Genetic Phenomena Commons^™

Secondary Acmg And Non-Acmg Genetic Findings In A Multiethnic Cohort Of 16,713 Pediatric Participants, Amir Hossein Saeidian, Michael E March, Leila Youssefian, Deborah J Watson, Esha Bhandari, Xiang Wang, Xiaonan Zhao, Nichole Marie Owen, Alanna Strong, Margaret H Harr, Elizabeth Bhoj, Elaine Zackai, Hassan Vahidnezhad, Johann E Gudjonsson, Stephen D Cederbaum, Joshua L Deignan, Joseph Glessner, Wayne W Grody, Hakon Hakonarson

Faculty, Staff and Students Publications

Purpose: Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant's primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort that includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG-recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of …

Senescence Biomarkers And Trajectories Of Frailty And Physical Function After Kidney Transplantation, Elizabeth C Lorenz, Byron H Smith, Hani M Wadei, Girish Mour, Cassie C Kennedy, Carrie A Schinstock, Walter K Kremers, Andrea L Cheville, Latonya J Hickson, Elizabeth J Atkinson, Thomas A White, Andrew D Rule, Nathan K Lebrasseur

Faculty, Staff and Students Publications

Cellular senescence is a biological mechanism of aging and age-related diseases. The aim of this study was to examine whether senescence biomarkers are associated with frailty and physical function trajectories in patients undergoing kidney transplantation (KT). We also discussed the relationship between senescence biomarkers and KT function. In this multicenter study, we prospectively assessed plasma levels of senescence biomarkers, frailty as measured by the Physical Frailty Phenotype, and physical function as measured by the Short Physical Performance Battery prior to KT. Frailty, physical function, and KT function were also measured 1 year after KT. Variable associations were assessed using Cox …

Burden Re-Analysis Of Neurodevelopmental Disorder Cohorts For Prioritization Of Candidate Genes, Noor Smal, Fatma Majdoub, Katrien Janssens, Edwin Reyniers, Marije E C Meuwissen, Berten Ceulemans, Hope Northrup, Jeremy B Hill, Lingying Liu, Edoardo Errichiello, Simone Gana, Alanna Strong, Luis Rohena, Rachel Franciskovich, Chaya N Murali, An Huybrechs, Telma Sulem, Run Fridriksdottir, Patrick Sulem, Kari Stefansson, Yan Bai, Jill A Rosenfeld, Seema R Lalani, Haley Streff, Undiagnosed Diseases Network, R Frank Kooy, Sarah Weckhuysen

Faculty, Staff and Students Publications

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden …

Family Lore, A Variant Of Uncertain Significance, And Cadasil, Rhys Duarte, Liesbeth Vossaert, Sandra A Darilek, Chelsi Rose, Evan Schauer, Christian Parobek, Emily Bland, Keren Machol, Elizabeth Mizerik, Chaya N Murali

Faculty, Staff and Students Publications

An infant presents in extremis. After the medical team stabilizes him, the race is on to figure out why he got so sick in the first place. The consulting genetics team thinks that it is unlikely his problems are due to a genetic cause, but his extreme, confounding presentation is enough to justify trio exome sequencing. When the results reveal an unexpected, paternally inherited variant of uncertain significance (VUS) in NOTCH3, fresh questions arise. The infant's presenting symptoms and descriptive diagnoses, including hematemesis, epistaxis, and gastric ulcers, certainly do not fit the mold of CADASIL. However, closer inspection of his …

Neurodevelopmental Disorder Caused By Deletion Of Chaserr, A Lncrna Gene, Vijay S Ganesh, Kevin Riquin, Nicolas Chatron, Esther Yoon, Kay-Marie Lamar, Miriam C Aziz, Pauline Monin, Melanie C O'Leary, Julia K Goodrich, Kiran V Garimella, Eleina England, Ben Weisburd, François Aguet, Carlos A Bacino, David R Murdock, Hongzheng Dai, Jill A Rosenfeld, Lisa T Emrick, Shamika Ketkar, Yael Sarusi, Damien Sanlaville, Saima Kayani, Brian Broadbent, Alisée Pengam, Bertrand Isidor, Stéphane Bezieau, Benjamin Cogné, Daniel G Macarthur, Igor Ulitsky, Gemma L Carvill, Anne O'Donnell-Luria

Faculty, Staff and Students Publications

No abstract provided.

