Genetics and Genomics Commons^™

Morphometric And Genetic Analyses Of The Sheat Catfish Genus Ompok And Kryptopterus (Siluriidae) From The Mahakam River, East Kalimantan, Indone-Sia, Jusmaldi Jusmaldi, Rudhy Gustiano, Haryono Haryono, Rusdianto Rusdianto, Gema Wahyudewantoro, Syahroma Husni Nasution, Yulianto Yulianto, Muhammad Hunaina Fariduddin Aththar, Safar Dody, Amran Ronny Syam, Irin Iriana Kusmini, Yosmaniar Yosmaniar

Makara Journal of Science

Anthropogenic impacts within the watershed threaten the survival of sheat catfish. Therefore, species of the genera Ompok and Kryptopterus should be conserved and domesticated to ensure their long-term persistence. Moreover, the accurate documentation of the existence and taxonomic validity of Ompok and Kryptopterus species is crucial. Accordingly, this study aims to assess the species diversity of the genera Ompok and Kryptopterus in the Mahakam River, East Kalimantan, Indonesia. The study was conducted between June and December 2014, with an update in August 2024. Fish samples were collected from the upstream and middle reaches of the Mahakam River. A total of …

Evaluating Cancer Rates, Cancer Types, And Variant Hotspots Between Different Races And Ethnicities In Individuals With Li-Fraumeni Syndrome, Hillary Esplen

Dissertations and Theses (Open Access)

Li Fraumeni Syndrome (LFS) is a cancer predisposition syndrome that increases the risk for numerous cancer types in both children and adults. In the general population, incidence rates for various cancer types differ among races and ethnicities. Although a few germline TP53 pathogenic/likely pathogenic (P/LP) variants in those with LFS have been studied and associated with specific populations, such as the South and Southeast Brazil founder variant, p.Arg337His, there still lacks research on the variable expressivity of cancers within the LFS population based on specific variant, race and/or ethnicity. This study aims to describe the specific TP53 germline variants, the …

Meta-Ea: A Gene-Specific Combination Of Available Computational Tools For Predicting Missense Variant Effects, Panagiotis Katsonis, Olivier Lichtarge

Faculty, Staff and Students Publications

Computational methods for estimating missense variant impact suffer from inconsistent performance across genes, which poses a major challenge for their reliable use in clinical practice. While ensemble scores leverage multiple prediction methods to enhance consistency, the overrepresentation of certain genes in the training data can bias their outcomes. To address this critical limitation, we propose a gene-specific ensemble framework trained on reference computational annotations rather than on clinical or experimental data. Accordingly, we generate Meta-EA ensemble scores that achieve comparable performance to the top individual predicting method for each gene set. Incorporating the effects of splicing and the allele frequency …

The Cdk8 Kinase Module: A Novel Player In The Transcription Of Translation Initiation And Ribosomal Genes, Brittany Friedson, Stephen D Willis, Natalia Shcherbik, Alicia N Campbell, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Survival following stress is dependent upon reprogramming transcription and translation. Communication between these programs following stress is critical for adaptation but is not clearly understood. The Cdk8 kinase module (CKM) of the Mediator complex modulates the transcriptional response to various stresses. Its involvement in regulating translational machinery has yet to be elucidated, highlighting an existing gap in knowledge. Here, we report that the CKM positively regulates a subset of ribosomal protein (RP) and translation initiation factor (TIF)-encoding genes under physiological conditions in Saccharomyces cerevisiae. In mouse embryonic fibroblasts and HCT116 cells, the CKM regulates unique sets of RP and TIF …

Patterns Of Kinship And Sociality In North American River Otters, Whitney E. Vickers

Cal Poly Humboldt theses and projects

Previous studies of river otters (Lontra canadensis) in coastal Humboldt County, California have documented varying social group compositions over the last four decades. It has been assumed that otters travel between coastal wetland sites, but the extent of movement has been unknown. Socially, river otters have been observed alone, in small family groups that consisted of an otter mom and pup(s), in larger helper groups that consisted of an otter mom, pup(s), and at least one additional adult or juvenile (helpers), and in all-adult social groups. Until now it was unknown whether the composition of social groups was …

