Medicine and Health Sciences Commons^™

Extrachromosomal Dna (Ecdna): An Origin Of Tumor Heterogeneity, Genomic Remodeling, And Drug Resistance., Lauren T Pecorino, Roel G W Verhaak, Anton Henssen, Paul S Mischel

Faculty Research 2022

The genome of cancer cells contains circular extrachromosomal DNA (ecDNA) elements not found in normal cells. Analysis of clinical samples reveal they are common in most cancers and their presence indicates poor prognosis. They often contain enhancers and driver oncogenes that are highly expressed. The circular ecDNA topology leads to an open chromatin conformation and generates new gene regulatory interactions, including with distal enhancers. The absence of centromeres leads to random distribution of ecDNAs during cell division and genes encoded on them are transmitted in a non-mendelian manner. ecDNA can integrate into and exit from chromosomal DNA. The numbers of …

Taxonomic Assessment Of Two Wild House Mouse Subspecies Using Whole-Genome Sequencing., Raman Akinyanju Lawal, Verity L Mathis, Mary Barter, Jeremy R. Charette, Alexis Garretson, Beth L Dumont

Faculty Research 2022

The house mouse species complex (Mus musculus) is comprised of three primary subspecies. A large number of secondary subspecies have also been suggested on the basis of divergent morphology and molecular variation at limited numbers of markers. While the phylogenetic relationships among the primary M. musculus subspecies are well-defined, relationships among secondary subspecies and between secondary and primary subspecies remain less clear. Here, we integrate de novo genome sequencing of museum-stored specimens of house mice from one secondary subspecies (M. m. bactrianus) and publicly available genome sequences of house mice previously characterized as M. m. helgolandicus, with whole genome sequences …

Return Of Non-Acmg Recommended Incidental Genetic Findings To Pediatric Patients: Considerations And Opportunities From Experiences In Genomic Sequencing, Kevin M Bowling, Michelle L Thompson, Melissa A Kelly, Sarah Scollon, Anne M Slavotinek, Bradford C Powell, Brian M Kirmse, Laura G Hendon, Kyle B Brothers, Bruce R Korf, Gregory M Cooper, John M Greally, Anna C E Hurst

2020-Current year OA Pubs

BACKGROUND: The uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations.

METHODS: The Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought …

Collective Genomic Segments With Differential Pleiotropic Patterns Between Cognitive Dimensions And Psychopathology, Max Lam, Chia-Yen Chen, W David Hill, Charley Xia, Ruoyu Tian, Daniel F Levey, Joel Gelernter, Murray B Stein, Alexander S Hatoum, Hailiang Huang, Anil K Malhotra, Heiko Runz, Tian Ge, Todd Lencz

2020-Current year OA Pubs

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call "meta-loci", showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant …

Adding Gene Transcripts Into Genomic Prediction Improves Accuracy And Reveals Sampling Time Dependence., Bruno C Perez, Marco C A M Bink, Karen L. Svenson, Gary Churchill, Mario P L Calus

Faculty Research 2022

Recent developments allowed generating multiple high-quality 'omics' data that could increase the predictive performance of genomic prediction for phenotypes and genetic merit in animals and plants. Here, we have assessed the performance of parametric and nonparametric models that leverage transcriptomics in genomic prediction for 13 complex traits recorded in 478 animals from an outbred mouse population. Parametric models were implemented using the best linear unbiased prediction, while nonparametric models were implemented using the gradient boosting machine algorithm. We also propose a new model named GTCBLUP that aims to remove between-omics-layer covariance from predictors, whereas its counterpart GTBLUP does not do …

Comparative Genomics Of Streptococcus Oralis Identifies Large Scale Homologous Recombination And A Genetic Variant Associated With Infection, Luke R. Joyce, Madison A. Youngblom, Harshini Cormaty, Evelyn Gartstein

Faculty and Student Publications

The viridans group streptococci (VGS) are a large consortium of commensal streptococci that colonize the human body. Many species within this group are opportunistic pathogens causing bacteremia and infective endocarditis (IE), yet little is known about why some strains cause invasive disease. Identification of virulence determinants is complicated by the difficulty of distinguishing between the closely related species of this group. Here, we analyzed genomic data from VGS that were isolated from blood cultures in patients with invasive infections and oral swabs of healthy volunteers and then determined the best-performing methods for species identification. Using whole-genome sequence data, we characterized …

Emergence Of Compensatory Mutations Reveals The Importance Of Electrostatic Interactions Between Hiv-1 Integrase And Genomic Rna, Christian Shema Mugisha, Tung Dinh, Abhishek Kumar, Kasyap Tenneti, Jenna E Eschbach, Keanu Davis, Robert Gifford, Mamuka Kvaratskhelia, Sebla B Kutluay

