith, Desmond J.; Akbarian, Schahram; Thorgeirsson, Thorgeir; Walton, Dave; Baker, Erich; Jacobson, Daniel; Palmer, Abraham A.; Miles, Michael; Chesler, Elissa J.; Emerson, Jake; Agrawal, Arpana; Martone, Maryann; Williams, Robert W.; Medical and Molecular Genetics, School of Medicine
    The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.
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    MPRAVarDB: an online database and web server for exploring regulatory effects of genetic variants
    (Oxford University Press, 2024) Jin, Weijia; Xia, Yi; Nizomov, Javlon; Liu, Yunlong; Li, Zhigang; Lu, Qing; Chen, Li; Medical and Molecular Genetics, School of Medicine
    Summary: Massively parallel reporter assay (MPRA) is an important technology for evaluating the impact of genetic variants on gene regulation. Here, we present MPRAVarDB, an online database and web server for exploring regulatory effects of genetic variants. MPRAVarDB harbors 18 MPRA experiments designed to assess the regulatory effects of genetic variants associated with GWAS loci, eQTLs, and genomic features, totaling 242 818 variants tested more than 30 cell lines and 30 human diseases or traits. MPRAVarDB enables users to query MPRA variants by genomic region, disease and cell line, or any combination of these parameters. Notably, MPRAVarDB offers a suite of pretrained machine-learning models tailored to the specific disease and cell line, facilitating the prediction of regulatory variants. The user-friendly interface allows users to receive query and prediction results with just a few clicks. Availability and implementation: https://mpravardb.rc.ufl.edu.
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    SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics
    (American Thoracic Society, 2023) Sangam, Shreya; Sun, Xutong; Schwantes-An, Tae-Hwi; Yegambaram, Manivannan; Lu, Qing; Shi, Yinan; Cook, Todd; Fisher, Amanda; Frump, Andrea L.; Coleman, Anna; Sun, Yanan; Liang, Shuxin; Crawford, Howard; Lutz, Katie A.; Maun, Avinash D.; Pauciulo, Michael W.; Karnes, Jason H.; Chaudhary, Ketul R.; Stewart, Duncan J.; Langlais, Paul R.; Jain, Mohit; Alotaibi, Mona; Lahm, Tim; Jin, Yan; Gu, Haiwei; Tang, Haiyang; Nichols, William C.; Black, Stephen M.; Desai, Ankit A.; Medical and Molecular Genetics, School of Medicine
    Rationale: Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. Objectives: On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. Methods: We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. Measurements and Main Results: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n = 1,326). Conclusions: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.