Biomedical Informatics Commons^™

Nuclear Export Signal Mutation Of Epidermal Growth Factor Receptor Enhances Malignant Phenotypes Of Cancer Cells, Lei Nie, Ying-Nai Wang, Jung-Mao Hsu, Junwei Hou, Yu-Yi Chu, Li-Chuan Chan, Longfei Huo, Yongkun Wei, Rong Deng, Jun Tang, Yi-Hsin Hsu, How-Wen Ko, Seung-Oe Lim, Kebin Huang, Mei-Kuang Chen, Tai-Jan Chiu, Chien-Chia Cheng, Yueh-Fu Fang, Chia-Wei Li, Aarthi Goverdhan, Hsing-Ju Wu, Cheng-Chung Lee, Wen-Ling Wang, Jennifer Hsu, Paul Chiao, Shao-Chun Wang, Mien-Chie Hung

Faculty, Staff and Student Publications

Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) …

Ethnic-Specific Predictors Of Neurotoxicity Among Patients With Pediatric Acute Lymphoblastic Leukemia After High-Dose Methotrexate, Rachel D Harris, Melanie Brooke Bernhardt, Mark C Zobeck, Olga A Taylor, Maria Monica Gramatges, Eric S Schafer, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Faculty, Staff and Students Publications

High-dose methotrexate (HD-MTX; 5,000 mg/m2) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity which may disproportionately affect Latino children. Thus, we evaluated risk factors for neurotoxicity in an ethnically diverse population of 351 patients (58.1% Latino) who received 1,183 HD-MTX infusions. Overall, thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, we found that serum creatinine elevations ≥50% of baseline were associated with a 3-fold increased odds (OR = 3.32, 95% CI: 0.98-11.21, p=0.05) for …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

Low And Differential Polygenic Score Generalizability Among African Populations Due Largely To Genetic Diversity, Lerato Majara, Allan Kalungi, Nastassja Koen, Kristin Tsuo, Ying Wang, Rahul Gupta, Lethukuthula L Nkambule, Heather Zar, Dan J Stein, Eugene Kinyanda, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across …

Foxi3 Pathogenic Variants Cause One Form Of Craniofacial Microsomia, Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro De Luca, Giuseppe Merla, Shouqin Zhao, Timothy C Cox, Andrew K Groves, James R Lupski, Qingguo Zhang, Yong-Biao Zhang, Stylianos E Antonarakis

Faculty, Staff and Students Publications

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in …

Toward Practical Integration Of Omic And Imaging Data In Co-Clinical Trials, Emel Alkim, Heidi Dowst, Julie Dicarlo, Lacey E Dobrolecki, Anadulce Hernández-Herrera, David A Hormuth, Yuxing Liao, Apollo Mcowiti, Robia Pautler, Mothaffar Rimawi, Ashley Roark, Ramakrishnan Rajaram Srinivasan, Jack Virostko, Bing Zhang, Fei Zheng, Daniel L Rubin, Thomas E Yankeelov, Michael T Lewis

Faculty, Staff and Students Publications

Co-clinical trials are the concurrent or sequential evaluation of therapeutics in both patients clinically and patient-derived xenografts (PDX) pre-clinically, in a manner designed to match the pharmacokinetics and pharmacodynamics of the agent(s) used. The primary goal is to determine the degree to which PDX cohort responses recapitulate patient cohort responses at the phenotypic and molecular levels, such that pre-clinical and clinical trials can inform one another. A major issue is how to manage, integrate, and analyze the abundance of data generated across both spatial and temporal scales, as well as across species. To address this issue, we are developing MIRACCL …

Metabolic Dysregulation Impairs Lymphocyte Function During Severe Sars-Cov-2 Infection, Sanjeev Gurshaney, Anamaria Morales-Alvarez, Kevin Ezhakunnel, Andrew Manalo, Thien-Huong Huynh, Jun-Ichi Abe, Nhat-Tu Le, Daniela Weiskopf, Alessandro Sette, Daniel S Lupu, Stephen J Gardell, Hung Nguyen

