Genetics and Genomics Commons^™

Multi-Ancestry Polygenic Risk Scores For The Prediction Of Type 2 Diabetes And Complications In Diverse Ancestries, Alicia Huerta-Chagoya, Joohyun Kim, Ravi Mandla, Yingchang Lu, Ken Suzuki, Lauren E. Petty, Hong Kiat Ng, Jaewon Choi, Simon Lee, John Blangero

Human Genetics Publications

Background: Polygenic risk scores (PRSs) improve prediction of the development of type 2 diabetes over the use of clinical risk factors alone; however, they perform poorly in populations of non-European ancestry, limiting their global clinical utility. We aimed to deliver comprehensive and rigorously tested multi-ancestry PRSs for prediction in type 2 diabetes.

Methods: We conducted meta-analyses using data from type 2 diabetes genome-wide association studies (GWAS) across cohorts from five major global ancestries: European, African or African American, Admixed American, South Asian, and East Asian. We used summary statistics from the GWAS to construct single-ancestry PRSs (using the continuous-shrinkage PRS-CS …

Deconstructing Systemic Sclerosis Heterogeneity: From Patient Subtypes To Pathogenic Fibroblasts, Rezvan Parvizi

Dartmouth College Ph.D Dissertations

This thesis advances heterogeneity as the central barrier both to interpreting therapeutic response and to identifying the molecular regulators that drive fibrosis in systemic sclerosis (SSc). In SSc, heterogeneity is manifest at every level at which the disease can be measured: clinically, in the variable extent of skin and organ involvement; molecularly, in the distinct gene-expression programs that distinguish otherwise comparable patients; and cellularly, in the diverse fibroblast populations from which the fibrotic signal ultimately arises.

Leveraging longitudinal skin transcriptomics from a large cohort treated with mycophenolate mofetil (MMF), the first study demonstrates that intrinsic molecular subtypes are dynamic rather …

Crispr/Cas9-Based Genome Editing: Understanding Differences In Dna Repair Pathways, Profiles, And Outcomes, Samuel Effah, Shirley Barrera, Nahia Urturi Ortiz, Will Dampier, Michael Nonnemacher, Brian Wigdahl

Kimmel Cancer Center Faculty Papers

Over a decade of advances in Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9)-based technologies have culminated in the first-ever FDA-approved CRISPR/Cas-based therapy. Aside from this approved therapy for sickle cell anemia, several CRISPR/Cas-based therapies are currently under development or testing for a range of chronic diseases, including viral diseases like human immunodeficiency virus type 1 (HIV-1) infection, genetic diseases like familial hypercholesterolemia, and cancer. The success of these therapies hinges on the effective delivery of CRISPR/Cas9 components to target regions, efficient Cas endonuclease editing, repair profiles generated, and their resulting outcomes. Here, we discuss the …

Mobile Genetic Elements Shape Microbial Diversity And Functions In Thawing Permafrost Soils, Jiarong Guo, Samuel T. N. Aroney, Guillermo Domínguez-Huerta, Derek Smith, Dean Vik, Carlos Owusu-Ansah, Akbar Adjie Pratama, Sergei Solonenko, Funing Tian, Cristina Howard-Varona, Zhi-Ping Zhong, Aminata Fofana, Garrett J. Smith, Suzanne B. Hodgkins, Dylan Cronin, Isogenie Field Teams 2010–2017, 2019, Emerge Coordinators, Ben J. Woodcroft, Gene W. Tyson, Virginia I. Rich, Matthew B. Sullivan, Simon Roux, Sarah C. Bagby, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Ecosystems are shaped by communities of microorganisms whose niches and impacts depend on functional profiles influenced by gene gains and losses. Culture-based experiments demonstrate that mobile genetic elements (MGEs) can mediate gene flux, but quantitative understanding of these dynamics in natural systems remains limited. Here we develop and apply a systematic, meta-omic framework to investigate MGEs in a complex natural system using an 8-year soil time series collected at Stordalen Mire, in Sweden’s thawing permafrost margin. In this climate-critical peatland, we identify ~2.1 million MGE recombinases across 89 microbial phyla and assess ecological distributions, affected functions, past mobility and current …

