Genetics and Genomics Commons^™

Assessment Of The First Presentations Of Common Variable Immunodeficiency In A Large Cohort Of Patients, Hossein Esmaeilzadeh, Armita Jokar-Derisi, Amir Hossein Hassani, Reza Yazdani, Samaneh Delavari, Hassan Abolhassani, Negar Mortazavi, Aida Askarisarvestani

Department of Neurology Faculty Papers

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations.

METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated.

RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) …

Relative Genetic Homogeneity Within A Phenotypically Diverse Group; A Case Of The Lake Tana Labeobarbus (Cyprinidae) Species Flock, Ethiopia, Kebede Beshera

Faculty Publications

The Lake Tana Labeobarbus species flock represents one of the world’s most famous examples of lacustrine species radiations. Previous studies of this group have resulted in the description of at least 15 species based on their differences in functional morphology and definition of two clades (lacustrine and riverine spawning clades) based on life history traits. A total of 166 fish representing 14 Labeobarbus species were genotyped using 10 lineage-specific hexaploid microsatellite loci. Six of these loci were developed for this study based on DNA sequence contigs derived from a microsatellite-enriched genomic library of Labeobarbus intermedius from Lake Tana; the remaining …

Viral Dna Accumulation Regulates Replication Efficiency Of Chlorovirus Osy-Ne5 In Two Closely Related Chlorella Variabilis Strains, Ahmed Esmael, Irina V. Agarkova, David D. Dunigan, You Zhou, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

Many chloroviruses replicate in Chlorella variabilis algal strains that are ex-endosymbionts isolated from the protozoan Paramecium bursaria, including the NC64A and Syngen 2-3 strains. We noticed that indigenous water samples produced a higher number of plaque-forming viruses on C. variabilis Syngen 2-3 lawns than on C. variabilis NC64A lawns. These observed differences led to the discovery of viruses that replicate exclusively in Syngen 2-3 cells, named Only Syngen (OSy) viruses. Here, we demonstrate that OSy viruses initiate infection in the restricted host NC64A by synthesizing some early virus gene products and that approximately 20% of the cells produce a …

Phylogeography Of The Pacific Sardine, Sardinops Sagax, In The Northeastern Pacific, Ella Adams

Theses

The Pacific Sardine, (Sardinops sagax), is a small, coastal pelagic species in the family Clupeidae. Sardine are an ecologically important forage fish for many animals, including larger, economically and ecologically important fishes, and have historically supported an important commercial fishery. When the fishery declined in the 1940s, a massive effort in understanding population structure for the Pacific Sardine resulted in a wealth of literature. Initially, these studies agreed on a large panmictic population with high annual variation, but the general consensus has since been that there are multiple subpopulations of the Pacific Sardine along the West Coast of …

Germline Genetic Variants And Pediatric Rhabdomyosarcoma Outcomes: A Report From The Children’S Oncology Group, Bailey A Martin-Giacalone, Melissa A Richard, Michael E Scheurer, Javed Khan, Pagna Sok, Priya B Shetty, Stephen J Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A Marquez-Do, Donald A Barkauskas, David Hall, Matthew T Mcevoy, Austin L Brown, Aniko Sabo, Paul Scheet, Chad D Huff, Stephen X Skapek, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J Lupo

Faculty, Staff and Student Publications

BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.

METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical …

Genotype-Degree Of Hemolysis Correlation In Hereditary Spherocytosis, Yimeng Shi, Yuan Li, Xiawan Yang, Xiaoxia Li, Guangxin Peng, Xin Zhao, Xu Liu, Yufei Zhao, Jing Hu, Xiangrong Hu, Baohang Zhang, Kang Zhou, Yang Yang, Youzhen Xiong, Jianping Li, Huihui Fan, Wenrui Yang, Lei Ye, Liping Jing, Li Zhang, Fengkui Zhang

Faculty, Staff and Student Publications

BACKGROUND: Hereditary spherocytosis (HS) is a common inherited hemolytic anemia, caused by mutations in five genes that encode erythrocyte membrane skeleton proteins. The red blood cell (RBC) lifespan could directly reflect the degree of hemolysis. In the present cohort of 23 patients with HS, we performed next-generation sequencing (NGS) and Levitt's carbon monoxide (CO) breath test to investigate the potential genotype-degree of hemolysis correlation.