Atr Inhibition Radiosensitizes Cells Through Augmented Dna Damage And G2 Cell Cycle Arrest Abrogation, Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H Mcfadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 …

Semi-Supervised Machine Learning Method For Predicting Homogeneous Ancestry Groups To Assess Hardy-Weinberg Equilibrium In Diverse Whole-Genome Sequencing Studies, Derek Shyr, Rounak Dey, Xihao Li, Hufeng Zhou, Eric Boerwinkle, Steve Buyske, Mark Daly, Richard A Gibbs, Ira Hall, Tara Matise, Catherine Reeves, Nathan O Stitziel, Michael Zody, Benjamin M Neale, Xihong Lin

Faculty, Staff and Student Publications

Large-scale, multi-ethnic whole-genome sequencing (WGS) studies, such as the National Human Genome Research Institute Genome Sequencing Program's Centers for Common Disease Genomics (CCDG), play an important role in increasing diversity for genetic research. Before performing association analyses, assessing Hardy-Weinberg equilibrium (HWE) is a crucial step in quality control procedures to remove low quality variants and ensure valid downstream analyses. Diverse WGS studies contain ancestrally heterogeneous samples; however, commonly used HWE methods assume that the samples are homogeneous. Therefore, directly applying these to the whole dataset can yield statistically invalid results. To account for this heterogeneity, HWE can be tested on …

Horizontal Gene Transfer And Beyond: The Delivery Of Biological Matter By Bacterial Membrane Vesicles To Host And Bacterial Cells, Alice X Wen, Christophe Herman

Faculty, Staff and Students Publications

Membrane vesicles (MVs) are produced in all domains of life. In eukaryotes, extracellular vesicles have been shown to mediate the horizontal transfer of biological material between cells [1]. Therefore, bacterial MVs are also thought to mediate horizontal material transfer to host cells and other bacteria, especially in the context of cell stress. In this review, we discuss the mechanisms of bacterial MV production, evidence that their contents can be trafficked to host cells and other bacteria, and the biological relevance of horizontal material transfer by bacterial MVs.

Metabolic Dependencies Of Acute Myeloid Leukemia Stem Cells, Xiangguo Shi, Mengdie Feng, Daisuke Nakada

Faculty, Staff and Students Publications

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy primarily driven by an immature population of AML cells termed leukemia stem cells (LSCs) that are implicated in AML development, chemoresistance, and relapse. An emerging area of research in AML focuses on identifying and targeting the aberrant metabolism in LSCs. Dysregulated metabolism is involved in sustaining functional properties of LSCs, impeding myeloid differentiation, and evading programmed cell death, both in the process of leukemogenesis and in response to chemotherapy. This review discusses recent discoveries regarding the aberrant metabolic processes of AML LSCs that have begun to change the therapeutic landscape of …

Cancer Drug-Tolerant Persister Cells: From Biological Questions To Clinical Opportunities, Mariangela Russo, Mengnuo Chen, Elisa Mariella, Haoning Peng, Sumaiyah K Rehman, Elena Sancho, Alberto Sogari, Tzen S Toh, Nathalie Q Balaban, Eduard Batlle, Rene Bernards, Mathew J Garnett, Matthew Hangauer, Eleonora Leucci, Jean-Christophe Marine, Catherine A O'Brien, Yaara Oren, E Elizabeth Patton, Caroline Robert, Susan M Rosenberg, Shensi Shen, Alberto Bardelli

Faculty, Staff and Students Publications

The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit …

Perspectives On Hand Hygiene In Belizean Healthcare Facilities During The Covid-19 Pandemic: A Qualitative Evaluation With Healthcare Workers, Kelsey Mcdavid, Christina Craig, Anh N Ly, Nicholas Bivens, Francis Morey, Russell Manzanero, Gerhaldine Morazan, Ella Hawes, Alexandra Medley, Kristy Murray, Matthew Lozier