Weighted Family History Density Of Substance Use: Influence On Participant Substance Use Onset, Escalation, And Duration, Carleigh A. Litteral

Theses and Dissertations--Psychology

Substance use disorders impose a staggering toll on the United States (U.S.), straining healthcare systems, destabilizing communities, and profoundly impacting both individuals and families. Approximately one in six Americans aged 12 and older had a past-year substance use disorder in 2022 (Key Substance Use, 2022), and nearly one-third of adults experience a substance use disorder in their lifetime (Wu, 2010), contributing to an economic burden exceeding $400 billion annually (National Drug Threat Assessment, 2011). Family history of substance use disorders is a key predictor of vulnerability, with individuals who have affected relatives being 2–8 times more …

Using Multiplexed Functional Data To Reduce Variant Classification Inequities In Underrepresented Populations, Moez Dawood, Shawn Fayer, Sriram Pendyala, Mason Post, Divya Kalra, Karynne Patterson, Eric Venner, Lara A Muffley, Douglas M Fowler, Alan F Rubin, Jennifer E Posey, Sharon E Plon, James R Lupski, Richard A Gibbs, Lea M Starita, Carla Daniela Robles-Espinoza, Willow Coyote-Maestas, Irene Gallego Romero

Faculty, Staff and Students Publications

BACKGROUND: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS).

METHODS: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource's Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN.

RESULTS: Using two orthogonal statistical approaches, we …

Long-Read Sequencing Of An Advanced Cancer Cohort Resolves Rearrangements, Unravels Haplotypes, And Reveals Methylation Landscapes, Kieran O'Neill, Erin Pleasance, Jeremy Fan, Vahid Akbari, Glenn Chang, Katherine Dixon, Veronika Csizmok, Signe Maclennan, Vanessa Porter, Andrew Galbraith, Cameron J Grisdale, Luka Culibrk, John H Dupuis, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan Pandoh, Duane E Smailus, Dean Cheng, Tina Wong, Connor Frey, Yaoqing Shen, Eleanor Lewis, Luis F Paulin, Fritz J Sedlazeck, Jessica M T Nelson, Eric Chuah, Karen L Mungall, Richard A Moore, Robin Coope, Andrew J Mungall, Melissa K Mcconechy, Laura M Williamson, Kasmintan A Schrader, Stephen Yip, Marco A Marra, Janessa Laskin, Steven J M Jones

Faculty, Staff and Students Publications

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can …

Large-Scale Application Of Clingen-Insight Apc-Specific Acmg/Amp Variant Classification Criteria Leads To Substantial Reduction In Vus, Xiaoyu Yin, Marcy Richardson, Andreas Laner, Xuemei Shi, Elisabet Ognedal, Valeria Vasta, Thomas V O Hansen, Marta Pineda, Deborah Ritter, Johan De Dunnen, Emadeldin Hassanin, Wencong Lyman Lin, Ester Borras, Karl Krahn, Margareta Nordling, Alexandra Martins, Khalid Mahmood, Emily Nadeau, Victoria Beshay, Carli Tops, Maurizio Genuardi, Tina Pesaran, Ian M Frayling, Gabriel Capellá, Andrew Latchford, Sean V Tavtigian, Carlo Maj, Sharon E Plon, Marc S Greenblatt, Finlay A Macrae, Isabel Spier, Stefan Aretz

Faculty, Staff and Students Publications

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation …

Pelage Variation And Morphometrics Of Closely Related Callithrix Marmoset Species And Their Hybrids, Joanna Malukiewicz, Kerryn Warren, Vanner Boere, Illaira L C Bandeira, Nelson H A Curi, Fabio T Das Dores, Lilian S Fitorra, Haroldo R Furuya, Claudia S Igayara, Liliane Milanelo, Silvia B Moreira, Camila V Molina, Marcello S Nardi, Patricia A Nicola, Marcelo Passamani, Valeria S Pedro, Luiz C M Pereira, Bruno Petri, Alcides Pissinatti, Adriana Alves Quirino, Jeffrey Rogers, Carlos R Ruiz-Miranda, Daniel L Silva, Ita O Silva, Monique O M Silva, Juliana L Summa, Ticiana Zwarg, Rebecca R Ackermann