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 …

Regional, Functional And Transcriptomic Decoding Of Multidimensional Brain Structure Alterations In Obsessive-Compulsive Disorder, Leonardo Cardoso Saraiva, João Ricardo Sato, Isaac Sebenius, Nadza Dzinalija, Carla Del Río-Torné, Fábio Godinho, Antonio C. Lopes, Thomas V. Fernandez, Monicke O. Lima, Anderson M. Winkler

Human Genetics Publications

Studies of brain morphology in mental illness often focus on a few neuroimaging phenotypes. Here we present a comprehensive morphological characterization in obsessive-compulsive disorder (OCD) in a large sample (2255 OCD, 2264 controls) using nine cortical and four subcortical phenotypes, including several not previously examined in OCD, among them a subcortical structural similarity network phenotype developed here. Spatially distinct regional alterations emerged across structural phenotypes: cortical curvature alterations in default mode and frontoparietal networks, increased structural similarity network node degree in sensorimotor regions, widespread volume reductions associated with medication use, and localized subcortical shape alterations. In brain-behavior predictive models, curvature …

Advocating For A Care-Based Ethic: Stories Of Pregnancy And Birth From Caregivers Of Children With Down Syndrome, Lydia Ocasio-Stoutenburg, Nayma Sultana Mim

Developmental Disabilities Network Journal

Down syndrome (DS) impacts about 1 in every 640 childbirths in the United States. While quality of life has improved for people with DS, systemic inequities and deficit-based perceptions have persisted throughout history, with material impacts on people with DS and their caregivers. Researchers have documented how caregivers of children with DS have had negative experiences with healthcare providers and genetic counselors, whose biased views about DS translate into subtle and overt pressures. Few studies explicitly focus on the experiences of Caregivers of Color, multilingual families, as well as families with varying economic experiences who have children with DS. This …

Quantitative Genetic Analysis Of Baboon Facial Variation Challenges A Classic Papionin Trait, A. Thiebaut, C. C. Roseman, Michael Mahaney, Leslea J. Hlusko

Human Genetics Publications

The Linnaean family of monkeys that includes baboons, macaques, and mandrills (among others) is notably characterized by large, extended muzzles that vary in lateral nasal dorsum profile. In paleontological studies, this variation is referred to as the anteorbital drop (AOD). Here, we first devise a method to quantify this phylogenetic character. We then employ quantitative genetic analyses using a MCMCglmm model of facial variation in a captive, pedigreed baboon colony (n = 934), including admixed individuals derived from at least two Papio species, from the Southwest National Primate Research Center to assess the quantitative variation of the AOD, its …

Enhancer Rna Transcription Near Segmentation Gene Enhancers Can Be Analyzed In Situ Using Fish, Christine Mau, Benjamin Schmid, Ezzat El-Sherif

School of Integrative Biological & Chemical Sciences Faculty Publications

Enhancer RNAs (eRNAs) are non-coding transcripts produced at enhancer regions, which appear to be involved in transcriptional regulation. Up to date, these have been primarily investigated using labor- and cost-intensive genomic techniques. However, the precise mechanisms by which eRNA transcription or eRNA transcripts themselves mediate transcriptional regulation remain unclear. Here, we present a novel experimental approach that allows us to analyze characteristics of eRNA transcription in fixed and live whole Drosophila melanogaster embryos. We employ the anterior–posterior patterning genes as a model system to investigate the dynamics of eRNA expression, utilizing an imaging-based approach. We combined high-sensitivity fluorescence in situ …

Interview With Orca Winner John Hibbing, Political Science; How Political Attitudes Correlate With Physiological Traits, Mark A. Griep, John Hibbing

UNL ORCA Interview Series

Dr. John Hibbing was awarded the ORCA in 1993. John was born in 1953 in Paullina, Iowa. He earned a bachelor's in secondary education from Dana College in Blair, Nebraska, but then realized that teaching high school wasn't for him. Instead, he attended the University of Iowa, where he earned a master's and doctorate in political science. In 1981, he joined the University of Nebraska-Lincoln as an assistant professor of political science and rose quickly through the ranks. Initially, he studied the reasons that members of the U.S. Congress retire. This led to a longer-term collaboration with Kevin Smith and …

Investigating The Role Of Centromere Deletion In Chromosome Segregation, Azait Imtiaz

ETDs from 2020-2029

Centromeres are critical genomic regions responsible for ensuring accurate chromosome segregation during cell division. Disruptions in the structural or functional integrity of centromeric DNA could impair kinetochore assembly, leading to chromosome missegregation and chromosomal instability (CIN), a hallmark of various human diseases, including systemic sclerosis (SSc). This study investigated the contribution of centromeric DNA damage and deletion to CIN and explored potential pathogenic mechanisms relevant to SSc. We utilized hTERT-immortalized fibroblast cell lines (CHON-002 and BJ-5ta) to implement two complementary approaches: (i) treatment with bleomycin, a chemotherapeutic agent known to induce DNA double-strand breaks (DSBs), and (ii) targeted deletion of …

Elucidating The Function Of Yedk In Response To Dna Damage, Hank Munro

University Honors Theses

Apurinic/Apyrimidinic (AP) sites are one of the most prevalent forms of DNA damage. These lesions arise spontaneously or during base excision repair of modified DNA bases and are potentially mutagenic in both mammalian and bacterial cells. 5-hydroxymethylcytosine binding, ES cell specific (HMCES), a protein found in eukaryotic cells, has been shown to form a stable DNA-protein crosslink with AP sites in single stranded DNA and to reduce the number of AP sites occurring either spontaneously or after alkylative DNA damage, resulting in increased genome stability. YedK, the Escherichia coli ortholog of HMCES exhibits some of the same biochemical properties as …

Gene × Sex Interactions On Cognition In The Philadelphia Neurodevelopmental Cohort, Josephine Mollon, Emma M. Knowles, Samuel R. Mathias, Amanda Rodrigue, Ruben C. Gur, Juan M. Peralta, Daniel J. Weiner, Elise B. Robinson, Armin Raznahan, Raquel E. Gur, John Blangero, Laura Almasy, David C. Glahn

School of Medicine Publications

Background: Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences.

Methods: Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic factors (i.e., Gene × Sex interactions) underlying cognitive ability. Participants completed …

Disease-Causing Mfn2 Mutants Impair Mitochondrial Fission Dynamics By Distinct Drp1 Dysregulation, Daniel Lagos, Pamela R. De Santiago, Nicolás Pérez-Bravo, Benjamín Cartes-Saavedra, Josefa Vial-Brizzi, Diego Troncoso-Chandía, Oliver Podmanicky, Rita Horvath, Verónica Eisner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular …

Biologically Informed Negative Samplingfor Antibody Chain Pairing Classification, Ishita Singh

Computer Science Senior Theses

Antibody heavy and light chain (H/L) pairing is fundamental to antigen recognition and stability. While single-cell sequencing preserves native pairing information, widely used bulk repertoire and spatial transcriptomics platforms do not, motivating the need for efficient ML methods to infer H/L pairing. Training a binary classifier for this task faces the methodological challenge of a lack of true biological negatives, since natural selection eliminates B cells with incompatible H/L pairs.

In this thesis, I introduce a biologically informed negative sampling strategy for H/L pairing classification, drawing on known V-gene biases in heavy and light chain pairing. Pseudo-negatives are constructed by …

The Evolutionary Response Of HawaiʻI ʻAmakihi (Chlorodrepanis Virens) To The Introduction Of Avian Malaria (Plasmodium Relictum), Gabrielle Atkinson