Faculty, Staff and Students Publications

The World Health Organization recommends healthcare workers (HCWs) practice hand hygiene (HH) while providing care. Making alcohol-based hand rub (ABHR) available at points of care is recommended during times of high patient volume, such as the COVID-19 pandemic. In low- and middle-income countries, such as Belize, there may be limited access to HH materials within healthcare facilities (HCF). This paper examines the motivators and barriers to HH among HCWs in the 11 largest public healthcare facilities in Belize and HCWs' experiences with an intervention. In 2021, focus group discussions (FGDs) gathered HCWs' HH perceptions and preferences. An intervention was then …

Characterization And Visualization Of Tandem Repeats At Genome Scale, Egor Dolzhenko, Adam English, Harriet Dashnow, Guilherme De Sena Brandine, Tom Mokveld, William J Rowell, Caitlin Karniski, Zev Kronenberg, Matt C Danzi, Warren A Cheung, Chengpeng Bi, Emily Farrow, Aaron Wenger, Khi Pin Chua, Verónica Martínez-Cerdeño, Trevor D Bartley, Peng Jin, David L Nelson, Stephan Zuchner, Tomi Pastinen, Aaron R Quinlan, Fritz J Sedlazeck, Michael A Eberle

Faculty, Staff and Students Publications

Tandem repeat (TR) variation is associated with gene expression changes and numerous rare monogenic diseases. Although long-read sequencing provides accurate full-length sequences and methylation of TRs, there is still a need for computational methods to profile TRs across the genome. Here we introduce the Tandem Repeat Genotyping Tool (TRGT) and an accompanying TR database. TRGT determines the consensus sequences and methylation levels of specified TRs from PacBio HiFi sequencing data. It also reports reads that support each repeat allele. These reads can be subsequently visualized with a companion TR visualization tool. Assessing 937,122 TRs, TRGT showed a Mendelian concordance of …

Reconstructing Oral Cavity Tumor Evolution Through Brush Biopsy, Evit John, Tom Lesluyes, Toby M Baker, Maxime Tarabichi, Ann Gillenwater, Jennifer R Wang, Peter Van Loo, Xiao Zhao

Faculty, Staff and Student Publications

Oral potentially malignant disorders (OPMDs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are typically obtained through invasive tissue biopsy. However, brush biopsy is a non-invasive method that has been utilized for identifying dysplastic cells in OPMD but its effectiveness in reflecting the genomic landscape of OPMDs remains uncertain. This pilot study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile and tumor evolution in a patient with both OPMD and OSCC. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal architectures in …

The Association Of The Oral Microbiota With Cognitive Functioning In Adolescence, Oxana Y Naumova, Pavel V Dobrynin, Galina V Khafizova, Elena L Grigorenko

Faculty, Staff and Students Publications

Background: A growing body of research supports the role of the microbial communities residing in the digestive system in the host's cognitive functioning. Most of these studies have been focused on the gut microbiome and its association with clinical phenotypes in middle-aged and older adults. There is an insufficiency of population-based research exploring the association of normative cognitive functioning with the microbiome particularly with the oral microbiota.

Methods: In this study, using metagenomics and metabolomics, we characterized the salivary microbiome diversity in a sample of 51 males of Hispanic and African American origin aged 12-18 years and explored …

Exploring The Complexity Of Systemic Sclerosis Etiology By Trio Whole Genome Sequencing, Hongzheng Dai, Shamika Ketkar, Taotao Tan, Elizabeth G Atkinson, Lindsay Burrage, Kim C Worley, Brian Christopher, Marka A Lyons, Shervin Assassi, Maureen D Mayes, Brendan Lee

Faculty, Staff and Students Publications

Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants …

Phase Ii Study Of Samotolisib In Children And Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target Of Rapamycin Pathway Alterations: Pediatric Match Apec1621d, Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons

Faculty, Staff and Students Publications

Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was …

Phylogenetically Diverse Bacterial Species Produce Histamine, Kristen A Engevik, Amber Hazzard, Brenton Puckett, Kathleen M Hoch, Sigmund J Haidacher, Anthony M Haag, Jennifer K Spinler, James Versalovic, Melinda A Engevik, Thomas D Horvath

Faculty, Staff and Students Publications

Histamine is an important biogenic amine known to impact a variety of patho-physiological processes ranging from allergic reactions, gut-mediated anti-inflammatory responses, and neurotransmitter activity. Histamine is found both endogenously within specialized host cells and exogenously in microbes. Exogenous histamine is produced through the decarboxylation of the amino acid L-histidine by bacterial-derived histidine decarboxylase enzymes. To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbial Genomes Database and identified 3,679 bacterial genomes (3.6 %) which possess the enzymatic machinery to generate histamine. These bacteria belonged to 10 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, …

Satisfaction With Mode Of Delivery Of Genomic Sequencing Results In A Diverse National Sample Of Research Participants Through The Clinical Sequencing Evidence-Generating Research Consortium, Sarah Scollon, Jill O Robinson, Eunji Jo, Sabrina A Suckiel, Laura M Amendola, Ann Katherine M Foreman, Gail P Jarvik, Christine Rini, Tao Wang, Anne Slavotinek

Faculty, Staff and Students Publications

Purpose: Research that includes diverse patient populations is necessary to optimize implementation of telehealth.

Methods: As part of a Clinical Sequencing Evidence-Generating Research Consortium cross-site study, we assessed satisfaction with mode of return of results (RoR) delivery across a diverse sample of participants receiving genetic testing results in person vs telemedicine (TM).

Results: Ninety-eight percent of participants were satisfied with their mode of results delivery. Participants receiving results by TM were more likely to report a preference for receiving results in a different way and challenges with providers noticing difficulties with understanding. More than 90% reported satisfaction across all items …

The Icf Syndrome Protein Cdca7 Harbors A Unique Dna Binding Domain That Recognizes A Cpg Dyad In The Context Of A Non-B Dna, Swanand Hardikar, Ren Ren, Zhengzhou Ying, Jujun Zhou, John R Horton, Matthew D Bramble, Bin Liu, Yue Lu, Bigang Liu, Luis Della Coletta, Jianjun Shen, Jiameng Dan, Xing Zhang, Xiaodong Cheng, Taiping Chen

Faculty, Staff and Student Publications

CDCA7, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout …

Regulatory Complexity Of Cellular Differentiation In Candida Albicans Revealed Through Systematic Screening Of Protein Kinase Mutants, Michael C Lorenz

Faculty, Staff and Student Publications

A recent study in mBio reports the construction and preliminary screening of a library containing mutants of 99 of the 119 predicted protein kinases in Candida albicans (the majority of the remaining 20 are probably essential) (J. Kramara, M.-J. Kim, T. L. Ollinger, L. C. Ristow, et al., mBio e01249-24, 2024, https://doi.org/10.1128/mbio.01249-24). Using a quantitative competition assay in 10 conditions that represent nutritional, osmotic, cell wall, and pH stresses that are considered to model various aspects of the host environment allowed them to phenotypically cluster kinases, which highlight both the integration and specialization of signaling pathways, suggesting novel functions …

Correction: Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

No abstract provided.

Frontiers In Congenital Disorders Of Glycosylation Consortium, A Cross-Sectional Study Report At Year 5 Of 280 Individuals In The Natural History Cohort, Christina Lam, Fernando Scaglia, Gerard T Berry, Austin Larson, Kyriakie Sarafoglou, Hans C Andersson, Evgenia Sklirou, Queenie K G Tan, Rodrigo T Starosta, Mustafa Sadek, Lynne Wolfe, Seishu Horikoshi, May Ali, Rita Barone, Teresa Campbell, Irene J Chang, Kiaira Coles, Edward Cook, Erik A Eklund, Nicole M Engelhardt, Mary Freeman, Jennifer Friedman, Debbie Y T Fu, Grace Botzo, Brandy Rawls, Christien Hernandez, Christin Johnsen, Kierstin Keller, Sara Kramer, Bryce Kuschel, Angela Leshinski, Ivan Martinez-Duncker, Gina L Mazza, Saadet Mercimek-Andrews, Bradley S Miller, Karthik Muthusamy, Juanita Neira, Marc C Patterson, Natalie Pogorelc, Lex N Powers, Elizabeth Ramey, Michaela Reinhart, Audrey Squire, Jenny Thies, Jerry Vockley, Hayden Vreugdenhil, Peter Witters, Mehdi Youbi, Aziza Zeighami, Roni Zemet, Andrew C Edmondson, Eva Morava

Faculty, Staff and Students Publications

Objective: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study.