Faculty, Staff and Students Publications

BACKGROUND: Hybrids are expected to show greater phenotypic variation than their parental species, yet how hybrid phenotype expression varies with genetic distances in closely-related parental species remains surprisingly understudied. Here, we investigate pelage and morphometric trait variation in anthropogenic hybrids between four species of Brazilian Callithrix marmosets, a relatively recent primate radiation. Marmoset species are distinguishable by pelage phenotype and morphological specializations for eating tree exudates. In this work, we (1) describe qualitative phenotypic pelage differences between parental species and hybrids; (2) test whether significant quantitative differences exist between parental and hybrid morphometric phenotypes; and (3) determine which hybrid morphometic …

3d Chromatin Architecture, Brd4, And Mediator Have Distinct Roles In Regulating Genome-Wide Transcriptional Bursting And Gene Network, Pawel Trzaskoma, Seolkyoung Jung, Aleksandra Pękowska, Christopher H Bohrer, Xiang Wang, Faiza Naz, Stefania Dell'orso, Wendy D Dubois, Ana Olivera, Supriya V Vartak, Yongbing Zhao, Subhashree Nayak, Andrew Overmiller, Maria I Morasso, Vittorio Sartorelli, Daniel R Larson, Carson C Chow, Rafael Casellas, John J O'Shea

Faculty, Staff and Student Publications

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion …

A Harmonized Public Resource Of Deeply Sequenced Diverse Human Genomes, Zan Koenig, Mary T Yohannes, Lethukuthula L Nkambule, Xuefang Zhao, Julia K Goodrich, Heesu Ally Kim, Michael W Wilson, Grace Tiao, Stephanie P Hao, Nareh Sahakian, Katherine R Chao, Mark A Walker, Yunfei Lyu, Heidi L Rehm, Benjamin M Neale, Michael E Talkowski, Mark J Daly, Harrison Brand, Konrad J Karczewski, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

Underrepresented populations are often excluded from genomic studies owing in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high-quality set of 4094 whole genomes from 80 populations in the HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, …

Phenome-Wide Identification Of Therapeutic Genetic Targets, Leveraging Knowledge Graphs, Graph Neural Networks, And Uk Biobank Data, Lawrence Middleton, Ioannis Melas, Chirag Vasavda, Arwa Raies, Benedek Rozemberczki, Ryan S Dhindsa, Justin S Dhindsa, Blake Weido, Quanli Wang, Andrew R Harper, Gavin Edwards, Slavé Petrovski, Dimitrios Vitsios

Faculty, Staff and Students Publications

The ongoing expansion of human genomic datasets propels therapeutic target identification; however, extracting gene-disease associations from gene annotations remains challenging. Here, we introduce Mantis-ML 2.0, a framework integrating AstraZeneca's Biological Insights Knowledge Graph and numerous tabular datasets, to assess gene-disease probabilities throughout the phenome. We use graph neural networks, capturing the graph's holistic structure, and train them on hundreds of balanced datasets via a robust semi-supervised learning framework to provide gene-disease probabilities across the human exome. Mantis-ML 2.0 incorporates natural language processing to automate disease-relevant feature selection for thousands of diseases. The enhanced models demonstrate a 6.9% average classification power …

Patient Preferences For Ultrasound Soft Sign Disclosure With Prior Negative Cfdna Screening, Disha Patel

Dissertations and Theses (Open Access)

Soft signs are nonstructural fetal anomalies that can be identified by the second-trimester comprehensive ultrasound examination. In isolation, soft signs are insufficient to diagnose chromosome conditions but can adjust an individual's risk for aneuploidy, primarily Down syndrome. In the age of noninvasive cell-free DNA (cfDNA) prenatal screening, which exhibits superior sensitivity and specificity for aneuploidy compared to what can be provided by soft sign risk adjustment, the utility of these soft signs is arguably waning. Thus, this study aimed to establish patient preferences for whether and how soft signs are disclosed in pregnancy to inform recommendations for disclosure. A survey …