2020-Current year OA Pubs

HIV-1 integrase (IN) has a noncatalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Class II IN substitutions inhibit IN-gRNA binding and result in the formation of virions with aberrant morphologies marked by mislocalization of the gRNA between the capsid lattice and the lipid envelope. These viruses are noninfectious due to a block at an early reverse transcription stage in target cells. HIV-1 IN utilizes basic residues within its C-terminal domain (CTD) to bind to the gRNA; however, the molecular nature of how these residues mediate gRNA binding and whether other regions of IN are …

Pooled Image-Base Screening Of Mitochondria With Microraft Isolation Distinguishes Pathogenic Mitofusin 2 Mutations, Alex L Yenkin, John C Bramley, Colin L Kremitzki, Jason E Waligorski, Mariel J Liebeskind, Xinyuan E Xu, Vinay D Chandrasekaran, Maria A Vakaki, Graham W Bachman, Robi D Mitra, Jeffrey D Milbrandt, William J Buchser

2020-Current year OA Pubs

Most human genetic variation is classified as variants of uncertain significance. While advances in genome editing have allowed innovation in pooled screening platforms, many screens deal with relatively simple readouts (viability, fluorescence) and cannot identify the complex cellular phenotypes that underlie most human diseases. In this paper, we present a generalizable functional genomics platform that combines high-content imaging, machine learning, and microraft isolation in a method termed "Raft-Seq". We highlight the efficacy of our platform by showing its ability to distinguish pathogenic point mutations of the mitochondrial regulator Mitofusin 2, even when the cellular phenotype is subtle. We also show …

Discovery Of A Novel Genomic Alteration That Renders Leukemic Cells Resistant To Cd19-Targeted Immunotherapies, Armin Ghobadi, Jack H Landmann, Alun Carter, Matthew L Cooper, Mehmet Emrah Selli, Jufang Chang, Christopher A Miller, Francesca Ferraro, David Y Chen, Amanda M Smith, Taylor A Lavalle, Eric J Duncavage, Nathan Singh, Et Al.

2020-Current year OA Pubs

No abstract provided.

Semi-Automated Assembly Of High-Quality Diploid Human Reference Genomes, Erich D Jarvis, Sarah Cody, Robert S Fulton, Lucinda L Fulton, Daofeng Li, Tina Lindsay, Nathan O Stitziel, Ting Wang, Et Al.

2020-Current year OA Pubs

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society^1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals^3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome⁵. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a …

A Quantitative Metric Of Pioneer Activity Reveals That Hnf4a Has Stronger In Vivo Pioneer Activity Than Foxa1, Jeffrey L Hansen, Barak A Cohen

2020-Current year OA Pubs

BACKGROUND: We and others have suggested that pioneer activity - a transcription factor's (TF's) ability to bind and open inaccessible loci - is not a qualitative trait limited to a select class of pioneer TFs. We hypothesize that most TFs display pioneering activity that depends on the TF concentration and the motif content at their target loci.

RESULTS: Here, we present a quantitative in vivo measure of pioneer activity that captures the relative difference in a TF's ability to bind accessible versus inaccessible DNA. The metric is based on experiments that use CUT&Tag to measure the binding of doxycycline-inducible TFs. …

Genomic Data Mining Reveals Abundant Uncharacterized Transporters In Coccidioides Immitis And Coccidioides Posadasii, Hong Cai, Hao Zhang, Daniel H. Guo, Yufeng Wang, Jianying Gu

Publications and Research

Coccidioides immitis and Coccidioides posadasii are causative agents of coccidioidomycosis, commonly known as Valley Fever. The increasing Valley Fever cases in the past decades, the expansion of endemic regions, and the rising azole drug-resistant strains have underscored an urgent need for a better understanding of Coccidioides biology and new antifungal strategies. Transporters play essential roles in pathogen survival, growth, infection, and adaptation, and are considered as potential drug targets. However, the composition and roles of transport machinery in Coccidioides remain largely unknown. In this study, genomic data mining revealed an abundant, uncharacterized repertoire of transporters in Coccidioides genomes. The catalog …

Functional Genomics Of Complex Cancer Genomes., Francesca Menghi, Edison Liu

Faculty Research 2022

Cancer functional genomics is the study of how genetic, epigenetic, and transcriptional alterations affect cancer phenotypes, such as growth and therapeutic response. Here, we comment on how, taking advantage of next generation sequencing, functional genomics, often combined with systems biology approaches, has revealed novel cancer vulnerabilities beyond the original paradigm of one gene-one phenotype.

