Medical Genetics Commons^™

Current State Of The Art In Hypoplastic Left Heart Syndrome, Aditya K Birla, Sunita Brimmer, Walker D Short, Oluyinka O Olutoye, Jason A Shar, Suriya Lalwani, Philippe Sucosky, Anitha Parthiban, Sundeep G Keswani, Christopher A Caldarone, Ravi K Birla

Faculty, Staff and Students Publications

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart condition in which a neonate is born with an underdeveloped left ventricle and associated structures. Without palliative interventions, HLHS is fatal. Treatment typically includes medical management at the time of birth to maintain patency of the ductus arteriosus, followed by three palliative procedures: most commonly the Norwood procedure, bidirectional cavopulmonary shunt, and Fontan procedures. With recent advances in surgical management of HLHS patients, high survival rates are now obtained at tertiary treatment centers, though adverse neurodevelopmental outcomes remain a clinical challenge. While surgical management remains the standard of care for …

In Alzheimer-Prone Brain Regions, Metabolism And Risk-Gene Expression Are Strongly Correlated, Fengdan Ye, Quentin Funk, Elijah Rockers, Joshua M Shulman, Joseph C Masdeu, Belen Pascual

Duncan NRI Faculty and Staff Publications

Neuroimaging in the preclinical phase of Alzheimer’s disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer’s disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer’s disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer’s disease. From their fluorodeoxyglucose PET we constructed metabolic …

A Mixed-Methods Protocol To Develop And Validate A Stewardship Maturity Matrix For Human Genomic Data In The Cloud, Vasiliki Rahimzadeh, Ge Peng, Mildred Cho

Center for Medical Ethics and Health Policy Staff Publications

This article describes a mixed-methods protocol to develop and test the implementation of a stewardship maturity matrix (SMM) for repositories which govern access to human genomic data in the cloud. It is anticipated that the cloud will host most human genomic and related health datasets generated as part of publicly funded research in the coming years. However, repository managers lack practical tools for identifying what stewardship outcomes matter most to key stakeholders as well as how to track progress on their stewardship goals over time. In this article we describe a protocol that combines Delphi survey methods with SMM modeling …

An Asian Case Of Combined 17Α-Hydroxylase/17,20-Lyase Deficiency Due To Homozygous Pr96q Mutation: A Case Report And Review Of The Literature, Qian Liao, Rufei Shen, Mingyu Liao, Chenxi Ran, Ling Zhou, Yuling Zhang, Guiliang Peng, Zheng Sun, Hongting Zheng, Min Long

Center on Aging Staff Publications

Background: Combined 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a very rare form of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene. Almost 100 different mutations of the CYP17A1 gene have been reported, including p.R96Q mutation, but no case of p.R96Q mutation has been described in Asian populations.

Case presentation: We describe a 22-year-old female patient of 46,XY karyotype, who presented with pseudohermaphrodism, primary amenorrhea, underdeveloped secondary sexual characteristics, delayed epiphyseal healing, hypertension, and hypokalemia. The diagnosis of 17-OHD was reached by measurement of steroid hormones and abdominal CT scan and confirmed by genetic sequencing, which revealed a homozygous p.R96Q …

Identification Of Lung Cancer Drivers By Comparison Of The Observed And The Expected Numbers Of Missense And Nonsense Mutations In Individual Human Genes, Olga Y Gorlova, Marek Kimmel, Spiridon Tsavachidis, Christopher I Amos, Ivan P Gorlov

Faculty, Staff and Students Publications

Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the …

Modeling Nonsegmented Negative-Strand Rna Virus (Nnsv) Transcription With Ejective Polymerase Collisions And Biased Diffusion, Felipe-Andrés Piedra, David Henke, Anubama Rajan, Donna M Muzny, Harsha Doddapaneni, Vipin K Menon, Kristi L Hoffman, Matthew C Ross, Sara J Javornik Cregeen, Ginger Metcalf, Richard A Gibbs, Joseph F Petrosino, Vasanthi Avadhanula, Pedro A Piedra