Matrin3 Mediates Differentiation Through Stabilizing Chromatin Loop-Domain Interactions And Yy1 Mediated Enhancer-Promoter Interactions, Tianxin Liu, Qian Zhu, Yan Kai, Trevor Bingham, Stacy Wang, Hye Ji Cha, Stuti Mehta, Thorsten M Schlaeger, Guo-Cheng Yuan, Stuart H Orkin

Faculty, Staff and Students Publications

Although emerging evidence indicates that alterations in proteins within nuclear compartments elicit changes in chromosomal architecture and differentiation, the underlying mechanisms are not well understood. Here we investigate the direct role of the abundant nuclear complex protein Matrin3 (Matr3) in chromatin architecture and development in the context of myogenesis. Using an acute targeted protein degradation platform (dTAG-Matr3), we reveal the dynamics of development-related chromatin reorganization. High-throughput chromosome conformation capture (Hi-C) experiments revealed substantial chromatin loop rearrangements soon after Matr3 depletion. Notably, YY1 binding was detected, accompanied by the emergence of novel YY1-mediated enhancer-promoter loops, which occurred concurrently with changes in …

Factors Associated With Blood Mercury Concentrations And Their Interactions With Three Glutathione S-Transferase Genes (Gstt1, Gstm1, And Gstp1): An Exposure Assessment Study Of Typically Developing Jamaican Children, Sheikh Farzana Zaman, Maureen Samms-Vaughan, Sepideh Saroukhani, Jan Bressler, Manouchehr Hessabi, Megan L Grove, Sydonnie Shakespeare Pellington, Katherine A Loveland, Mohammad H Rahbar

Faculty, Staff and Student Publications

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms.

METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general …

Creation Of A Digital Storage System For Genome Sequencing Metadata, Jacquelin W. Olexa

Undergraduate Theses, Professional Papers, and Capstone Artifacts

As the field of computational genomics continues to expand in both potential and application, it is now more imperative than ever to ensure that massive genetic sequencing datasets are properly stored in an accessible manner. This project sought to establish a practical, user-friendly, secure system for a genomics research lab (the Good Lab; thegoodlab.org) at the University of Montana. A MySQL database and connected web application was ruled the best configuration to maximize utility and accessibility for the lab’s researchers. Building the logical framework for the database, creating the server, and sourcing data occurred over several months. The dataset ranged …

Identifying New Cancer Genes Based On The Integration Of Annotated Gene Sets Via Hypergraph Neural Networks, Chao Deng, Hong-Dong Li, Li-Shen Zhang, Yiwei Liu, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

Motivation

Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited.

Results

Here, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of …

Hite: A Fast And Accurate Dynamic Boundary Adjustment Approach For Full-Length Transposable Element Detection And Annotation, Kang Hu, Peng Ning, Minghua Xu, You Zou, Jianye Chang, Xin Gao, Yaohang Li, Jue Ruan, Bin Hu, Jianxin Wang

Computer Science Faculty Publications

Recent advancements in genome assembly have greatly improved the prospects for comprehensive annotation of Transposable Elements (TEs). However, existing methods for TE annotation using genome assemblies suffer from limited accuracy and robustness, requiring extensive manual editing. In addition, the currently available gold-standard TE databases are not comprehensive, even for extensively studied species, highlighting the critical need for an automated TE detection method to supplement existing repositories. In this study, we introduce HiTE, a fast and accurate dynamic boundary adjustment approach designed to detect full-length TEs. The experimental results demonstrate that HiTE outperforms RepeatModeler2, the state-of-the-art tool, across various species. Furthermore, …