RESULTS: In the present cohort, we identified 8 ANK1,9 SPTB,5 SLC4A1 and 1 SPTA1 mutations in 23 patients with HS, and the median RBC lifespan was 14(8-48) days. The median RBC lifespan of patients with ANK1, …

Basic Fibroblast Growth Factor Induces Proliferation And Collagen Production By Fibroblasts Derived From The Bovine Corpus Luteum, Corrine F. Monaco, Michele R. Plewes, Emilia Przygrodzka, Jitu W. George, Fang Qiu, Peng Xiao, Jennifer R. Wood, Andrea S. Cupp, John S. Davis

Department of Animal Science: Faculty Publications

Cyclic regression of the ovarian corpus luteum, the endocrine gland responsible for progesterone production, involves rapid matrix remodeling. Despite fibroblasts in other systems being known for producing and maintaining extracellular matrix, little is known about fibroblasts in the functional or regressing corpus luteum. Vast transcriptomic changes occur in the regressing corpus luteum, among which are reduced levels of vascular endothelial growth factor A (VEGFA) and increased expression of fibroblast growth factor 2 (FGF2) after 4 and 12 h of induced regression, when progesterone is declining and the microvasculature is destabilizing. We hypothesized that FGF2 activates luteal …

Autolysosomal Exocytosis Of Lipids Protect Neurons From Ferroptosis, Isha Ralhan, Jinlan Chang, Matthew J Moulton, Lindsey D Goodman, Nathanael Y J Lee, Greg Plummer, H Amalia Pasolli, Doreen Matthies, Hugo J Bellen, Maria S Ioannou

Faculty, Staff and Students Publications

During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role in several neurodegenerative diseases. Yet, the mechanisms of lipid release and its consequences on neuronal health are unclear. Here, we demonstrate that lipid-protein particle release by autolysosome exocytosis protects neurons from ferroptosis, a form of cell death driven by lipid peroxidation. We show that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis which requires the exocytic machinery VAMP7 and syntaxin 4. We observe membrane-bound lipid-protein particles by TEM and demonstrate that these particles are …

Machine Learning Reveals Lipidome Remodeling Dynamics In A Mouse Model Of Ovarian Cancer, Olatomiwa O Bifarin, Samyukta Sah, David A Gaul, Samuel G Moore, Ruihong Chen, Murugesan Palaniappan, Jaeyeon Kim, Martin M Matzuk, Facundo M Fernández

Faculty, Staff and Students Publications

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. …

The Landscape Of Tolerated Genetic Variation In Humans And Primates, Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G Schraiber, Jeremy Mcrae, Moriel Singer-Berk, Yanshen Yang, Anastasia S D Dietrich, Petko P Fiziev, Lukas F K Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi Do Amaral, Mariluce Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Bataillon, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Monkol Lek, Shamil Sunyaev, Anne O'Donnell-Luria, Heidi L Rehm, Jinbo Xu, Jeffrey Rogers, Tomas Marques-Bonet, Kyle Kai-How Farh

Faculty, Staff and Students Publications

INTRODUCTION:

Millions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.

RATIONALE:

As a result of the short evolutionary distance between humans and nonhuman primates, …

Effect Of Vitamin C And Probiotics On Broilers Performance And Claudin-2 (Cldn-2) Expression Under Heat Stress [Research Note], Mohammad Chamani, Mohammad Chamani, Farhad Foroudi, Ali Asghar Sadeghi, Mehdi Aminafshar

The Philippine Agricultural Scientist

This study was conducted to investigate the effect of vitamin C and probiotic which consists of five species of beneficial bacteria and two species of fungi on performance, blood parameters, and intestinal CLDN-2 gene expression of broilers during heat stress (HS). A total of 400 broilers were randomly divided into five groups, each of which received a different treatment. The first group was considered a negative control and did not experience any HS (C^-); the second group was considered a positive control (C⁺) and was exposed to HS; the third group received only vitamin C (250 …

Investigating The Role Of Holoenzyme C In Restoring Replication Following Uv-Induced Dna Damage In Escherichia Coli, Rahul Shimpi