Faculty, Staff and Students Publications

Infections by non-segmented negative-strand RNA viruses (NNSV) are widely thought to entail gradient gene expression from the well-established existence of a single promoter at the 3' end of the viral genome and the assumption of constant transcriptional attenuation between genes. But multiple recent studies show viral mRNA levels in infections by respiratory syncytial virus (RSV), a major human pathogen and member of NNSV, that are inconsistent with a simple gradient. Here we integrate known and newly predicted phenomena into a biophysically reasonable model of NNSV transcription. Our model succeeds in capturing published observations of respiratory syncytial virus and vesicular stomatitis …

Germline Polymorphisms In Mgmt Associated With Temozolomide-Related Myelotoxicity Risk In Patients With Glioblastoma Treated On Nrg Oncology/Rtog 0825, Michael E Scheurer, Renke Zhou, Mark R Gilbert, Melissa L Bondy, Erik P Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, Emad F Youssef, Volker W Stieber, Ritsuko R Komaki, John C Flickinger, Lawrence C Kenyon, H Ian Robins, Grant K Hunter, Ian R Crocker, Samuel T Chao, Stephanie L Pugh, Terri S Armstrong

Faculty, Staff and Students Publications

BACKGROUND: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma.

METHODS:Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity.

RESULTS: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 …

Hypermethylation Of Pi3k-Akt Signalling Pathway Genes Is Associated With Human Neural Tube Defects, Tian Tian, Xinyuan Lai, Kuanhui Xiang, Xiao Han, Shengju Yin, Robert M Cabrera, John W Steele, Yunping Lei, Xuanye Cao, Richard H Finnell, Linlin Wang, Aiguo Ren

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are a group of common and severe congenital malformations. The PI3K-AKT signalling pathway plays a crucial role in the neural tube development. There is limited evidence concerning any possible association between aberrant methylation in PI3K-AKT signalling pathway genes and NTDs. Therefore, we aimed to investigate potential associations between aberrant methylation of PI3K-AKT pathway genes and NTDs. Methylation studies of PI3K-AKT pathway genes utilizing microarray genome-methylation data derived from neural tissues of ten NTD cases and eight non-malformed controls were performed. Targeted DNA methylation analysis was subsequently performed in an independent cohort of 73 NTD cases and …

Decidualization Of Human Endometrial Stromal Cells Requires Steroid Receptor Coactivator-3, Vineet K Maurya, Maria M Szwarc, David M Lonard, William E Gibbons, San-Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal …

Advancements In The Quest To Map, Monitor, And Manipulate Neural Circuitry, Jessica L Swanson, Pey-Shyuan Chin, Juan M Romero, Snigdha Srivastava, Joshua Ortiz-Guzman, Patrick J Hunt, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors …

Quantification Of Behavioral Deficits In Developing Mice With Dystonic Behaviors., Meike E Van Der Heijden, Jason S Gill, Alejandro G Rey Hipolito, Luis E Salazar Leon, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. …

Epithelial Morphogenesis In The Drosophila Egg Chamber Requires Parvin And Ilk, Athina Keramidioti, Evgenia Golegou, Eleni Psarra, Nikolaos Paschalidis, Konstantina Kalodimou, Shinya Yamamoto, Christos Delidakis, Katerina M Vakaloglou, Christos G Zervas

Duncan NRI Faculty and Staff Publications

Integrins are the major family of transmembrane proteins that mediate cell-matrix adhesion and have a critical role in epithelial morphogenesis. Integrin function largely depends on the indirect connection of the integrin cytoplasmic tail to the actin cytoskeleton through an intracellular protein network, the integrin adhesome. What is currently unknown is the role of individual integrin adhesome components in epithelia dynamic reorganization. Drosophila egg chamber consists of the oocyte encircled by a monolayer of somatic follicle epithelial cells that undergo specific cell shape changes. Egg chamber morphogenesis depends on a developmental array of cell-cell and cell-matrix signalling events. Recent elegant work …