Life, The Genome And Everything, Susan M Rosenberg

Faculty, Staff and Students Publications

In this issue of the Journal of Bacteriology, N. J. Bonde, E. A. Wood, K. S. Myers, M. Place, J. L. Keck, and M. M. Cox (J Bacteriol 205:e00184-23, 2023, https://doi.org/10.1128/jb.00184-23) used an unbiased transposon-sequencing (Tn-seq) screen to identify proteins required for life when cells lose the RecG branched-DNA helicase (synthetic lethality). The proteins’ identities indicate pathways that prevent endogenous DNA damage, pathways that prevent its homology-directed repair (HDR) “strand-exchange” intermediates between sister chromosomes, and pathways that resolve those intermediates. All avoid intermediate pile-up, which blocks chromosome segregation, causing “death-by-recombination.” DNA damage is managed to regulate crucial but …

Complex Evolutionary History With Extensive Ancestral Gene Flow In An African Primate Radiation, Axel Jensen, Frances Swift, Dorien De Vries, Robin M D Beck, Lukas F K Kuderna, Sascha Knauf, Idrissa S Chuma, Julius D Keyyu, Andrew C Kitchener, Kyle Farh, Jeffrey Rogers, Tomas Marques-Bonet, Kate M Detwiler, Christian Roos, Katerina Guschanski

Faculty, Staff and Students Publications

Understanding the drivers of speciation is fundamental in evolutionary biology, and recent studies highlight hybridization as an important evolutionary force. Using whole-genome sequencing data from 22 species of guenons (tribe Cercopithecini), one of the world's largest primate radiations, we show that rampant gene flow characterizes their evolutionary history and identify ancient hybridization across deeply divergent lineages that differ in ecology, morphology, and karyotypes. Some hybridization events resulted in mitochondrial introgression between distant lineages, likely facilitated by cointrogression of coadapted nuclear variants. Although the genomic landscapes of introgression were largely lineage specific, we found that genes with immune functions were overrepresented …

Multi-Tissue Epigenetic Analysis Identifies Distinct Associations Underlying Insulin Resistance And Alzheimer's Disease At Cpt1a Locus, Chloé Sarnowski, Tianxiao Huan, Yiyi Ma, Roby Joehanes, Alexa Beiser, Charles S Decarli, Nancy L Heard-Costa, Daniel Levy, Honghuang Lin, Ching-Ti Liu, Chunyu Liu, James B Meigs, Claudia L Satizabal, Jose C Florez, Marie-France Hivert, Josée Dupuis, Philip L De Jager, David A Bennett, Sudha Seshadri, Alanna C Morrison

Faculty, Staff and Student Publications

BACKGROUND: Insulin resistance (IR) is a major risk factor for Alzheimer's disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.

METHODS: We conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified …

Further Refinement Of The Differentially Methylated Distant Lung-Specific Foxf1 Enhancer In A Neonate With Alveolar Capillary Dysplasia, Przemyslaw Szafranski, Rijutha P Garimella, Haresh Mani, Ryan Hartman, Gail Deutsch, Alan Silk, Alan Benheim, Paweł Stankiewicz

Faculty, Staff and Students Publications

Heterozygous SNVs or CNV deletions involving the FOXF1 gene, or its distant enhancer, are causative for 80-90% of cases of alveolar capillary dysplasia with misalignment of pulmonary veins. Recently, we proposed bimodal structure and parental functional dimorphism of the lung-specific FOXF1 enhancer, with Unit 1 having higher activity on the paternal chr16 and Unit 2 on the maternal chr16. Here, we describe a novel unusually sized pathogenic de novo copy-number variant deletion involving a portion of the FOXF1 enhancer on maternal chr16 that implies narrowing Unit 2 to an essential ~ 9-kb segment. Using a restrictase-based assay, we found that …

Epigenomic Signature Of Major Congenital Heart Defects In Newborns With Down Syndrome, Julia S Mouat, Shaobo Li, Swe Swe Myint, Benjamin I Laufer, Philip J Lupo, Jeremy M Schraw, John P Woodhouse, Adam J De Smith, Janine M Lasalle

Faculty, Staff and Students Publications

BACKGROUND: Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.

METHODS: We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the …

Mammalian Aging Driven By Transcription Going Awry, Brenna S Mccauley, Weiwei Dang

Faculty, Staff and Students Publications

The mechanisms that underlie increased cryptic transcription during senescence and aging have been poorly understood. Sen et al. recently identified cryptic transcription start sites (cTSSs) and chromatin state changes that may contribute to cTSS activation in mammals. Their results indicate that enhancer-promoter conversion may drive cryptic transcription in senescence.