University Honors Theses

The recovery of replication following UV-induced DNA damage in Escherichia coli correlates with the time at which the lesions are repaired, suggesting that the two processes may be coupled. holC encodes the Chi-subunit of replicative DNA polymerase III, and is nonessential for viability, but renders cells hypersensitive to UV-induced damage when mutated, suggesting it may play a specific role in restoring replication when it encounters DNA damage. Here, I characterized the role of HolC in restoring DNA replication following disruption by UV-induced damage. I found that survival following UV in strains deleted for holC was similar to that of strains …

Illuminating The Drivers Of Genomic Diversification In Lamprologine Cichlids Of The Lower Congo River, Naoko P. Kurata

Dissertations, Theses, and Capstone Projects

Freshwater fishes are extraordinarily diverse, considering their available habitats represent a tiny proportion of the earth’s surface. Rivers connect heterogeneous habitats in a linear form and provide excellent simplified models to understand how aquatic biodiversity evolves. In particular, the lower Congo River (LCR) in west Central Africa consists of a dynamic hydroscape exhibiting extraordinary aquatic biodiversity, endemicity, and morphological and ecological specialization. This system is thus an excellent natural laboratory for understanding complex speciation and population diversification processes. In my research, I explore various drivers of diversification, and adaptive evolution in rheophilic lamprologine cichlids endemic to the LCR, including Lamprologus …

The Integrative Studies On The Functional A-To-I Rna Editing Events In Human Cancers, Sijia Wu, Zhiwei Fan, Pora Kim, Liyu Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Adenosine-to-inosine (A-to-I) RNA editing, constituting nearly 90% of all RNA editing events in humans, has been reported to contribute to the tumorigenesis in diverse cancers. However, the comprehensive map for functional A-to-I RNA editing events in cancers is still insufficient. To fill this gap, we systematically and intensively analyzed multiple tumorigenic mechanisms of A-to-I RNA editing events in samples across 33 cancer types from The Cancer Genome Atlas. For individual candidate among ∼ 1,500,000 quantified RNA editing events, we performed diverse types of downstream functional annotations. Finally, we identified 24,236 potentially functional A-to-I RNA editing events, including the cases …

An Fbn1 Deep Intronic Variant Is Associated With Pseudoexon Formation And A Variable Marfan Phenotype In A Five Generation Family, Dong-Chuan Guo, Xueyan Duan, Kathleen Mimnagh, Alana C Cecchi, Isabella C Marin, Yang Yu, Walter V Velasco, Kwanghyuk Lee, Xue Zhu, David R Murdock, Suzanne M Leal, Marsha M Wheeler, Josh Smith, Michael J Bamshad, Dianna M Milewicz

Faculty, Staff and Student Publications

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to …

Integrative Analyses Of Genomic And Metabolomic Data Reveal Molecular Mechanisms Associated With Uterine Disease Traits In Transitioning Dairy Cattle, Leanna C. Sanchez, Mohammed Abo-Ismail, Daniel Peterson, Fernando Campos-Chillon

Master's Theses

The metritis complex (MC), characterizing post-partum uterine diseases in dairy cattle has negative implications on animal welfare, production efficiency, and the economic stability of the dairy industry. The studies in this thesis aimed to investigate the genetic architecture of the metritis complex and identify genomic regions and metabolites associated with the development of MC. Thereby enhancing our understanding of the biological pathways and molecular mechanisms involved in the pathophysiology of MC during the transition period in Jersey and Holstein dairy cattle.

Chapter 2 sheds light on the previous work done on MC. The goals of this review were to (1) …

Novel Isolation Method Reveals Sex-Specific Composition And Neurotoxicity Of Small Extracellular Vesicles In A Mouse Model Of Alzheimer’S Disease, Ahmed Elsherbini, Zhihui Zhu, Zainuddin Quadri, Simone M. Crivelli, Xiaojia Ren, Hemendra J. Vekaria, Priyanka Tripathi, Liping Zhang, Wenbo Zhi, Erhard Bieberich