A Standardized Nomenclature For Mammalian Histone Genes., Ruth L Seal, Paul Denny, Elspeth A Bruford, Anna K Gribkova, David Landsman, William F Marzluff, Monica Mcandrews, Anna R Panchenko, Alexey K Shaytan, Paul B Talbert

Faculty Research 2022

Histones have a long history of research in a wide range of species, leaving a legacy of complex nomenclature in the literature. Community-led discussions at the EMBO Workshop on Histone Variants in 2011 resulted in agreement amongst experts on a revised systematic protein nomenclature for histones, which is based on a combination of phylogenetic classification and historical symbol usage. Human and mouse histone gene symbols previously followed a genome-centric system that was not applicable across all vertebrate species and did not reflect the systematic histone protein nomenclature. This prompted a collaboration between histone experts, the Human Genome Organization (HUGO) Gene …

Phenotype-Driven Approaches To Enhance Variant Prioritization And Diagnosis Of Rare Disease., Julius O B Jacobsen, Catherine Kelly, Valentina Cipriani, Genomics England Research Consortium, Christopher J Mungall, Justin Reese, Daniel Danis, Peter N Robinson, Damian Smedley

Faculty Research 2022

Rare disease diagnostics and disease gene discovery have been revolutionized by whole-exome and genome sequencing but identifying the causative variant(s) from the millions in each individual remains challenging. The use of deep phenotyping of patients and reference genotype-phenotype knowledge, alongside variant data such as allele frequency, segregation, and predicted pathogenicity, has proved an effective strategy to tackle this issue. Here we review the numerous tools that have been developed to automate this approach and demonstrate the power of such an approach on several thousand diagnosed cases from the 100,000 Genomes Project. Finally, we discuss the challenges that need to be …

The University Of Pennsylvania Glioblastoma (Upenn-Gbm) Cohort: Advanced Mri, Clinical, Genomics, & Radiomics, Spyridon Bakas, Aristeidis Sotiras, Sung Min Ha, Et Al

2020-Current year OA Pubs

Glioblastoma is the most common aggressive adult brain tumor. Numerous studies have reported results from either private institutional data or publicly available datasets. However, current public datasets are limited in terms of: a) number of subjects, b) lack of consistent acquisition protocol, c) data quality, or d) accompanying clinical, demographic, and molecular information. Toward alleviating these limitations, we contribute the "University of Pennsylvania Glioblastoma Imaging, Genomics, and Radiomics" (UPenn-GBM) dataset, which describes the currently largest publicly available comprehensive collection of 630 patients diagnosed with de novo glioblastoma. The UPenn-GBM dataset includes (a) advanced multi-parametric magnetic resonance imaging scans acquired during …

A Research Agenda To Support The Development And Implementation Of Genomics-Based Clinical Informatics Tools And Resources., Ken Wiley, Laura Findley, Madison Goldrich, Tejinder K Rakhra-Burris, Ana Stevens, Pamela Williams, Carol J Bult, Rex Chisholm, Patricia Deverka, Geoffrey S Ginsburg, Eric D Green, Gail Jarvik, George A Mensah, Erin Ramos, Mary V Relling, Dan M Roden, Robb Rowley, Gil Alterovitz, Samuel Aronson, Lisa Bastarache, James J Cimino, Erin L Crowgey, Guilherme Del Fiol, Robert R Freimuth, Mark A Hoffman, Janina Jeff, Kevin Johnson, Kensaku Kawamoto, Subha Madhavan, Eneida A Mendonca, Lucila Ohno-Machado, Siddharth Pratap, Casey Overby Taylor, Marylyn D Ritchie, Nephi Walton, Chunhua Weng, Teresa Zayas-Cabán, Teri A Manolio, Marc S Williams

Faculty Research 2022

OBJECTIVE: The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled "Developing a Clinical Genomic Informatics Research Agenda". The meeting's goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings.