Evolutionary Action-Machine Learning Model Identifies Candidate Genes Associated With Early-Onset Coronary Artery Disease, Dillon Shapiro, Kwanghyuk Lee, Jennifer Asmussen, Thomas Bourquard, Olivier Lichtarge

Faculty, Staff and Students Publications

Background Coronary artery disease is a primary cause of death around the world, with both genetic and environmental risk factors. Although genome-wide association studies have linked >100 unique loci to its genetic basis, these only explain a fraction of disease heritability. Methods and Results To find additional gene drivers of coronary artery disease, we applied machine learning to quantitative evolutionary information on the impact of coding variants in whole exomes from the Myocardial Infarction Genetics Consortium. Using ensemble-based supervised learning, the Evolutionary Action-Machine Learning framework ranked each gene's ability to classify case and control samples and identified 79 significant associations. …

The Diagnostic Odyssey Of Hypermobile Eds Patients: Diagnosis, Clinical Expectations, And Psychosocial Concerns, Madeline Alpar

Dissertations and Theses (Open Access)

Background: Ehlers-Danlos syndrome (EDS) is a highly variable, heritable connective tissue disorder. Hypermobile EDS (hEDS) is the most common subtype of EDS and has no identifiable underlying genetic etiology. Patients with clinical features of hEDS face a long diagnostic odyssey due to lack of genetic testing and wide clinical heterogeneity. Additionally, recent research has shown that genetic institutions limit evaluations for suspected hEDS, adding another barrier to care.

Methods: We developed an online patient survey to explore the diagnostic odyssey of hEDS for those who were diagnosed with or suspicious for hEDS. This survey included sections on demographics, diagnostic information …

Dna Methylation Analysis Is Used To Identify Novel Genetic Loci Associated With Circulating Fibrinogen Levels In Blood, Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L Mccartney, Alexander Teumer, Jenny Van Dongen, Marcus E Kleber, Dylan Aïssi, Brenton R Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R Brown, Ricardo Costeira, Eco J C De Geus, Graciela E Delgado, Dre'von A Dobson, Paul Elliott, Hans J Grabe, Xiuqing Guo, Sarah E Harris, Jennifer E Huffman, Sharon L R Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E Marioni, Matthias Nauck, Scott M Ratliff, Maria Sabater-Lleal, Tim D Spector, Pierre Suchon, Kent D Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L Wiggins, Gonneke Willemsen, Jordana T Bell, Dorret I Boomsma, Shelley A Cole, Simon R Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A Smith, Andrew D Johnson, Myriam Fornage, Nicholas L Smith, Alisa S Wolberg, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background:

Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.

Methods:

We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific …

Epigenetic Age Acceleration Among Survivors Of Pediatric Medulloblastoma And Primitive Neuroectodermal Tumor, Rachel D Harris, Melissa A Richard, Maria Monica J Gramatges, Kevin Wilhelm, Michael E Scheurer, Philip J Lupo, Austin L Brown

Faculty, Staff and Students Publications

Survivors of childhood central nervous system (CNS) tumors experience early-onset aging-related phenotypes. DNA methylation (DNAm) age is an emerging epigenetic biomarker of physiologic age and may be predictive of chronic health conditions in long-term survivors. This report describes the course of epigenetic age acceleration using post-diagnosis blood samples (median: 3.9 years post-diagnosis; range: 0.04–15.96) from 83 survivors of pediatric CNS tumors. Epigenetic age acceleration was detected in 72% of patients, with an average difference between chronologic and dnam age of 2.58 years (95% Ci: 1.75–3.41, p < 0.001). Time from diagnosis to sample collection correlated with the magnitude of epigenetic age acceleration.

A Weakly Structured Stem For Human Origins In Africa, Aaron P Ragsdale, Timothy D Weaver, Elizabeth G Atkinson, Eileen G Hoal, Marlo Möller, Brenna M Henn, Simon Gravel

Faculty, Staff and Students Publications

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated …