Genetics and Genomics Commons^™

Leveraging The T2t Assembly To Resolve Rare And Pathogenic Inversions In Reference Genome Gaps, Kristine Bilgrav Saether, Jesper Eisfeldt, Jesse D Bengtsson, Ming Yin Lun, Christopher M Grochowski, Medhat Mahmoud, Hsiao-Tuan Chao, Jill A Rosenfeld, Pengfei Liu, Marlene Ek, Jakob Schuy, Adam Ameur, Hongzheng Dai, Undiagnosed Diseases Network, James Paul Hwang, Fritz J Sedlazeck, Weimin Bi, Ronit Marom, Josephine Wincent, Ann Nordgren, Claudia M B Carvalho, Anna Lindstrand

Faculty, Staff and Students Publications

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the …

High-Coverage Nanopore Sequencing Of Samples From The 1000 Genomes Project To Build A Comprehensive Catalog Of Human Genetic Variation, Jonas A Gustafson, Sophia B Gibson, Nikhita Damaraju, Miranda P G Zalusky, Kendra Hoekzema, David Twesigomwe, Lei Yang, Anthony A Snead, Phillip A Richmond, Wouter De Coster, Nathan D Olson, Andrea Guarracino, Qiuhui Li, Angela L Miller, Joy Goffena, Zachary B Anderson, Sophie H R Storz, Sydney A Ward, Maisha Sinha, Claudia Gonzaga-Jauregui, Wayne E Clarke, Anna O Basile, André Corvelo, Catherine Reeves, Adrienne Helland, Rajeeva Lochan Musunuri, Mahler Revsine, Karynne E Patterson, Cate R Paschal, Christina Zakarian, Sara Goodwin, Tanner D Jensen, Esther Robb, 1000 Genomes Ont Sequencing Consortium, University Of Washington Center For Rare Disease Research (Uw-Crdr), Genomics Research To Elucidate The Genetics Of Rare Diseases (Gregor) Consortium, William Richard Mccombie, Fritz J Sedlazeck, Justin M Zook, Stephen B Montgomery, Erik Garrison, Mikhail Kolmogorov, Michael C Schatz, Richard N Mclaughlin, Harriet Dashnow, Michael C Zody, Matt Loose, Miten Jain, Evan E Eichler, Danny E Miller

Faculty, Staff and Students Publications

Fewer than half of individuals with a suspected Mendelian or monogenic condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control data sets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project (1KGP) Oxford Nanopore Technologies Sequencing Consortium aims to generate LRS data from at least 800 of the 1KGP samples. Our goal is to use LRS to identify a broader spectrum of variation …

Porcine Peritoneal Macrophages Are Susceptible To Porcine Reproductive And Respiratory Syndrome Virus Infection, Kassandra Durazo-Martinez, Jayeshbhai Chaudhari, Sushmita Kumari, Hiep Vu

Department of Animal Science: Faculty Publications

Previous studies have suggested that porcine peritoneal macrophages (PPMs) are resistant to PRRSV infection, whereas porcine alveolar macrophages (PAMs) are highly susceptible. This contrast is intriguing, as both cell types belong to the same monocyte/macrophage family. The current study aimed to investigate the host factors contributing to the differing susceptibility of PPMs and PAMs to PRRSV infection. We found that PPMs exhibit a higher frequency of CD14+ cells compared to PAMs, suggesting a more immature macrophage phenotype in PPMs. Importantly, PPMs expressed both CD163 and CD169, the key receptors for PRRSV entry, although the frequency and intensity of CD163 and …

Disruption Of The Oswrky71 Transcription Factor Gene Results In Early Rice Seed Germination Under Normal And Cold Stress Conditions, Santiago Bataller, James A. Davis, Lingkun Gu, Sophia Baca, Gaelan Chen, Azeem Majid, Anne J. Villacastin, Dylan Barth, Mira V. Han, Paul J. Rushton, Qingxi J. Shen

Life Sciences Faculty Research

Background

Early seed germination in crops can confer a competitive advantage against weeds and reduce the time to maturation and harvest. WRKY transcription factors regulate many aspects of plant development including seed dormancy and germination. Both positive and negative regulators of seed germination have been reported in many plants such as rice and Arabidopsis. Using a transient expression system, we previously demonstrated that OsWRKY71 is a negative regulator of gibberellin (GA) signaling in aleurone cells and likely forms a “repressosome” complex with other transcriptional repressors. Hence, it has the potential to impact seed germination properties.