MATERIALS AND METHODS: Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …

The Rd-Connect Genome-Phenome Analysis Platform: Accelerating Diagnosis, Research, And Gene Discovery For Rare Diseases., Steven Laurie, Davide Piscia, Leslie Matalonga, Alberto Corvó, Marcos Fernández-Callejo, Carles Garcia-Linares, Carles Hernandez-Ferrer, Cristina Luengo, Inés Martínez, Anastasios Papakonstantinou, Daniel Picó-Amador, Joan Protasio, Rachel Thompson, Raul Tonda, Mònica Bayés, Gemma Bullich, Jordi Camps-Puchadas, Ida Paramonov, Jean-Rémi Trotta, Angel Alonso, Marcella Attimonelli, Christophe Béroud, Virginie Bros-Facer, Orion J Buske, Andrés Cañada-Pallarés, José M Fernández, Mats G Hansson, Rita Horvath, Julius O B Jacobsen, Rajaram Kaliyaperumal, Séverine Lair-Préterre, Luana Licata, Pedro Lopes, Estrella López-Martín, Deborah Mascalzoni, Lucia Monaco, Luis A Pérez-Jurado, Manuel Posada De La Paz, Jordi Rambla, Ana Rath, Olaf Riess, Peter N Robinson, David Salgado, Damian Smedley, Dylan Spalding, Peter A C 'T Hoen, Ana Töpf, Irina Zaharieva, Holm Graessner, Ivo G Gut, Hanns Lochmüller, Sergi Beltran

Faculty Research 2022

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is …

Integrated Multilayer Omics Reveals The Genomic, Proteomic, And Metabolic Influences Of Histidyl Dipeptides On The Heart, Keqiang Yan, Zhanlong Mei, Jingjing Zhao, Md Aminul Islam Prodhan, Detlef Obal, Kartik Katragadda, Benjamin Doelling, David Hoetker, Dheeraj Kumar Posa

Internal Medicine, East Africa

Background: Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking.

Methods and Results: To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in …

Gene-Lifestyle Interactions In The Genomics Of Human Complex Traits, Vincent Laville, Yun J Sung, Karen Schwander, Mary F Feitosa, Aldi T Kraja, Mike Province, C Charles Gu, D C Rao, Et Al

2020-Current year OA Pubs

The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that …

Genomic And Transcriptomic Somatic Alterations Of Hepatocellular Carcinoma In Non-Cirrhotic Livers, Zachary L Skidmore, Jason Kunisaki, Yiing Lin, Kelsy C Cotto, Erica K Barnell, Jasreet Hundal, Kilannin Krysiak, Vincent Magrini, Lee Trani, Jason R Walker, Robert Fulton, Elizabeth M Brunt, Christopher A Miller, Richard K Wilson, Elaine R Mardis, Malachi Griffith, William Chapman, Obi L Griffith

2020-Current year OA Pubs

No abstract provided.

Recurrent Inversion Polymorphisms In Humans Associate With Genetic Instability And Genomic Disorders., David Porubsky, Wolfram Höps, Hufsah Ashraf, Pinghsun Hsieh, Bernardo Rodriguez-Martin, Feyza Yilmaz, Jana Ebler, Pille Hallast, Flavia Angela Maria Maggiolini, William T Harvey, Barbara Henning, Peter A Audano, David S Gordon, Peter Ebert, Patrick Hasenfeld, Eva Benito, Qihui Zhu, Charles Lee, Francesca Antonacci, Matthias Steinrücken, Christine R Beck, Ashley D Sanders, Tobias Marschall, Evan E Eichler, Jan O Korbel

Faculty Research 2022

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversionsretrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 10

Combining Genomic And Epidemiological Data To Compare The Transmissibility Of Sars-Cov-2 Variants Alpha And Iota., Mary E Petrone, Jessica E Rothman, Mallery I Breban, Isabel M Ott, Alexis Russell, Erica Lasek-Nesselquist, Hamada Badr, Kevin Kelly, Gregory Omerza, Nicholas Renzette, Anne E Watkins, Chaney C Kalinich, Tara Alpert, Anderson F Brito, Rebecca Earnest, Irina R Tikhonova, Christopher Castaldi, John P Kelly, Matthew Shudt, Jonathan Plitnick, Erasmus Schneider, Steven Murphy, Caleb Neal, Eva Laszlo, Ahmad Altajar, Claire Pearson, Anthony Muyombwe, Randy Downing, Jafar Razeq, Linda Niccolai, Madeline S Wilson, Margaret L Anderson, Jianhui Wang, Chen Liu, Pei Hui, Shrikant Mane, Bradford P Taylor, William P Hanage, Marie L Landry, David R Peaper, Kaya Bilguvar, Joseph R Fauver, Chantal B F Vogels, Lauren M Gardner, Virginia E Pitzer, Kirsten St George, Mark D Adams, Nathan D Grubaugh

Faculty Research 2022

SARS-CoV-2 variants shaped the second year of the COVID-19 pandemic and the discourse around effective control measures. Evaluating the threat posed by a new variant is essential for adapting response efforts when community transmission is detected. In this study, we compare the dynamics of two variants, Alpha and Iota, by integrating genomic surveillance data to estimate the effective reproduction number (R_t) of the variants. We use Connecticut, United States, in which Alpha and Iota co-circulated in 2021. We find that the R_t of these variants were up to 50% larger than that of other variants. We then …

