Medicine and Health Sciences Commons^™

Determinants Of Mosaic Chromosomal Alteration Fitness, Yash Pershad, Taralynn Mack, Hannah Poisner, Yasminka A Jakubek, Adrienne M Stilp, Braxton D Mitchell, Joshua P Lewis, Eric Boerwinkle, Ruth J F Loos, Nathalie Chami, Zhe Wang, Kathleen Barnes, Nathan Pankratz, Myriam Fornage, Susan Redline, Bruce M Psaty, Joshua C Bis, Ali Shojaie, Edwin K Silverman, Michael H Cho, Jeong H Yun, Dawn Demeo, Daniel Levy, Andrew D Johnson, Rasika A Mathias, Margaret A Taub, Donna Arnett, Kari E North, Laura M Raffield, April P Carson, Margaret F Doyle, Stephen S Rich, Jerome I Rotter, Xiuqing Guo, Nancy J Cox, Dan M Roden, Nora Franceschini, Pinkal Desai, Alex P Reiner, Paul L Auer, Paul A Scheet, Siddhartha Jaiswal, Joshua S Weinstock, Alexander G Bick

Journal Articles

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI toPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our …

Deleterious Heteroplasmic Mitochondrial Mutations Are Associated With An Increased Risk Of Overall And Cancer-Specific Mortality, Yun Soo Hong, Stephanie L Battle, Wen Shi, Daniela Puiu, Vamsee Pillalamarri, Jiaqi Xie, Nathan Pankratz, Nicole J Lake, Monkol Lek, Jerome I Rotter, Stephen S Rich, Charles Kooperberg, Alex P Reiner, Paul L Auer, Nancy Heard-Costa, Chunyu Liu, Meng Lai, Joanne M Murabito, Daniel Levy, Megan L Grove, Alvaro Alonso, Richard Gibbs, Shannon Dugan-Perez, Lukasz P Gondek, Eliseo Guallar, Dan E Arking

Journal Articles

Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint …

Tmem27 Suppresses Tumor Development By Promoting Ret Ubiquitination, Positioning, And Degradation, Qianjin Guo, Zi-Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N Landry, Hector Lopez, Cynthia M Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M Mulligan, Ricardo C T Aguiar, Patricia L M Dahia

Journal Articles

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell …

Clonal Hematopoiesis Is Associated With Protection From Alzheimer's Disease, Hind Bouzid, Julia A Belk, Max Jan, Yanyan Qi, Chloé Sarnowski, Sara Wirth, Lisa Ma, Matthew R Chrostek, Herra Ahmad, Daniel Nachun, Winnie Yao, Alexa Beiser, Alexander G Bick, Joshua C Bis, Myriam Fornage, William T Longstreth, Oscar L Lopez, Pradeep Natarajan, Bruce M Psaty, Claudia L Satizabal, Joshua Weinstock, Eric B Larson, Paul K Crane, C Dirk Keene, Sudha Seshadri, Ansuman T Satpathy, Thomas J Montine, Siddhartha Jaiswal

Journal Articles

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P …

Overcoming The Challenges To Clinical Development Of X-Linked Retinitis Pigmentosa Therapies: Proceedings Of An Expert Panel, David G Birch, Janet K Cheetham, Stephen P Daiger, Carel Hoyng, Christine Kay, Ian M Macdonald, Mark E Pennesi, Lori S Sullivan

Journal Articles

UNLABELLED: X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease manifesting as impaired night vision and peripheral vision loss that progresses to legal blindness. Although several trials of ocular gene therapy for XLRP have been conducted or are in progress, there is currently no approved treatment. In July 2022, the Foundation Fighting Blindness convened an expert panel to examine relevant research and make recommendations for overcoming the challenges and capitalizing on the opportunities in conducting clinical trials of RPGR-targeted therapy for XLRP. Data presented concerned RPGR structure and mutation types known to cause XLRP, RPGR mutation-associated retinal phenotype diversity, …

Ad-Syn-Net: Systematic Identification Of Alzheimer's Disease-Associated Mutation And Co-Mutation Vulnerabilities Via Deep Learning, Xingxin Pan, Zeynep H Coban Akdemir, Ruixuan Gao, Xiaoqian Jiang, Gloria M Sheynkman, Erxi Wu, Jason H Huang, Nidhi Sahni, S Stephen Yi