Markey Cancer Center Faculty Publications

We developed a new method to isolate small extracellular vesicles (sEVs) from male and female wild-type and 5xFAD mouse brains to investigate the sex-specific functions of sEVs in Alzheimer’s disease (AD). A mass spectrometric analysis revealed that sEVs contained proteins critical for EV formation and Aβ. ExoView analysis showed that female mice contained more GFAP and Aβ-labeled sEVs, suggesting that a larger proportion of sEVs from the female brain is derived from astrocytes and/or more likely to bind to Aβ. Moreover, sEVs from female brains had more acid sphingomyelinase (ASM) and ceramide, an enzyme and its sphingolipid product important for …

Genome-Wide Association Study And Functional Characterization Identifies Candidate Genes For Insulin-Stimulated Glucose Uptake, Alice Williamson, Dougall M Norris, Xianyong Yin, K Alaine Broadaway, Anne H Moxley, Swarooparani Vadlamudi, Emma P Wilson, Anne U Jackson, Vasudha Ahuja, Mette K Andersen, Zorayr Arzumanyan, Lori L Bonnycastle, Stefan R Bornstein, Maxi P Bretschneider, Thomas A Buchanan, Yi-Cheng Chang, Lee-Ming Chuang, Ren-Hua Chung, Tine D Clausen, Peter Damm, Graciela E Delgado, Vanessa D De Mello, Josée Dupuis, Om P Dwivedi, Michael R Erdos, Lilian Fernandes Silva, Timothy M Frayling, Christian Gieger, Mark O Goodarzi, Xiuqing Guo, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Gad Hatem, Sandra Herrmann, Kurt Højlund, Katrin Horn, Willa A Hsueh, Yi-Jen Hung, Chii-Min Hwu, Anna Jonsson, Line L Kårhus, Marcus E Kleber, Peter Kovacs, Timo A Lakka, Marie Lauzon, I-Te Lee, Cecilia M Lindgren, Jaana Lindström, Allan Linneberg, Ching-Ti Liu, Jian'an Luan, Dina Mansour Aly, Elisabeth Mathiesen, Angela P Moissl, Andrew P Morris, Narisu Narisu, Nikolaos Perakakis, Annette Peters, Rashmi B Prasad, Roman N Rodionov, Kathryn Roll, Carsten F Rundsten, Chloé Sarnowski, Kai Savonen, Markus Scholz, Sapna Sharma, Sara E Stinson, Sufyan Suleman, Jingyi Tan, Kent D Taylor, Matti Uusitupa, Dorte Vistisen, Daniel R Witte, Romy Walther, Peitao Wu, Anny H Xiang, Björn Zethelius, Emma Ahlqvist, Richard N Bergman, Yii-Der Ida Chen, Francis S Collins, Tove Fall, Jose C Florez, Andreas Fritsche, Harald Grallert, Leif Groop, Torben Hansen, Heikki A Koistinen, Pirjo Komulainen, Markku Laakso, Lars Lind, Markus Loeffler, Winfried März, James B Meigs, Leslie J Raffel, Rainer Rauramaa, Jerome I Rotter, Peter E H Schwarz, Michael Stumvoll, Johan Sundström, Anke Tönjes, Tiinamaija Tuomi, Jaakko Tuomilehto, Robert Wagner, Inês Barroso, Mark Walker, Niels Grarup, Michael Boehnke, Nicholas J Wareham, Karen L Mohlke, Eleanor Wheeler, Stephen O'Rahilly, Daniel J Fazakerley, Claudia Langenberg

Faculty, Staff and Student Publications

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

Impact Of Cross-Ancestry Genetic Architecture On Gwass In Admixed Populations, Rachel Mester, Kangcheng Hou, Yi Ding, Gillian Meeks, Kathryn S Burch, Arjun Bhattacharya, Brenna M Henn, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust …

Bi-Allelic Variants In Hmgcr Cause An Autosomal-Recessive Progressive Limb-Girdle Muscular Dystrophy, Joel A Morales-Rosado, Tanya L Schwab, Sarah K Macklin-Mantia, A Reghan Foley, Filippo Pinto E Vairo, Davut Pehlivan, Sandra Donkervoort, Jill A Rosenfeld, Grace E Boyum, Ying Hu, Anh T Q Cong, Timothy E Lotze, Carrie A Mohila, Dimah Saade, Diana Bharucha-Goebel, Katherine R Chao, Christopher Grunseich, Christine C Bruels, Hannah R Littel, Elicia A Estrella, Lynn Pais, Peter B Kang, Michael T Zimmermann, James R Lupski, Brendan Lee, Matthew J Schellenberg, Karl J Clark, Klaas J Wierenga, Carsten G Bönnemann, Eric W Klee