Results

In this study, we …

Tumor-Associated Antigen Prediction Using A Single-Sample Gene Expression State Inference Algorithm, Xinpei Yi, Hongwei Zhao, Shunjie Hu, Liangqing Dong, Yongchao Dou, Jing Li, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

We developed a Bayesian-based algorithm to infer gene expression states in individual samples and incorporated it into a workflow to identify tumor-associated antigens (TAAs) across 33 cancer types using RNA sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA). Our analysis identified 212 candidate TAAs, with 78 validated in independent RNA-seq datasets spanning seven cancer types. Eighteen of these TAAs were further corroborated by proteomics data, including 10 linked to liver cancer. We predicted that 38 peptides derived from these 10 TAAs would bind strongly to HLA-A02, the most common HLA allele. Experimental validation confirmed …

Therapeutic Potential Of Astrocyte-Derived Extracellular Vesicles In Mitigating Cytotoxicity And Transcriptome Changes In Human Brain Endothelial Cells, Ruth Juliana Stewart

Doctoral Dissertations

Extracellular vesicles (EVs) play a major role in cell-to-cell communication via the horizontal transfer of RNA, DNA, proteins, and lipids that affect the physiological response of the recipient cells. Astrocytes are a type of glial cell that exerts a protective effect on neurons and brain endothelial cells. The astrocytes and the endothelial cells form the blood-brain barrier. Due to their nano-size and non-complex structure, EVs can efficiently cross the blood-brain barrier. This study investigated and assessed the impact of EVs on reducing oxidative DNA damage in human brain endothelial cells (HBECs). The protective potential of astrocyte-derived EVs was determined by …

Multi-Decadal Aspen Dynamics Show Recruitment Bottleneck Across Complex Mountain Community, Michael T. Stoddard, Kyle C. Rodman, Connor D. Crouch, David W. Huffman, Peter Z. Fulé, Kristen M. Waring, Margaret M. Moore

Aspen Bibliography

Changes in forest structure and shifts in tree species composition have occurred globally due to climate change and altered disturbance regimes. With climate trending toward warmer and drier conditions, these altered forest communities may reorganize in diverse and unpredictable ways. This is especially true in mountain environments where a range of vegetation types and abiotic conditions coexist. In this study, we used long-term permanent plot data from a site spanning broad environmental gradients to assess regeneration and mortality patterns in populations of aspen (Populus tremuloides). The study site, located on the San Francisco Peaks, Arizona, USA, is near …

Sample Multiplexing For Retinal Single-Cell Rna Sequencing, Justin Ma, Ting-Kuan Chu, Maria Polo-Prieto, Yong H Park, Yumei Li, Rui Chen, Graeme Mardon, Benjamin J Frankfort, Nicholas M Tran

Faculty, Staff and Students Publications

Rare cell populations can be challenging to characterize using microfluidic single-cell RNA sequencing (scRNA-seq) platforms. Typically, the population of interest must be enriched and pooled from multiple biological specimens for efficient collection. However, these practices preclude the resolution of sample origin together with phenotypic data and are problematic in experiments in which biological or technical variation is expected to be high (e.g., disease models, genetic perturbation screens, or human samples). One solution is sample multiplexing whereby each sample is tagged with a unique sequence barcode that is resolved bioinformatically. We have established a scRNA-seq sample multiplexing pipeline for mouse retinal …

Analyzing And Extending Machine Learning Frameworks On High Risk Domains, Chengbin Hu

USF Tampa Graduate Theses and Dissertations

Machine learning (ML) has become a transformative force in high-risk domains such as genomics and cybersecurity, where accurate predictions and robust defenses are essential. This dissertation advances ML frameworks in these areas by developing methods to enhance predictive power in health applications and assess vulnerabilities in machine learning systems.