Methods: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. …

Fetal Malrotation With Midgut Volvulus: Prenatal Diagnosis And Planning, Jai Sidpra, Sniya Sudhakar, Asthik Biswas, Flavia Massey, Valentina Turchetti, Tracy Lau, Edward Cook, Javeria Raza Alvi, Hasnaa M Elbendary, Jerry L Jewell, Antonella Riva, Alessandro Orsini, Aglaia Vignoli, Zara Federico, Jessica Rosenblum, An-Sofie Schoonjans, Matthias De Wachter, Ignacio Delgado Alvarez, Ana Felipe-Rucián, Nourelhoda A Haridy, Shahzad Haider, Mashaya Zaman, Selina Banu, Najwa Anwaar, Fatima Rahman, Shazia Maqbool, Rashmi Yadav, Vincenzo Salpietro, Reza Maroofian, Rajan Patel, Rupa Radhakrishnan, Sanjay P Prabhu, Klaske Lichtenbelt, Helen Stewart, Yoshiko Murakami, Ulrike Löbel, Felice D'Arco, Emma Wakeling, Wendy Jones, Eleanor Hay, Sanjay Bhate, Thomas S Jacques, David M Mirsky, Matthew T Whitehead, Maha S Zaki, Tipu Sultan, Pasquale Striano, Anna C Jansen, Maarten Lequin, Linda S De Vries, Mariasavina Severino, Andrew C Edmondson, Lara Menzies, Philippe M Campeau, Henry Houlden, Amy Mctague, Stephanie Efthymiou, Kshitij Mankad

Faculty, Staff and Students Publications

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or …

Histone Serotonylation Regulates Ependymoma Tumorigenesis, Hsiao-Chi Chen, Peihao He, Malcolm Mcdonald, Michael R Williamson, Srinidhi Varadharajan, Brittney Lozzi, Junsung Woo, Dong-Joo Choi, Debosmita Sardar, Emmet Huang-Hobbs, Hua Sun, Siri M Ippagunta, Antrix Jain, Ganesh Rao, Thomas E Merchant, David W Ellison, Jeffrey L Noebels, Kelsey C Bertrand, Stephen C Mack, Benjamin Deneen

Faculty, Staff and Students Publications

Bidirectional communication between tumors and neurons has emerged as a key facet of the tumor microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, where alterations in gene expression influences cell states and interactions with the tumor microenvironment3. Ependymoma (EPN) is a pediatric brain tumor that relies on epigenomic remodeling to engender malignancy4,5; how these epigenetic mechanisms intersect with extrinsic neuronal signaling during EPN tumor progression is unknown. Here we show that activity of serotonergic neurons regulates EPN tumorigenesis, while serotonin itself also serves as an activating …

Novel Mutation Leading To Splice Donor Loss In A Conserved Site Of Dmd Gene Causes Duchenne Muscular Dystrophy With Cryptorchidism, Jianhai Chen, Yangying Jia, Jie Zhong, Kun Zhang, Hongzheng Dai, Guanglin He, Fuping Li, Li Zeng, Chuanzhu Fan, Huayan Xu

Faculty, Staff and Students Publications

Background: As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants.

Methods: In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype.