Faculty, Staff and Student Publications

Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose …

Bi-Allelic Snapc4 Variants Dysregulate Global Alternative Splicing And Lead To Neuroregression And Progressive Spastic Paraparesis, F Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M Oud, Elise A Ferreira, Vinodh Narayanan, Sampath Rangasamy, Matt Huentelman, Lisa T Emrick, Ikuko Sato-Shirai, Satoko Kumada, Nicole I Wolf, Peter J Steinbach, Yan Huang, Undiagnosed Diseases Network, Barbara N Pusey, Sandrine Passemard, Jonathan Levy, Séverine Drunat, Marie Vincent, Agnès Guet, Emanuele Agolini, Antonio Novelli, Maria Cristina Digilio, Jill A Rosenfeld, Jennifer L Murphy, James R Lupski, Gilbert Vezina, Ellen F Macnamara, David R Adams, Maria T Acosta, Cynthia J Tifft, William A Gahl, May Christine V Malicdan

Faculty, Staff and Students Publications

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development …

Bi-Allelic Variants In The Esam Tight-Junction Gene Cause A Neurodevelopmental Disorder Associated With Fetal Intracranial Hemorrhage, Mauro Lecca, Davut Pehlivan, Damià Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarella, Alberto Neri, Carlo Fusco, Dana Marafi, Tadahiro Mitani, Jennifer Ellen Posey, Sadik Etka Bayramoglu, Alper Gezdirici, Jessica Hernandez-Rodriguez, Emilia Amengual Cladera, Elena Miravet, Jorge Roldan-Busto, María Angeles Ruiz, Cristofol Vives Bauzá, Liat Ben-Sira, Sabine Sigaudy, Anaïs Begemann, Sheila Unger, Serdal Güngör, Semra Hiz, Ece Sonmezler, Yoav Zehavi, Michael Jerdev, Alessandra Balduini, Orsetta Zuffardi, Rita Horvath, Hanns Lochmüller, Anita Rauch, Livia Garavelli, Elisabeth Tournier-Lasserve, Ronen Spiegel, James R Lupski, Edoardo Errichiello

Faculty, Staff and Students Publications

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in …

Rapid Profiling Of Dna Replication Dynamics Using Mass Spectrometry-Based Analysis Of Nascent Dna, Mohamed E Ashour, Andrea K Byrum, Alice Meroni, Jun Xia, Saurabh Singh, Roberto Galletto, Susan M Rosenberg, Alessandro Vindigni, Nima Mosammaparast

Faculty, Staff and Students Publications

The primary method for probing DNA replication dynamics is DNA fiber analysis, which utilizes thymidine analog incorporation into nascent DNA, followed by immunofluorescent microscopy of DNA fibers. Besides being time-consuming and prone to experimenter bias, it is not suitable for studying DNA replication dynamics in mitochondria or bacteria, nor is it adaptable for higher-throughput analysis. Here, we present mass spectrometry-based analysis of nascent DNA (MS-BAND) as a rapid, unbiased, quantitative alternative to DNA fiber analysis. In this method, incorporation of thymidine analogs is quantified from DNA using triple quadrupole tandem mass spectrometry. MS-BAND accurately detects DNA replication alterations in both …

De Novo Mutations Disturb Early Brain Development More Frequently Than Common Variants In Schizophrenia, Toshiyuki Itai, Peilin Jia, Yulin Dai, Jingchun Chen, Xiangning Chen, Zhongming Zhao

Faculty, Staff and Student Publications

Investigating functional, temporal, and cell-type expression features of mutations is important for understanding a complex disease. Here, we collected and analyzed common variants and de novo mutations (DNMs) in schizophrenia (SCZ). We collected 2,636 missense and loss-of-function (LoF) DNMs in 2,263 genes across 3,477 SCZ patients (SCZ-DNMs). We curated three gene lists: (a) SCZ-neuroGenes (159 genes), which are intolerant to LoF and missense DNMs and are neurologically important, (b) SCZ-moduleGenes (52 genes), which were derived from network analyses of SCZ-DNMs, and (c) SCZ-commonGenes (120 genes) from a recent GWAS as reference. To compare temporal gene expression, we used the BrainSpan …