Recurrent Liponeurocytoma: A Case Report And Systematic Review Of The Literature, Darsh S Shah, Himanshu Sharma, Prem Patel, Arya Shetty, Collin William English, J Clay Goodman, Ashwin Viswanathan, Akash J Patel

Duncan NRI Faculty and Staff Publications

Background: Liponeurocytomas are rare neurocytic neoplasms that most often arise in the posterior fossa and affect individuals in the third and fifth decades of life. Most reported cases of this unique tumor in the literature have described a favorable clinical prognosis without recurrence. However, increasing reports of recurrent cases prompted the World Health Organization, in 2016, to recategorize the tumor from Grade I to the less favorable Grade II classification. We conducted a systematic review to identify recurrent cases of this unique tumor and to summarize differences between the primary and recurrent cases of liponeurocytoma.

Methods: A systematic review exploring …

Functional Studies Of Genetic Variants Associated With Human Diseases In Notch Signaling-Related Genes Using Drosophila, Sheng-An Yang, Jose L Salazar, David Li-Kroeger, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Rare variants in the many genes related to Notch signaling cause diverse Mendelian diseases that affect myriad organ systems. In addition, genome- and exome-wide association studies have linked common and rare variants in Notch-related genes to common diseases and phenotypic traits. Moreover, somatic mutations in these genes have been observed in many types of cancer, some of which are classified as oncogenic and others as tumor suppressive. While functional characterization of some of these variants has been performed through experimental studies, the number of ‘variants of unknown significance’ identified in patients with diverse conditions keeps increasing as high-throughput sequencing technologies …

Emerging Roles Of Alternative Cleavage And Polyadenylation (Apa) In Human Disease, Prakash Dharmalingam, Rajasekaran Mahalingam, Hari Krishna Yalamanchili, Tingting Weng, Harry Karmouty-Quintana, Ashrith Guha, Rajarajan A Thandavarayan

Duncan NRI Faculty and Staff Publications

In the messenger RNA (mRNA) maturation process, the 3'-end of pre-mRNA is cleaved and a poly(A) sequence is added, this is an important determinant of mRNA stability and its cellular functions. More than 60%-70% of human genes have three or more polyadenylation (APA) sites and can be cleaved at different sites, generating mRNA transcripts of varying lengths. This phenomenon is termed as alternative cleavage and polyadenylation (APA) and it plays role in key biological processes like gene regulation, cell proliferation, senescence, and also in various human diseases. Loss of regulatory microRNA binding sites and interactions with RNA-binding proteins leading to …

The Third International Hackathon For Applying Insights Into Large-Scale Genomic Composition To Use Cases In A Wide Range Of Organisms, Kimberly Walker, Divya Kalra, Rebecca Lowdon, Guangyi Chen, David Molik, Daniela C Soto, Fawaz Dabbaghie, Ahmad Al Khleifat, Medhat Mahmoud, Luis F Paulin, Muhammad Sohail Raza, Susanne P Pfeifer, Daniel Paiva Agustinho, Elbay Aliyev, Pavel Avdeyev, Enrico R Barrozo, Sairam Behera, Kimberley Billingsley, Li Chuin Chong, Deepak Choubey, Wouter De Coster, Yilei Fu, Alejandro R Gener, Timothy Hefferon, David Morgan Henke, Wolfram Höps, Anastasia Illarionova, Michael D Jochum, Maria Jose, Rupesh K Kesharwani, Sree Rohit Raj Kolora, Jędrzej Kubica, Priya Lakra, Damaris Lattimer, Chia-Sin Liew, Bai-Wei Lo, Chunhsuan Lo, Anneri Lötter, Sina Majidian, Suresh Kumar Mendem, Rajarshi Mondal, Hiroko Ohmiya, Nasrin Parvin, Carolina Peralta, Chi-Lam Poon, Ramanandan Prabhakaran, Marie Saitou, Aditi Sammi, Philippe Sanio, Nicolae Sapoval, Najeeb Syed, Todd Treangen, Gaojianyong Wang, Tiancheng Xu, Jianzhi Yang, Shangzhe Zhang, Weiyu Zhou, Fritz J Sedlazeck, Ben Busby

Faculty, Staff and Students Publications

In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics.

Genetic Testing In Ambulatory Cardiology Clinics Reveals High Rate Of Findings With Clinical Management Implications, David R Murdock, Eric Venner, Donna M Muzny, Ginger A Metcalf, Mullai Murugan, Trevor D Hadley, Varuna Chander, Paul S De Vries, Xiaoming Jia, Aliza Hussain, Ali M Agha, Aniko Sabo, Shoudong Li, Qingchang Meng, Jianhong Hu, Xia Tian, Michelle Cohen, Victoria Yi, Christie L Kovar, Marie-Claude Gingras, Viktoriya Korchina, Chad Howard, Daniel L Riconda, Stacey Pereira, Hadley S Smith, Zohra A Huda, Alexandria Buentello, Patricia R Marino, Lee Leiber, Ashok Balasubramanyam, Christopher I Amos, Andrew B Civitello, Mihail G Chelu, Ronald Maag, Amy L Mcguire, Eric Boerwinkle, Xander H T Wehrens, Christie M Ballantyne, Richard A Gibbs

Faculty, Staff and Students Publications

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.

METHODS: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.

RESULTS: Notably, 32% of patients had a genetic finding with clinical …

Super-Resolution Microscopy Reveals Photoreceptor-Specific Subciliary Location And Function Of Ciliopathy-Associated Protein Cep290, Valencia L Potter, Abigail R Moye, Michael A Robichaux, Theodore G Wensel

Faculty, Staff and Students Publications

Mutations in the cilium-associated protein CEP290 cause retinal degeneration as part of multiorgan ciliopathies or as retina-specific diseases. The precise location and the functional roles of CEP290 within cilia and, specifically, the connecting cilia (CC) of photoreceptors, remain unclear. We used super-resolution fluorescence microscopy and electron microscopy to localize CEP290 in the CC and in the primary cilia of cultured cells with subdiffraction resolution and to determine effects of CEP290 deficiency in 3 mutant models. Radially, CEP290 localizes in close proximity to the microtubule doublets in the region between the doublets and the ciliary membrane. Longitudinally, it is distributed throughout …

Supercoiling And Looping Promote Dna Base Accessibility And Coordination Among Distant Sites, Jonathan M Fogg, Allison K Judge, Erik Stricker, Hilda L Chan, Lynn Zechiedrich

Faculty, Staff and Students Publications

DNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential …

Discovery Of Potent Bet Bromodomain 1 Stereoselective Inhibitors Using Dna-Encoded Chemical Library Selections, Rajesh Sharma, Kyoung-Jae Choi, My Diem Quan, Sonum Sharma, Banumathi Sankaran, Hyekyung Park, Anel Lagrone, Jean J Kim, Kevin R Mackenzie, Allan Chris M Ferreon, Choel Kim, Josephine C Ferreon

Faculty, Staff and Students Publications

Expression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid-liquid condensation of the isolated KLF4 …

Determining Effective Drug Concentrations For Selection And Counterselection Genetics In Drosophila Melanogaster, Nick Matinyan, Yezabel Gonzalez, Herman A Dierick, Koen J T Venken

Faculty, Staff and Students Publications

We recently integrated into fly genetics a set of four selection and two counterselection markers and their corresponding drugs that can be used individually or in combination. These markers eliminate the need to visually screen progeny. Before using these markers in new genetic backgrounds, effective selection/counterselection concentrations should be established for each marker/drug combination. This protocol describes how to set up, perform, and analyze a drug titration curve to determine the effective selection/counterselection drug concentrations for their corresponding markers. For complete details on the use and execution of this protocol, please refer to Matinyan et al., 2021.