Faculty, Staff and Students Publications

Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. …

Impact Of Race And Ethnicity On Presentation And Outcomes Of Patients Treated On Rhabdomyosarcoma Clinical Trials: A Report From The Children’S Oncology Group, Senna R Munnikhuysen, Princess A Ekpo, Wei Xue, Zhengya Gao, Philip J Lupo, Rajkumar Venkatramani, Christine M Heske

Faculty, Staff and Students Publications

BACKGROUND: Racial and ethnic disparities have been demonstrated in pediatric and adult cancers. However, there is no consensus on whether such disparities exist in the presentation, treatment, and outcome of patients with rhabdomyosarcoma (RMS).

METHODS: Patient information from the seven most recent RMS clinical trials was obtained from the Children's Oncology Group (COG). Chi-squared analyses were used to compare patient, tumor, and treatment characteristics across racial and ethnic groups. Pairwise analyses comparing Non-Hispanic Black (NHB) versus Non-Hispanic White (NHW) racial groups and Hispanic versus NHW ethnic groups were conducted for significant characteristics. Kaplan-Meier method and Wilcoxon signed-rank tests were performed …

Optimising Clinical Care Through Cdh1-Specific Germline Variant Curation: Improvement Of Clinical Assertions And Updated Curation Guidelines, Xi Luo, Jamie L Maciaszek, Bryony A Thompson, Huei San Leong, Katherine Dixon, Sónia Sousa, Michael Anderson, Maegan E Roberts, Kristy Lee, Amanda B Spurdle, Arjen R Mensenkamp, Terra Brannan, Carolina Pardo, Liying Zhang, Tina Pesaran, Sainan Wei, Grace-Ann Fasaye, Chimene Kesserwan, Brian H Shirts, Jeremy L Davis, Carla Oliveira, Sharon E Plon, Kasmintan A Schrader, Rachid Karam, Clingen Cdh1 Variant Curation Expert Panel

Faculty, Staff and Students Publications

BACKGROUND: Germline pathogenic variants in CDH1 are associated with increased risk for diffuse gastric cancer and lobular breast cancer. Risk-reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding upon these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.

METHODS:CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge …

Comprehensive Ecg Reference Intervals In C57bl/6n Substrains Provide A Generalizable Guide For Cardiac Electrophysiology Studies In Mice, Manuela A Oestereicher, Janine M Wotton, Shinya Ayabe, Ghina Bou About, Tsz Kwan Cheng, Jae-Hoon Choi, Dave Clary, Emily M Dew, Lahcen Elfertak, Alain Guimond, Hamed Haseli Mashhadi, Jason D Heaney, Lois Kelsey, Piia Keskivali-Bond, Federico Lopez Gomez, Susan Marschall, Michael Mcfarland, Hamid Meziane, Violeta Munoz Fuentes, Ki-Hoan Nam, Zuzana Nichtová, Dale Pimm, Lynette Bower, Jan Prochazka, Jan Rozman, Luis Santos, Michelle Stewart, Nobuhiko Tanaka, Christopher S Ward, Amelia M E Willett, Robert Wilson, Robert E Braun, Mary E Dickinson, Ann M Flenniken, Yann Herault, K C Kent Lloyd, Ann-Marie Mallon, Colin Mckerlie, Stephen A Murray, Lauryl M J Nutter, Radislav Sedlacek, Je Kyung Seong, Tania Sorg, Masaru Tamura, Sara Wells, Elida Schneltzer, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe De Angelis, Jacqueline K White, Nadine Spielmann

Faculty, Staff and Students Publications

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key …

Discordant Calls Across Genotype Discovery Approaches Elucidate Variants With Systematic Errors, Elizabeth G Atkinson, Mykyta Artomov, Alexander A Loboda, Heidi L Rehm, Daniel G Macarthur, Konrad J Karczewski, Benjamin M Neale, Mark J Daly