The Heritage Family Study: A Review Of The Effects Of Exercise Training On Cardiometabolic Health, With Insights Into Molecular Transducers, Mark A Sarzynski, Treva K Rice, D C Rao, Et Al

2020-Current year OA Pubs

The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and …

Svanna: Efficient And Accurate Pathogenicity Prediction Of Coding And Regulatory Structural Variants In Long-Read Genome Sequencing., Daniel Danis, Julius O B Jacobsen, Parithi Balachandran, Qihui Zhu, Feyza Yilmaz, Justin Reese, Matthias Haimel, Gholson J Lyon, Ingo Helbig, Christopher J Mungall, Christine R Beck, Charles Lee, Damian Smedley, Peter N Robinson

Faculty Research 2022

Structural variants (SVs) are implicated in the etiology of Mendelian diseases but have been systematically underascertained owing to sequencing technology limitations. Long-read sequencing enables comprehensive detection of SVs, but approaches for prioritization of candidate SVs are needed. Structural variant Annotation and analysis (SvAnna) assesses all classes of SVs and their intersection with transcripts and regulatory sequences, relating predicted effects on gene function with clinical phenotype data. SvAnna places 87% of deleterious SVs in the top ten ranks. The interpretable prioritizations offered by SvAnna will facilitate the widespread adoption of long-read sequencing in diagnostic genomics. SvAnna is available at https://github.com/TheJacksonLaboratory/SvAnn a …

Crispr-Mediated Multiplexed Live Cell Imaging Of Nonrepetitive Genomic Loci With One Guide Rna Per Locus., Patricia A Clow, Menghan Du, Nathaniel L. Jillette, Aziz Taghbalout, Jacqueline J Zhu, Albert Cheng

Faculty Research 2022

Three-dimensional (3D) structures of the genome are dynamic, heterogeneous and functionally important. Live cell imaging has become the leading method for chromatin dynamics tracking. However, existing CRISPR- and TALE-based genomic labeling techniques have been hampered by laborious protocols and are ineffective in labeling non-repetitive sequences. Here, we report a versatile CRISPR/Casilio-based imaging method that allows for a nonrepetitive genomic locus to be labeled using one guide RNA. We construct Casilio dual-color probes to visualize the dynamic interactions of DNA elements in single live cells in the presence or absence of the cohesin subunit RAD21. Using a three-color palette, we track …

Prediction Performance Of Linear Models And Gradient Boosting Machine On Complex Phenotypes In Outbred Mice., Bruno C Perez, Marco C A M Bink, Karen L. Svenson, Gary Churchill, Mario P L Calus

Faculty Research 2022

We compared the performance of linear (GBLUP, BayesB, and elastic net) methods to a nonparametric tree-based ensemble (gradient boosting machine) method for genomic prediction of complex traits in mice. The dataset used contained genotypes for 50,112 SNP markers and phenotypes for 835 animals from 6 generations. Traits analyzed were bone mineral density, body weight at 10, 15, and 20 weeks, fat percentage, circulating cholesterol, glucose, insulin, triglycerides, and urine creatinine. The youngest generation was used as a validation subset, and predictions were based on all older generations. Model performance was evaluated by comparing predictions for animals in the validation subset …

Centers For Mendelian Genomics: A Decade Of Facilitating Gene Discovery, Samantha M Baxter, Jennifer E Posey, Nicole J Lake, Nara Sobreira, Jessica X Chong, Steven Buyske, Elizabeth E Blue, Lisa H Chadwick, Zeynep H Coban-Akdemir, Kimberly F Doheny, Colleen P Davis, Monkol Lek, Christopher Wellington, Shalini N Jhangiani, Mark Gerstein, Richard A Gibbs, Richard P Lifton, Daniel G Macarthur, Tara C Matise, James R Lupski, David Valle, Michael J Bamshad, Ada Hamosh, Shrikant Mane, Deborah A Nickerson, Heidi L Rehm, Anne O'Donnell-Luria

Journal Articles

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration.

METHODS: Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution.

RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships …

Parent-Of-Origin Effects Propagate Through Networks To Shape Metabolic Traits, Juan F Macias-Velasco, Celine L St Pierre, Jessica P Wayhart, Li Yin, Larry Spears, Mario A Miranda, Caryn Carson, Katsuhiko Funai, James M Cheverud, Clay F Semenkovich, Heather A Lawson

2020-Current year OA Pubs

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F