Doctoral Dissertations

The emergence of novel pathogens can impose intense selective pressures on natural populations, driving rapid evolutionary change or precipitating population collapse. In Hawaiʻi, the introduction of avian malaria (Plasmodium relictum) and its mosquito vector (Culex quinquefasciatus) have caused severe declines and extinctions among native forest birds. Yet some populations of Hawaiʻi ʻamakihi (Chlorodrepanis virens) persist across a broad elevational and disease gradient, providing a powerful natural system for examining the genomic basis of rapid adaptation, the role of gene flow in adaptive response, and the potential for parallel evolutionary responses. This dissertation integrates genomic, population genetic, and transcriptomic approaches to …

Filtered Genome Of Commercial Philippine Varieties Of Sugarcane (Saccharum Officinarum L.) For The Characterization And Identification Of Ssrs Associated With Resistance To Philippine Downy Mildew (Peronosclerospora Philippinensis), Antonio G. Lalusin, Jhun Lawrence S. Rasco

The Philippine Agricultural Scientist

Sugarcane is a major global source of sugar, with total production reaching 1.89 billion t. Although the Philippines produces about 1.85 million t of sugarcane annually, yields are limited by downy mildew and smut. Developing varieties resistant to these pathogens is the most economical and practical approach to mitigating losses from these biotic stresses. In this study, SSRs related to disease resistance were developed through Next-Generation Sequencing (NGS) of the filtered genomes of sugarcane varieties with known phenotypic responses to downy mildew. Two assemblies based on minimum contig lengths (450 and 900 bp) were performed using SoapDeNovo2. The 900-bp assembly …

Decentralizing Dementia Research To The Us–Mexico Border: The Rio Grande Valley Ad-Rcmar As A Model For Translational Equity, Gladys E. Maestre, John Blangero, Eron Manusov, Gabriel A. De Erausquin, Francisco Fernandez, Silvia Mejia-Arango, Vincent P. Diego, Juan C. Lopez-Alvarenga, Claudia Alaniz, Neyra García, Rosa V. Pirela, Andrew Tsin, Michael Mahaney

School of Medicine Publications

Translational equity means ensuring that diagnostics, treatments, care models, and prevention strategies are developed and implemented so they work for populations with the greatest burden and least access to care. In Alzheimer's disease and related dementias (ADRD), where most evidence derives from highly educated, non-Hispanic White participants at large academic centers, translational equity is critical to prevent misclassification, limited access, and widening disparities and to ensure that underrepresented communities shape how new knowledge moves into practice. Hispanic and other populations in the United States are disproportionately affected by ADRD yet remain underrepresented in research, with gaps especially pronounced in high-poverty …

Computational Insights Into Nucleosome Dynamics In Epigenetics Using Molecular Dynamics Simulations, Rutika Patel

Dissertations, Theses, and Capstone Projects

Nucleosome core particles (NCP) are the building blocks that form a highly organized and compact chromatin structure. Nucleosomes package DNA in the nucleus of eukaryotic cells. The NCP consists of about 147 base pairs of DNA wrapped around the histone octamer, with 1.65 superhelical turns in a left-handed manner. The histone octamer is composed of two copies of H3, H4, H2A, and H2B. Together with histone H1 and linker DNA, they further assemble into a higher-order chromatin structure. The nucleosome complex is stabilized by electrostatic interactions between positively charged histone residues and the negatively charged DNA backbone. To effectively access …

Marine Heatwaves And Fish Reproduction: Endocrine Responses In The Eurythermal Sheepshead Minnow (Cyprinodon Variegatus), Isabel Villafuerte

Master's Theses

Marine heatwaves associated with climate change are increasing in frequency and severity, posing significant threats to fish populations in shallow habitats such as estuaries and salt marshes. Because temperature is a primary regulator of fish reproduction, understanding how heatwaves affect reproductive physiology is critical for anticipating the biological consequences of ongoing climate change for coastal fishes. Here we examined how simulated heatwave conditions affect the reproductive hypothalamic-pituitary-gonadal (HPG) endocrine axis in the estuarine sheepshead minnow (Cyprinodon variegatus), a eurythermal fish well suited to studying thermal stress responses in estuarine environments. Adult sheepshead minnows acclimated to a daily oscillating …