In the genomics field, the work addresses challenges in Non-Invasive Prenatal Testing (NIPT) of monogenic disorders by proposing a deep learning model that reconstructs the fetal genome using maternal plasma cell-free DNA (cfDNA) and parental whole-genome sequencing (WGS) data. This model achieves high accuracy in single nucleotide variation (SNV) prediction, surpassing …

Long-Read Sequencing Of An Advanced Cancer Cohort Resolves Rearrangements, Unravels Haplotypes, And Reveals Methylation Landscapes, Kieran O'Neill, Erin Pleasance, Jeremy Fan, Vahid Akbari, Glenn Chang, Katherine Dixon, Veronika Csizmok, Signe Maclennan, Vanessa Porter, Andrew Galbraith, Cameron J Grisdale, Luka Culibrk, John H Dupuis, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan Pandoh, Duane E Smailus, Dean Cheng, Tina Wong, Connor Frey, Yaoqing Shen, Eleanor Lewis, Luis F Paulin, Fritz J Sedlazeck, Jessica M T Nelson, Eric Chuah, Karen L Mungall, Richard A Moore, Robin Coope, Andrew J Mungall, Melissa K Mcconechy, Laura M Williamson, Kasmintan A Schrader, Stephen Yip, Marco A Marra, Janessa Laskin, Steven J M Jones

Faculty, Staff and Students Publications

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can …

Multi-Organ Gene Expression Analysis And Network Modeling Reveal Regulatory Control Cascades During The Development Of Hypertension In Female Spontaneously Hypertensive Rat, Eden Hornung, Sirisha Achanta, Alison Moss, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Hypertension is a multifactorial disease with stage-specific gene expression changes occurring in multiple organs over time. The temporal sequence and the extent of gene regulatory network changes occurring across organs during the development of hypertension remain unresolved. In this study, female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats were used to analyze expression patterns of 96 genes spanning inflammatory, metabolic, sympathetic, fibrotic, and renin-angiotensin (RAS) pathways in five organs, at five time points from the onset to established hypertension. We analyzed this multi-dimensional dataset containing ~15,000 data points and developed a data-driven dynamic network model that accounts for …

Large-Scale Application Of Clingen-Insight Apc-Specific Acmg/Amp Variant Classification Criteria Leads To Substantial Reduction In Vus, Xiaoyu Yin, Marcy Richardson, Andreas Laner, Xuemei Shi, Elisabet Ognedal, Valeria Vasta, Thomas V O Hansen, Marta Pineda, Deborah Ritter, Johan De Dunnen, Emadeldin Hassanin, Wencong Lyman Lin, Ester Borras, Karl Krahn, Margareta Nordling, Alexandra Martins, Khalid Mahmood, Emily Nadeau, Victoria Beshay, Carli Tops, Maurizio Genuardi, Tina Pesaran, Ian M Frayling, Gabriel Capellá, Andrew Latchford, Sean V Tavtigian, Carlo Maj, Sharon E Plon, Marc S Greenblatt, Finlay A Macrae, Isabel Spier, Stefan Aretz

Faculty, Staff and Students Publications

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation …

Impact Of Pathologist-Directed Comprehensive Genomic Profiling In Advanced Non-Small-Cell Lung Cancer In A Large Healthcare System, R Meng, Carlo Bifulco, Brian Piening, See Full List Of Authors In Comments

Articles, Abstracts, and Reports

No abstract provided.

Genomic Landscape Of Fusions In Solid Tumors Detected By Dna And Rna Comprehensive Genomic Profiling At A Large Community Health System, A Dowdell, Carlo Bifulco, Brian Piening, See Full List Of Authors In Comments

Articles, Abstracts, and Reports

No abstract provided.

Protracted Maternal Malnutrition Induces Aberrant Changes In Maternal Uterine Artery Hemodynamics And The Metabolic Profiles Of The Dam And Neonate, Jennifer F. Thorson, Ligia D. Prezotto

Department of Animal Science: Faculty Publications

Malnutritional stress during gestation is a well-established driver of metabolic disfunction in offspring. Extended exposure to malnutrition requires metabolic plasticity as the animal shifts toward a catabolic state. In this paper we demonstrate the influence of malnutrition throughout gestation on uterine artery hemodynamics and the metabolism of the dam and neonate. We hypothesized that gestational malnutrition reduces blood flow of the maternal uterine artery and regulates the metabolic profile of the dam and offspring. Further, the combination of these factors consequently influences the concentration of metabolites in the cerebrospinal fluid of the neonate at birth. To test our hypotheses, pregnant …