Journal Articles

Alzheimer's disease (AD) is one of the most challenging neurodegenerative diseases because of its complicated and progressive mechanisms, and multiple risk factors. Increasing research evidence demonstrates that genetics may be a key factor responsible for the occurrence of the disease. Although previous reports identified quite a few AD-associated genes, they were mostly limited owing to patient sample size and selection bias. There is a lack of comprehensive research aimed to identify AD-associated risk mutations systematically. to address this challenge, we hereby construct a large-scale AD mutation and co-mutation framework ('AD-Syn-Net'), and propose deep learning models named Deep-SMCI and Deep-CMCI configured …

Gain-Of-Function Variomics And Multi-Omics Network Biology For Precision Medicine, Mark M Li, Sharad Awasthi, Sumanta Ghosh, Deepa Bisht, Zeynep H Coban Akdemir, Gloria M Sheynkman, Nidhi Sahni, S Stephen Yi

Journal Articles

Traditionally, disease causal mutations were thought to disrupt gene function. However, it becomes more clear that many deleterious mutations could exhibit a "gain-of-function" (GOF) behavior. Systematic investigation of such mutations has been lacking and largely overlooked. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in disease. Elucidating the functional pathways rewired by GOF mutations will be crucial for prioritizing disease-causing variants and their resultant therapeutic liabilities. In distinct cell types (with varying genotypes), precise signal transduction controls cell decision, including gene regulation and phenotypic output. …

Identification Of A Novel Large Multigene Deletion And A Frameshift Indel In Pde6b As The Underlying Cause Of Early-Onset Recessive Rod-Cone Degeneration, Riccardo Sangermano, Pooja Biswas, Lori S Sullivan, Emily M Place, Shyamanga Borooah, Juerg Straubhaar, Eric A Pierce, Stephen P Daiger, Kinga M Bujakowska, Radha Ayaggari

Journal Articles

A family, with two affected identical twins with early-onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare and previously reported causative variant (c.1923_1969delinsTCTGGG; p.Asn643Glyfs*29) in the

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S Regalado, Shaine A Morris, Alan C Braverman, Ellen M Hostetler, Julie De Backer, Ruosha Li, Reed E Pyeritz, Anji T Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott Lemaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M Milewicz

Journal Articles

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Analysis Of Sars-Cov-2 Genomes Of Samples From Peru, Johnny Leandro Saavedra-Camacho, Sebastian Iglesias-Osores, Miguel Alcántara-Mimbela, Lizbeth M. Córdova-Rojas

Revista de la Facultad de Medicina Humana

Introduction: Genomic analysis of samples from documented COVID-19 cases can be used successfully to help track sources of Sars-Cov-2 infection, which can be quarantined to prevent the recurrent spread of the disease around the world. Objective: To describe the SARS-CoV-2 sequences isolated from Peruvian patients. Methods: All genomes published up to March 2021, uploaded in the GISAID and Nextstrain repository, were selected. All data is on the web in a public way; In addition, the information was filtered by continent, country, region, clade, lineage, and sex from March 2020 to February 2021. Results: It was evidenced that the region with …

Hypertrophic Cardiomyopathy Associated E22k Mutation In Myosin Regulatory Light Chain Decreases Calcium-Activated Tension And Stiffness And Reduces Myofilament Ca, Jiajia Zhang, Li Wang, Katarzyna Kazmierczak, Hang Yun, Danuta Szczesna-Cordary, Masataka Kawai

Journal Articles

UNLABELLED: We investigated the mechanisms associated with E22K mutation in myosin regulatory light chain (RLC), found to cause hypertrophic cardiomyopathy (HCM) in humans and mice. Specifically, we characterized the mechanical profiles of papillary muscle fibers from transgenic mice expressing human ventricular RLC wild-type (Tg-WT) or E22K mutation (Tg-E22K). Because the two mouse models expressed different amounts of transgene, the B6SJL mouse line (NTg) was used as an additional control. Mechanical experiments were carried out on Ca

SUB-DISCIPLINE: Bioenergetics.

DATABASE: The data that support the findings of this study are available from the corresponding authors upon reasonable request.

ANIMAL PROTOCOL: BK20150353 …

Full Issue: The International Undergraduate Journal Of Health Sciences, Volume 1, Issue 1, June 2021

International Undergraduate Journal of Health Sciences

The full June 2021 issue (Volume 1, Issue 1) of the International Undergraduate Journal of Health Sciences

Covid-19: The Vaccine Race Continues, L. Hayley Burgess, Carley Castelein, Andrew Rubio, Mandelin K. Cooper

HCA Healthcare Journal of Medicine

Over a year has passed since the discovery of SARS-CoV-2 and the subsequent COVID-19 pandemic. As mitigation efforts continue, COVID-19 has claimed over half a million lives in the United States and 3.1 million lives globally. The development and availability of vaccines delivering immunity to prevent COVID-19 offers hope to end the pandemic.

Emergency use authorizations from the Food and Drug Administration have been issued in the United States for three vaccines, one each from Pfizer-BioNTech, Moderna and Janssen/J&J. Pfizer-BioNTech and Moderna are both mRNA vaccines with efficacy of 95% and 94.1% respectively, while the vector-based vaccine from Janssen/J&J has …

The Distribution In Native Populations From Mexico And Central America Of The C677t Variant In The Mthfr Gene, Lucio A. Reyes

USF Tampa Graduate Theses and Dissertations

Objectives: To explore evolutionary hypotheses for the high frequencies of a substitution in the methylenetetrahydrofolate reductase (MTHFR) gene, in Mexican and Central American Indigenous populations.

Materials and methods: We obtained allele frequencies for the C677T variant in the MTHFR gene and ecological information for 37 indigenous samples from Mexico and Central America. We calculated Hardy–Weinberg equilibrium and computed Fst statistics. We computed correlations between the samples' allele frequencies and ecological and geochemical variables.

Results: Many of the samples have extremely high frequencies of the T allele (q̄ = 0.62, median = 0.66). In this region, the frequency of the T …

Multiplex Qpcr Discriminates Variants Of Concern To Enhance Global Surveillance Of Sars-Cov-2, Chantal B. F. Vogels, Mallery I. Breban, Isabel M. Ott, Tara Alpert, Mary E. Petrone, Anne E. Watkins, Chaney C. Kalinich, Rebecca Earnest, Jessica E. Rothman, Jaqueline Goes De Jesus, Ingra Morales Claro, Giulia Magalhães Ferreira, Myuki A. E. Crispim, Brazil-Uk Cadde Genomic Network, Lavanya Singh, Houriiyah Tegally, Ugochukwu J. Anyaneji, Network For Genomic Surveillance In South Africa, Emma B. Hodcroft, Christopher E. Mason, Gaurav Khullar, Jessica Metti, Joel T. Dudley, Matthew J. Mackay, Megan Nash, Jianhui Wang, Chen Liu, Pei Hui, Steven Murphy, Caleb Neal, Eva Laszlo, Marie L. Landry, Anthony Muyombwe, Randy Downing, Jafar Razeq, Tulio De Oliveira, Nuno R. Faria, Ester C. Sabino, Richard A. Neher, Joseph R. Fauver, Nathan D. Grubaugh

Journal Articles: Epidemiology

With the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants that may increase transmissibility and/or cause escape from immune responses, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant, first detected in the United Kingdom, could be serendipitously detected by the Thermo Fisher TaqPath COVID-19 PCR assay because a key deletion in these viruses, spike Δ69-70, would cause a "spike gene target failure" (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern (VOC) that lack …

De Novo Mutations Across 1,465 Diverse Genomes Reveal Mutational Insights And Reductions In The Amish Founder Population, Michael D Kessler, Douglas P Loesch, James A Perry, Nancy L Heard-Costa, Daniel Taliun, Brian E Cade, Heming Wang, Michelle Daya, John Ziniti, Soma Datta, Juan C Celedón, Manuel E Soto-Quiros, Lydiana Avila, Scott T Weiss, Kathleen Barnes, Susan S Redline, Ramachandran S Vasan, Andrew D Johnson, Rasika A Mathias, Ryan Hernandez, James G Wilson, Deborah A Nickerson, Goncalo Abecasis, Sharon R Browning, Sebastian Zöllner, Jeffrey R O'Connell, Braxton D Mitchell, Timothy D O'Connor

Journal Articles

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a …

A Hierarchical Graph For Nucleotide Binding Domain 2, Samuel Kakraba

Electronic Theses and Dissertations

One of the most prevalent inherited diseases is cystic fibrosis. This disease is caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is known to function as a chloride channel that regulates the viscosity of mucus that lines the ducts of a number of organs. Generally, most of the prevalent mutations of CFTR are located in one of two nucleotide binding domains, namely, the nucleotide binding domain 1 (NBD1). However, some mutations in nucleotide binding domain 2 (NBD2) can equally cause cystic fibrosis. In this work, a hierarchical graph is built for NBD2. …

Experimental Evolution Of An Rna Virus In Wild Birds: Evidence For Host-Dependent Impacts On Population Structure And Competitive Fitness, Nathan D. Grubaugh, Darci R. Smith, Doug E. Brackney, Angela M. Bosco-Lauth, Joseph R. Fauver, Corey L. Campbell, Todd A. Felix, Hannah Romo, Nisha K. Duggal, Elizabeth A. Dietrich, Tyler Eike, Jennifer E. Beane, Richard A. Bowen, William C. Black, Aaron C. Brault, Gregory D. Ebel

Journal Articles: Epidemiology

Within hosts, RNA viruses form populations that are genetically and phenotypically complex. Heterogeneity in RNA virus genomes arises due to error-prone replication and is reduced by stochastic and selective mechanisms that are incompletely understood. Defining how natural selection shapes RNA virus populations is critical because it can inform treatment paradigms and enhance control efforts. We allowed West Nile virus (WNV) to replicate in wild-caught American crows, house sparrows and American robins to assess how natural selection shapes RNA virus populations in ecologically relevant hosts that differ in susceptibility to virus-induced mortality. After five sequential passages in each bird species, we …

Novel Nr5a1 Missense Mutation In Premature Ovarian Failure: Detection In Han Chinese Indicates Causation In Different Ethnic Groups, Xue Jiao, Yingying Qin, Guangyu Li, Shidou Zhao, Li You, Jinlong Ma, Joe Leigh Simpson, Zi-Jiang Chen

HWCOM Faculty Publications

Background

The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF.

Methods

Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated …

The Cradle Of The Deltaf508 Mutation, Danish Saleheen, Philippe M Frossard

Department of Biological & Biomedical Sciences

Cystic fibrosis (CF) is the most common autosomal recessive disorder caused due to mutation/s in the CFTR gene. The most common mutation in CFTR worldwide is deltaF508 and cystic fibrosis genetic analysis consortium revealed that this mutation is responsible for approximately 66% of all CF chromosomes in the world. Studies looking at the DNA polymorphic haplotypes created by CF linked markers suggest that deltaF508 has a single origin as this mutation has been found associated exclusively with one marker haplotype. Despite a high prevalence of this mutation in CF patients in northern parts of Europe, findings suggest that this mutation …

Sulfa Or Sulfone Prophylaxis And Geographic Region Predict Mutations In The Pneumocystis Carinii Dihydropteroate Synthase Gene, Laurence Huang, Charles B. Beard, Jennifer Creasman, Deborah A. Levy, Jeffrey S. Duchin, Sherline Lee, Norman Pieniazek, Jane L. Carter, Carlos Del Rio, David Rimland, Thomas R. Navin

Journal Articles: Epidemiology

To determine factors associated with mutations in the Pneumocystis carinii dihydropteroate synthase (DHPS) gene, a prospective study of human immunodeficiency virus (HIV)-infected patients with confirmed P. carinii pneumonia was conducted in Atlanta, Seattle, and San Francisco. Clinical information was obtained from patient interview and chart abstraction. DHPS genotype was determined from DNA sequencing. Overall, 76 (68.5%) of 111 patients had a mutant DHPS genotype, including 22 (81.5%) of 27 patients from San Francisco. In multivariate analysis, sulfa or sulfone prophylaxis and study site were independent predictors of a mutant genotype. Fourteen (53.8%) of 26 patients who were newly diagnosed with …