Results: In …

Long G4-Rich Enhancers Physically Interacts With Promoters Via A G4:G4 Dna-Based Mechanism, Jeffrey David Demeis

Graduate Theses and Dissertations (2019 - present)

Enhancers are genomic sequences that function as regulatory elements capable of increasing the transcription of a given gene often located at a considerable distance. The broadly accepted model of enhancer activation involves bringing an enhancer-bound activator protein complex into close spatial proximity to its target promoter through chromatin looping. Equally relevant to the work described herein, roles for guanine (G) rich sequences in transcriptional regulation are now widely accepted. Non-coding G-rich sequences are commonly found in gene promoters and enhancers, and various studies have described specific instances where G-rich sequences regulate gene expression via their capacity to form G-quadruplex (G4) …

Unveiling Novel Genetic Variants In 370 Challenging Medically Relevant Genes Using The Long Read Sequencing Data Of 41 Samples From 19 Global Populations, Yanfeng Ji, Junfan Zhao, Jiao Gong, Fritz J Sedlazeck, Shaohua Fan

Faculty, Staff and Students Publications

Background: A large number of challenging medically relevant genes (CMRGs) are situated in complex or highly repetitive regions of the human genome, hindering comprehensive characterization of genetic variants using next-generation sequencing technologies. In this study, we employed long-read sequencing technology, extensively utilized in studying complex genomic regions, to characterize genetic alterations, including short variants (single nucleotide variants and short insertions and deletions) and copy number variations, in 370 CMRGs across 41 individuals from 19 global populations.

Results: Our analysis revealed high levels of genetic variants in CMRGs, with 68.73% exhibiting copy number variations and 65.20% containing short variants that may …

Broadcasters, Receivers, Functional Groups Of Metabolites, And The Link To Heart Failure By Revealing Metabolomic Network Connectivity, Azam Yazdani, Raul Mendez-Giraldez, Akram Yazdani, Rui-Sheng Wang, Daniel J Schaid, Sek Won Kong, M Reza Hadi, Ahmad Samiei, Esmat Samiei, Clemens Wittenbecher, Jessica Lasky-Su, Clary B Clish, Jochen D Muehlschlegel, Francesco Marotta, Joseph Loscalzo, Samia Mora, Daniel I Chasman, Martin G Larson, Sarah H Elsea

Faculty, Staff and Students Publications

Background and objective: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline.

Methods: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. …

Genetic Diversity Of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation And Identifies Disease Models, Jun Wang, Meng Wang, Ala Moshiri, R Alan Harris, Muthuswamy Raveendran, Tracy Nguyen, Soohyun Kim, Laura Young, Keqing Wang, Roger Wiseman, David H O'Connor, Zach Johnson, Melween Martinez, Michael J Montague, Ken Sayers, Martha Lyke, Eric Vallender, Tim Stout, Yumei Li, Sara M Thomasy, Jeffrey Rogers, Rui Chen

Faculty, Staff and Students Publications

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which …

Improving Laboratory Animal Genetic Reporting: Lag-R Guidelines, Lydia Teboul, James Amos-Landgraf, Fernando J Benavides, Marie-Christine Birling, Steve D M Brown, Elizabeth Bryda, Rosie Bunton-Stasyshyn, Hsian-Jean Chin, Martina Crispo, Fabien Delerue, Michael Dobbie, Craig L Franklin, Ernst-Martin Fuchtbauer, Xiang Gao, Christelle Golzio, Rebecca Haffner, Yann Hérault, Martin Hrabe De Angelis, Kevin C Kent Lloyd, Terry R Magnuson, Lluis Montoliu, Stephen A Murray, Ki-Hoan Nam, Lauryl M J Nutter, Eric Pailhoux, Fernando Pardo Manuel De Villena, Kevin Peterson, Laura Reinholdt, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Cynthia Smith, Toru Takeo, Louise Tinsley, Jean-Luc Vilotte, Søren Warming, Sara Wells, C Bruce Whitelaw, Atsushi Yoshiki, Asian Mouse Mutagenesis Resource Association, Celphedia Infrastructure, Infrafrontier Consortium, International Mammalian Genome Society, International Mouse Phenotyping Consortium, International Society For Transgenic Technologies, Mutant Mouse Resource And Research Centers, Phenomics Australia, Rrrc- Rat Resource And Research Center, Guillaume Pavlovic

Faculty, Staff and Student Publications

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.