Identification Of Micrornas And Gene Regulatory Networks In Cleft Lip Common In Humans And Mice, Hiroki Yoshioka, Aimin Li, Akiko Suzuki, Sai Shankar Ramakrishnan, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

The etiology of cleft lip with/without cleft palate (CL/P), one of the most frequent craniofacial birth defects worldwide, is complicated by contributions of both genetic and environmental factors. Understanding the etiology of these conditions is essential for developing preventive strategies. This study thus aims to identify regulatory networks of microRNAs (miRNAs), transcriptional factors (TFs) and non-TF genes associated with cleft lip (CL) that are conserved in humans and mice. Notably, we found that miR-27b, miR-133b, miR-205, miR-376b and miR-376c were involved in the regulation of CL-associated gene expression in both humans and mice. Among the candidate miRNAs, the overexpression of …

Multiplexed Drug-Based Selection And Counterselection Genetic Manipulations In Drosophila, Nick Matinyan, Mansi S Karkhanis, Yezabel Gonzalez, Antrix Jain, Alexander Saltzman, Anna Malovannaya, Alejandro Sarrion-Perdigones, Herman A Dierick, Koen J T Venken

Faculty, Staff and Students Publications

The power of Drosophila melanogaster as a model system relies on tractable germline genetic manipulations. Despite Drosophila's expansive genetics toolbox, such manipulations are still accomplished one change at a time and depend predominantly on phenotypic screening. We describe a drug-based genetic platform consisting of four selection and two counterselection markers, eliminating the need to screen for modified progeny. These markers work reliably individually or in combination to produce specific genetic outcomes. We demonstrate three example applications of multiplexed drug-based genetics by generating (1) transgenic animals, expressing both components of binary overexpression systems in a single transgenesis step; (2) dual selectable …

Ankyrin-Dependent Na+ Channel Clustering Prevents Neuromuscular Synapse Fatigue, Chuansheng Zhang, Abhijeet Joshi, Yanhong Liu, Ozlem Sert, Seth G Haddix, Lindsay H Teliska, Anne Rasband, George G Rodney, Matthew N Rasband

Faculty, Staff and Students Publications

Skeletal muscle contraction depends on activation of clustered acetylcholine receptors (AchRs) and muscle-specific Na+ channels (Nav1.4). Some Nav1.4 channels are highly enriched at the neuromuscular junction (NMJ) and their clustering is thought to be essential for effective muscle excitation. However, this has not been experimentally tested, and how NMJ Na+ channels are clustered is unknown. Here, using muscle-specific AnkyrinR, AnkyrinB, and AnkyrinG single, double, and triple-conditional knockout mice we show that Nav1.4 channels fail to cluster only after deletion of all three ankyrins. Remarkably, ankyrin-deficient muscles have normal NMJ morphology, AchR clustering, sarcolemmal levels of Nav1.4, and muscle force, and …

Invariant Natural Killer T-Cell Subsets Have Diverse Graft-Versus-Host-Disease-Preventing And Antitumor Effects, Kristina Maas-Bauer, Juliane K Lohmeyer, Toshihito Hirai, Teresa Lopes Ramos, Furqan M Fazal, Ulrike M Litzenburger, Kathryn E Yost, Jessica V Ribado, Neeraja Kambham, Arielle S Wenokur, Po-Yu Lin, Maite Alvarez, Melissa Mavers, Jeanette Baker, Ami S Bhatt, Howard Y Chang, Federico Simonetta, Robert S Negrin

Faculty, Staff and Students Publications

Invariant natural killer T (iNKT) cells are a T-cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic graft-versus-host-disease (GVHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2, and iNKT17 sublineages, which differ transcriptomically and epigenomically and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GVHD is currently unknown. In this work, we generated highly purified murine iNKT sublineages, characterized their transcriptomic and epigenomic landscape, …