The Glycoprotein Cd147 Defines Mirna-Enriched Extracellular Vesicles That Derive From Cancer Cells, Song Yi Ko, Wonjae Lee, Melanie Weigert, Eric Jonasch, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) are ideal for liquid biopsy, but distinguishing cancer cell‐derived EVs and subpopulations of biomarker‐containing EVs in body fluids has been challenging. Here, we identified that the glycoproteins CD147 and CD98 define subpopulations of EVs that are distinct from classical tetraspanin+ EVs in their biogenesis. Notably, we identified that CD147+ EVs have substantially higher microRNA (miRNA) content than tetraspanin+ EVs and are selectively enriched in miRNA through the interaction of CD147 with heterogeneous nuclear ribonucleoprotein A2/B1. Studies using mouse xenograft models showed that CD147+ EVs predominantly derive from cancer cells, whereas the majority of tetraspanin+ EVs are not …

Molecular Function And Contribution Of Tbx4 In Development And Disease, Justyna A Karolak, Carrie L Welch, Christian Mosimann, Katarzyna Bzdęga, James D West, David Montani, Mélanie Eyries, Mary P Mullen, Steven H Abman, Matina Prapa, Stefan Gräf, Nicholas W Morrell, Anna R Hemnes, Frédéric Perros, Rizwan Hamid, Malcolm P O Logan, Jeffrey Whitsett, Csaba Galambos, Paweł Stankiewicz, Wendy K Chung, Eric D Austin

Faculty, Staff and Students Publications

Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box–containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research …

Natural History Of Tango2 Deficiency Disorder: Baseline Assessment Of 73 Patients, Christina Y Miyake, Erica J Lay, Claudia Soler-Alfonso, Kevin E Glinton, Kimberly M Houck, Mustafa Tosur, Nancy E Moran, Sara B Stephens, Fernando Scaglia, Taylor S Howard, Jeffrey J Kim, Tam Dam Pham, Santiago O Valdes, Na Li, Chaya N Murali, Lilei Zhang, Maina Kava, Deane Yim, Cheyenne Beach, Gregory Webster, Leonardo Liberman, Christopher M Janson, Prince J Kannankeril, Samantha Baxter, Moriel Singer-Berk, Jordan Wood, Samuel J Mackenzie, Michael Sacher, Lina Ghaloul-Gonzalez, Claudia Pedroza, Shaine A Morris, Saad A Ehsan, Mahshid S Azamian, Seema R Lalani

Faculty, Staff and Students Publications

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.

METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review.

RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at …

Machine Learning And Health Care: Potential Benefits And Issues, J Graham Atkinson, Elizabeth G Atkinson

Faculty, Staff and Students Publications

We discuss the potential for machine learning (ML) and artificial intelligence (AI) to improve health care, while detailing caveats and important considerations to ensure unbiased and equitable implementation. If disparities exist in the data used to train ML algorithms, they must be recognized and accounted for, so they do not bias performance accuracy or are not interpreted by the algorithm as simply a lack of need. We pay particular attention to an area in which bias in data composition is particularly striking, that is in large-scale genetics databases, as people of European descent are vastly overrepresented in the existing resources.

Loss Of Neuron Navigator 2 Impairs Brain And Cerebellar Development, Andrea Accogli, Shenzhao Lu, Ilaria Musante, Paolo Scudieri, Jill A Rosenfeld, Mariasavina Severino, Simona Baldassari, Michele Iacomino, Antonella Riva, Ganna Balagura, Gianluca Piccolo, Carlo Minetti, Denis Roberto, Fan Xia, Razaali Razak, Emily Lawrence, Mohamed Hussein, Emmanuel Yih-Herng Chang, Michelle Holick, Elisa Calì, Emanuela Aliberto, Rosalba De-Sarro, Antonio Gambardella, Undiagnosed Diseases Network, Synaps Study Group, Lisa Emrick, Peter J A Mccaffery, Margaret Clagett-Dame, Paul C Marcogliese, Hugo J Bellen, Seema R Lalani, Federico Zara, Pasquale Striano, Vincenzo Salpietro

Faculty, Staff and Students Publications

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In …

Familial Hypercholesterolemia In The Electronic Medical Records And Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, And Outcomes After Return Of Results, Ozan Dikilitas, Alborz Sherafati, Seyedmohammad Saadatagah, Benjamin A Satterfield, David C Kochan, Katherine C Anderson, Wendy K Chung, Scott J Hebbring, Zachary M Salvati, Richard R Sharp, Amy C Sturm, Richard A Gibbs, Robb Rowley, Eric Venner, Jodell E Linder, Laney K Jones, Emma F Perez, Josh F Peterson, Gail P Jarvik, Heidi L Rehm, Hana Zouk, Dan M Roden, Marc S Williams, Teri A Manolio, Iftikhar J Kullo

Faculty, Staff and Students Publications

BACKGROUND: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network.

METHODS: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including

RESULTS: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The …

Kcna1 Gain-Of-Function Epileptic Encephalopathy Treated With 4-Aminopyridine, Peter Müller, Danielle S Takacs, Ulrike B S Hedrich, Rohini Coorg, Laura Masters, Kevin E Glinton, Hongzheng Dai, Jon A Cokley, James J Riviello, Holger Lerche, Edward C Cooper

Faculty, Staff and Students Publications

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization.

Wwox P47t Partial Loss-Of-Function Mutation Induces Epilepsy, Progressive Neuroinflammation, And Cerebellar Degeneration In Mice Phenocopying Human Scar12, Tabish Hussain, Kevin Sanchez, Jennifer Crayton, Dhurjhoti Saha, Collene Jeter, Yue Lu, Martin Abba, Ryan Seo, Jeffrey L Noebels, Laura Fonken, C Marcelo Aldaz

Faculty, Staff and Student Publications

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. Wwox

The En-Tex Resource Of Multi-Tissue Personal Epigenomes & Variant-Impact Models, Joel Rozowsky, Jiahao Gao, Beatrice Borsari, Yucheng T Yang, Timur Galeev, Gamze Gürsoy, Charles B Epstein, Kun Xiong, Jinrui Xu, Tianxiao Li, Jason Liu, Keyang Yu, Ana Berthel, Zhanlin Chen, Fabio Navarro, Maxwell S Sun, James Wright, Justin Chang, Christopher J F Cameron, Noam Shoresh, Elizabeth Gaskell, Jorg Drenkow, Jessika Adrian, Sergey Aganezov, François Aguet, Gabriela Balderrama-Gutierrez, Samridhi Banskota, Guillermo Barreto Corona, Sora Chee, Surya B Chhetri, Gabriel Conte Cortez Martins, Cassidy Danyko, Carrie A Davis, Daniel Farid, Nina P Farrell, Idan Gabdank, Yoel Gofin, David U Gorkin, Mengting Gu, Vivian Hecht, Benjamin C Hitz, Robbyn Issner, Yunzhe Jiang, Melanie Kirsche, Xiangmeng Kong, Bonita R Lam, Shantao Li, Bian Li, Xiqi Li, Khine Zin Lin, Ruibang Luo, Mark Mackiewicz, Ran Meng, Jill E Moore, Jonathan Mudge, Nicholas Nelson, Chad Nusbaum, Ioann Popov, Henry E Pratt, Yunjiang Qiu, Srividya Ramakrishnan, Joe Raymond, Leonidas Salichos, Alexandra Scavelli, Jacob M Schreiber, Fritz J Sedlazeck, Lei Hoon See, Rachel M Sherman, Xu Shi, Minyi Shi, Cricket Alicia Sloan, J Seth Strattan, Zhen Tan, Forrest Y Tanaka, Anna Vlasova, Jun Wang, Jonathan Werner, Brian Williams, Min Xu, Chengfei Yan, Lu Yu, Christopher Zaleski, Jing Zhang, Kristin Ardlie, J Michael Cherry, Eric M Mendenhall, William S Noble, Zhiping Weng, Morgan E Levine, Alexander Dobin, Barbara Wold, Ali Mortazavi, Bing Ren, Jesse Gillis, Richard M Myers, Michael P Snyder, Jyoti Choudhary, Aleksandar Milosavljevic, Michael C Schatz, Bradley E Bernstein, Roderic Guigó, Thomas R Gingeras, Mark Gerstein

Faculty, Staff and Students Publications

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding …

Conjugation's Toolkit: The Roles Of Nonstructural Proteins In Bacterial Sex, Matthew B Cooke, Christophe Herman

Faculty, Staff and Students Publications

Bacterial conjugation, a form of horizontal gene transfer, relies on a type 4 secretion system (T4SS) and a set of nonstructural genes that are closely linked. These nonstructural genes aid in the mobile lifestyle of conjugative elements but are not part of the T4SS apparatus for conjugative transfer, such as the membrane pore and relaxosome, or the plasmid maintenance and replication machineries. While these nonstructural genes are not essential for conjugation, they assist in core conjugative functions and mitigate the cellular burden on the host. This review compiles and categorizes known functions of nonstructural genes by the stage of conjugation …

Renal Cell Carcinoma Unclassified With Medullary Phenotype In A Patient With Neurofibromatosis Type 2, Sanila Sarkar, Whitney Throckmorton, Racheal Bingham, Pavlos Msaouel, Giannicola Genovese, John Slopis, Priya Rao, Zsila Sadighi, Cynthia E Herzog

Faculty, Staff and Student Publications

We present, to our knowledge, the first reported case of germline neurofibromatosis Type 2 (NF2) associated with renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) with somatic loss by immunohistochemistry of the SMARCB1 tumor suppressor gene located centromeric to NF2 on chromosome 22q. Our patient is a 15-year-old with germline neurofibromatosis Type 2 (NF2) confirmed by pathogenic mutation of c.-854-??46+??deletion. Her NF2 history is positive for a right optic nerve sheath meningioma, CNIII schwannoma requiring radiation therapy and post gross total resection of right frontotemporal anaplastic meningioma followed by radiation. At age 15 she developed new onset weight loss and …

Tsks Localizes To Nuage In Spermatids And Regulates Cytoplasmic Elimination During Spermiation, Keisuke Shimada, Soojin Park, Seiya Oura, Taichi Noda, Akane Morohoshi, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Spermatozoa have a streamlined shape to swim through the oviduct to fertilize oocytes. To become svelte spermatozoa, spermatid cytoplasm must be eliminated in several steps including sperm release, which is part of spermiation. Although this process has been well observed, the molecular mechanisms that underlie it remain unclear. In male germ cells, there are membraneless organelles called nuage, which are observed by electron microscopy in various forms of dense material. Reticulated body (RB) and chromatoid body remnant (CR) are two types of nuage in spermatids, but the functions of both are unknown. Using CRISPR/Cas9 technology, we deleted the entire coding …

Prognostication Of Dna Damage Response Protein Expression Patterns In Chronic Lymphocytic Leukemia, Ti'ara L Griffen, Fieke W Hoff, Yihua Qiu, Jan Burger, William Wierda, Steven M Kornblau

Faculty, Staff and Student Publications

Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival outcomes. Patients within clusters C1 and C2 had poorer survival outcomes and responses to fludarabine, cyclophosphamide, and rituxan chemotherapy compared to patients within cluster C3. However, DDR protein expression patterns were not prognostic in more modern therapies with BCL2 inhibitors or a BTK/PI3K inhibitor. Individually, nine of the DDR proteins were prognostic for predicting overall survival and/or …

The P323l Substitution In The Sars-Cov-2 Polymerase (Nsp12) Confers A Selective Advantage During Infection, Hannah Goldswain, Xiaofeng Dong, Rebekah Penrice-Randal, Muhannad Alruwaili, Ghada T Shawli, Tessa Prince, Maia Kavanagh Williamson, Jayna Raghwani, Nadine Randle, Benjamin Jones, I'Ah Donovan-Banfield, Francisco J Salguero, Julia A Tree, Yper Hall, Catherine Hartley, Maximilian Erdmann, James Bazire, Tuksin Jearanaiwitayakul, Malcolm G Semple, Peter J M Openshaw, J Kenneth Baillie, Isaric4c Investigators, Stevan R Emmett, Paul Digard, David A Matthews, Lance Turtle, Alistair C Darby, Andrew D Davidson, Miles W Carroll, Julian A Hiscox

Faculty, Staff and Student Publications

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure.

RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant …

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated With Diabetic Kidney Disease, Yang Pan, Xiao Sun, Xuenan Mi, Zhijie Huang, Yenchih Hsu, James E Hixson, Donna Munzy, Ginger Metcalf, Nora Franceschini, Adrienne Tin, Anna Köttgen, Michael Francis, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium Topmed Kidney Function Working Group, Jennifer A Brody, Bryan Kestenbaum, Colleen M Sitlani, Josyf C Mychaleckyj, Holly Kramer, Leslie A Lange, Xiuqing Guo, Shih-Jen Hwang, Marguerite R Irvin, Jennifer A Smith, Lisa R Yanek, Dhananjay Vaidya, Yii-Der Ida Chen, Myriam Fornage, Donald M Lloyd-Jones, Lifang Hou, Rasika A Mathias, Braxton D Mitchell, Patricia A Peyser, Sharon L R Kardia, Donna K Arnett, Adolfo Correa, Laura M Raffield, Ramachandran S Vasan, L Adrienne Cupple, Daniel Levy, Robert C Kaplan, Kari E North, Jerome I Rotter, Charles Kooperberg, Alexander P Reiner, Bruce M Psaty, Russell P Tracy, Richard A Gibbs, Alanna C Morrison, Harold Feldman, Eric Boerwinkle, Jiang He, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Students Publications

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between …

The Fly Homolog Of Supt16h, A Gene Associated With Neurodevelopmental Disorders, Is Required In A Cell-Autonomous Fashion For Cell Survival, Mengqi Ma, Xi Zhang, Yiming Zheng, Shenzhao Lu, Xueyang Pan, Xiao Mao, Hongling Pan, Hyung-Lok Chung, Hua Wang, Hong Guo, Hugo J Bellen

Faculty, Staff and Students Publications

SUPT16H encodes the large subunit of the FAcilitate Chromatin Transcription (FACT) complex, which functions as a nucleosome organizer during transcription. We identified two individuals from unrelated families carrying de novo missense variants in SUPT16H. The probands exhibit global developmental delay, intellectual disability, epilepsy, facial dysmorphism and brain structural abnormalities. We used Drosophila to characterize two variants: p.T171I and p.G808R. Loss of the fly ortholog, dre4, causes lethality at an early developmental stage. RNAi-mediated knockdown of dre4 in either glia or neurons causes severely reduced eclosion and longevity. Tissue-specific knockdown of dre4 in the eye or wing leads to the loss …

Assigning Pathogenicity For Tab2 Variants Using A Novel Scalable Functional Assay And Expanding Tab2 Disease Spectrum, Weiyi Xu, Andrea Graves, Monika Weisz-Hubshman, Lamees Hegazy, Christina Magyar, Zian Liu, Eleni Nasiotis, Md Abul Hassan Samee, Thomas Burris, Seema Lalani, Lilei Zhang

Faculty, Staff and Students Publications

Haploinsufficiency of TGF-beta-activated kinase 1 (MAP3K7) binding protein 2 (TAB2) has been associated with congenital heart disease and more recently multiorgan structural abnormalities. Missense variant represents a major proportion of non-synonymous TAB2 variants reported in gnomAD (295/576) and Clinvar (16/73), most of which are variants of uncertain significance (VUSs). However, interpretation of TAB2 missense variants remains challenging because of lack of functional assays. To address this issue, we established a cell-based luciferase assay that enables high-throughput screening of TAB2 variants to assess the functional consequence for predicting variant pathogenicity. Using this platform, we screened 47 TAB2 variants including five pathogenic …

Effects Of Protein-Coding Variants On Blood Metabolite Measurements And Clinical Biomarkers In The Uk Biobank, Abhishek Nag, Ryan S Dhindsa, Lawrence Middleton, Xiao Jiang, Dimitrios Vitsios, Eleanor Wigmore, Erik L Allman, Anna Reznichenko, Keren Carss, Katherine R Smith, Quanli Wang, Benjamin Challis, Dirk S Paul, Andrew R Harper, Slavé Petrovski

Faculty, Staff and Students Publications

Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10