Faculty, Staff and Students Publications

Large-scale high-throughput sequencing data sets have been transformative for informing clinical variant interpretation and for use as reference panels for statistical and population genetic efforts. Although such resources are often treated as ground truth, we find that in widely used reference data sets such as the Genome Aggregation Database (gnomAD), some variants pass gold-standard filters, yet are systematically different in their genotype calls across genotype discovery approaches. The inclusion of such discordant sites in study designs involving multiple genotype discovery strategies could bias results and lead to false-positive hits in association studies owing to technological artifacts rather than a true …

The Voltage-Gated Sodium Channel In Drosophila, Para, Localizes To Dendrites As Well As Axons In Mechanosensitive Chordotonal Neurons, Thomas A Ravenscroft, Ashleigh Jacobs, Mingxue Gu, Daniel F Eberl, Hugo J Bellen

Faculty, Staff and Students Publications

The fruit fly Drosophila melanogaster has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CNs). Here, we show that, in addition to TRP channels, the sole voltage-gated sodium channel (NaV) in Drosophila, Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C …

Declining Autozygosity Over Time: An Exploration In Over 1 Million Individuals From Three Diverse Cohorts, Sarah M C Colbert, Frank R Wendt, Gita A Pathak, Drew A Helmer, Elizabeth R Hauser, Matthew C Keller, Renato Polimanti, Emma C Johnson

Faculty, Staff and Students Publications

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict F

Snv/Indel Hypermutator Phenotype In Biallelic Rad51c Variant: Fanconi Anemia, Roni Zemet, Haowei Du, Tomasz Gambin, James R Lupski, Pengfei Liu, Paweł Stankiewicz

Faculty, Staff and Students Publications

We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C. Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5 and 37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the hypothesis of a rare phenomenon of hypermutation. Eight-hundred-thirty apparent de novo SNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants. …

The Nanoflow Repository, Jessie E Arce, Joshua A Welsh, Sean Cook, John Tigges, Ionita Ghiran, Jennifer C Jones, Andrew Jackson, Matthew Roth, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Motivation

Extracellular particles (EPs) are the focus of a rapidly growing area of exploration due to the widespread interest in understanding their roles in health and disease. However, despite the general need for EP data sharing and established community standards for data reporting, no standard repository for EP flow cytometry data captures rigor and minimum reporting standards such as those defined by MIFlowCyt-EV (https://doi.org/10.1080/20013078.2020.1713526). We sought to address this unmet need by developing the NanoFlow Repository.

Results

We have developed The NanoFlow Repository to provide the first implementation of the MIFlowCyt-EV framework.

Availability and implementation

The NanoFlow Repository …

Delineating The Cellular Mechanisms Of Endoplasmic Reticulum-Retained Endoglin Mutants Causing Hereditary Hemorrhagic Telangiectasia Type 1, Nesrin Mohammed Gariballa

Dissertations

Endoglin, also known as cluster of differentiation 105 (CD105), is an auxiliary receptor in the TGFβ signaling pathway. It is predominantly expressed in endothelial cells as a component of the heterotetrameric receptor dimers comprising type I, type II receptors and the binding ligands. Mutations in ENG, the gene encoding endoglin, have been associated with Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), a rare autosomal dominant inherited disorder affecting about 1 in 5000-8000 individuals, which is generally characterized by vascular malformations. Secretory and many endomembrane proteins synthesized in the Endoplasmic Reticulum (ER) are subjected to a highly stringent protein folding and assembly …

Machine Learning And Network Embedding Methods For Gene Co-Expression Networks, Niloofar Aghaieabiane

Dissertations

High-throughput technologies such as DNA microarrays and RNA-seq are used to measure the expression levels of large numbers of genes simultaneously. To support the extraction of biological knowledge, individual gene expression levels are transformed into Gene Co-expression Networks (GCNs). GCNs are analyzed to discover gene modules. GCN construction and analysis is a well-studied topic, for nearly two decades. While new types of sequencing and the corresponding data are now available, the software package WGCNA and its most recent variants are still widely used, contributing to biological discovery.

The discovery of biologically significant modules of genes from raw expression data is …