The Concurrence Of Dna Methylation And Demethylation Is Associated With Transcription Regulation, Jiejun Shi, Jianfeng Xu, Yiling Elaine Chen, Jason Sheng Li, Ya Cui, Lanlan Shen, Jingyi Jessica Li, Wei Li

Children’s Nutrition Research Center Staff Publications

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. …

Primary Ciliary Dyskinesia: Ancestral Haplotypes Analysis Of The Rsph4a Founder Mutation In Puerto Rico, Wilfredo De Jesús-Rojas, Dalilah Reyes De Jesús, Angélica M Nieves, Ricardo A Mosquera, Juan C Martinez-Cruzado

Faculty, Staff and Student Publications

Genetic mutations in >50 genes, including RSPH4A, can lead to primary ciliary dyskinesia (PCD). RSPH4A mutations affect radial spokes, which alter the configuration of the ciliary ultrastructure and lead to chronic oto-sinopulmonary disease. The RSPH4A [c.921+3_6delAAGT] founder mutation was described as one cause of PCD without laterality defects in Puerto Rico. The average Puerto Rican genetic composition includes 64% European, 21% African ancestral, and 15% Native-American or Taino, a native tribe in the Caribbean at the start of the European colonization, genes. Due to the relatively elevated Taino ancestry on the island, it might have contributed to the endemicity of …

Vascular Disease Pathogenesis In Smooth Muscle Dysfunction Syndrome And Majewski Osteodysplastic Primordial Dwarfism Type Ii, Jamie Wright

Dissertations and Theses (Open Access)

Vascular diseases are a leading cause of morbidity and mortality world-wide. Understanding their pathogenesis is crucial to better diagnosis and management of these life-threatening conditions. Through the study of rare mutations that lead to early onset and severe vascular diseases, we can elucidate underlying mechanisms for vascular disease pathogenesis and develop better treatments to prevent and manage more common causes of vascular diseases. In this study we look at two rare diseases that lead to severe vascular phenotypes, Smooth Muscle Dysfunction Syndrome (SMDS) and Majewski Osteodysplastic Primordial Dwarfism Type II (MOPDII). SMDS is a rare condition due to pathogenic variants …

The Design And Rationale Of A Multicenter Real-World Trial: The Southeastern Collaboration To Improve Blood Pressure Control In The Us Black Belt – Addressing The Triple Threat, Tina O Findley, Hope Northrup

Faculty, Staff and Student Publications

The incidence of congenital heart defect (CHD) has increased over the past fifty years, partly attributed to routine fetal anatomical examination by sonography during obstetric care and improvements in ultrasound technology and technique. Fetal findings on ultrasound in addition to maternal biomarkers are the backbone of first- and second-trimester screening for common genetic conditions, namely aneuploidy. Since the introduction of non-invasive prenatal testing (NIPT) using next-generation sequencing to sequence cell-free fetal DNA, the detection rate of common trisomies as well as sex chromosomal aneuploidies have markedly increased. As the use of NIPT continues to broaden, the best means of incorporating …

Transcriptional Milestones In Dictyostelium Development, Mariko Katoh-Kurasawa, Karin Hrovatin, Shigenori Hirose, Amanda Webb, Hsing-I Ho, Blaž Zupan, Gad Shaulsky

Faculty, Staff and Students Publications

Dictyostelium development begins with single-cell starvation and ends with multicellular fruiting bodies. Developmental morphogenesis is accompanied by sweeping transcriptional changes, encompassing nearly half of the 13,000 genes in the genome. We performed time-series RNA-sequencing analyses of the wild type and 20 mutants to explore the relationships between transcription and morphogenesis. These strains show developmental arrest at different stages, accelerated development, or atypical morphologies. Considering eight major morphological transitions, we identified 1371 milestone genes whose expression changes sharply between consecutive transitions. We also identified 1099 genes as members of 21 regulons, which are groups of genes that remain coordinately regulated despite …