Repeated Shifts In Sociality Are Associated With Fine-Tuning Of Highly Conserved And Lineage-Specific Enhancers In A Socially Flexible Bee, Beryl M. Jones, Andrew E. Webb, Scott M. Geib, Sheina Sim, Rena M. Schweizer, Michael G. Branstetter, Jay D. Evans, Sarah D. Kocher

Entomology Faculty Publications

Comparative genomic studies of social insects suggest that changes in gene regulation are associated with evolutionary transitions in social behavior, but the activity of predicted regulatory regions has not been tested empirically. We used self-transcribing active regulatory region sequencing, a high-throughput enhancer discovery tool, to identify and measure the activity of enhancers in the socially variable sweat bee, Lasioglossum albipes. We identified over 36,000 enhancers in the L. albipes genome from 3 social and 3 solitary populations. Many enhancers were identified in only a subset of L. albipes populations, revealing rapid divergence in regulatory regions within this species. Population-specific enhancers …

Engineering The Coherent Phonon Transport In Polar Ferromagnetic Oxide Superlattices, In Hyeok Choi, Seung Gyo Jeong, Do-Gyeom Jeong, Ambrose Seo, Woo Seok Choi, Jong Seok Lee

Chemical and Materials Engineering Faculty Publications

Artificial superlattices composed of perovskite oxides serves as an essential platform for engineering coherent phonon transport by redefining the lattice periodicity, which strongly influences the lattice-coupled phase transitions in charge and spin degrees of freedom. However, previous methods of manipulating phonons have been limited to controlling the periodicity of superlattice, rather than utilizing complex mutual interactions that are prominent in transition metal oxides. In this study on oxide superlattices composed of ferromagnetic metallic SrRuO3 and quantum paraelectric SrTiO3 , phonon modulation by controlling the geometry of superlattice in atomic-scale precision is realized, demonstrating the coherent phonon engineering using structural and …

Xenomake: A Pipeline For Processing And Sorting Xenograft Reads From Spatial Transcriptomic Experiments, Benjamin S Strope, Katherine E Pendleton, William Z Bowie, Gloria V Echeverria, Qian Zhu

Faculty, Staff and Students Publications

SUMMARY: Xenograft models are attractive models that mimic human tumor biology and permit one to perturb the tumor microenvironment and study its drug response. Spatially resolved transcriptomics (SRT) provides a powerful way to study the organization of xenograft models, but currently there is a lack of specialized pipeline for processing xenograft reads originated from SRT experiments. Xenomake is a standalone pipeline for the automated handling of spatial xenograft reads. Xenomake handles read processing, alignment, xenograft read sorting, and connects well with downstream spatial analysis packages. We additionally show that Xenomake can correctly assign organism-specific reads, reduce sparsity of data by …

Loss-Of-Function In Rbbp5 Results In A Syndromic Neurodevelopmental Disorder Associated With Microcephaly, Yue Huang, Kristy L Jay, Alden Yen-Wen Huang, Jijun Wan, Sharayu V Jangam, Odelia Chorin, Annick Rothschild, Ortal Barel, Milena Mariani, Maria Iascone, Han Xue, Undiagnosed Diseases Network, Jing Huang, Cyril Mignot, Boris Keren, Virginie Saillour, Annelise Y Mah-Som, Stephanie Sacharow, Farrah Rajabi, Carrie Costin, Shinya Yamamoto, Oguz Kanca, Hugo J Bellen, Jill A Rosenfeld, Christina G S Palmer, Stanley F Nelson, Michael F Wangler, Julian A Martinez-Agosto

Faculty, Staff and Students Publications

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.

RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the …

Pharmacogenomic Insights In Psychiatric Care: Uncovering Novel Actionability, Allele-Specific Cyp2d6 Copy Number Variation, And Phenoconversion In 15,000 Patients, Jai N Patel, Sarah A Morris, Raul Torres, Brooke Rhead, Chris Vlangos, Daniel J Mueller, Lisa C Brown, Hailey Lefkofsky, Muneer Ali, Francisco M De La Vega, Kathleen C Barnes, Anthony Zoghbi, Joseph D Stanton, Marcus A Badgeley

Faculty, Staff and Students Publications

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and …