Genetic Phenomena Commons^™

Effects That The Methylenetetrahydrofolate Gene Mutation (Both The C677t And A1298c Polymorphisms) Have On Both Men And Women’S Fertility Abilities And Subsequent Fetal Development, As Well As What Nutritional Changes Can Possibly Do To Aid In Reversing These Supposed Negative Effects., Elizabeth Simkanin

Williams Honors College, Honors Research Projects

This study discusses the perceived negative effects of variants (C677T and A1298C) of the methylenetetrahydrofolate (MTHFR) gene on male and female fertility and fetal development, as well as the potential for nutrition changes to aid in reversing these negative effects. This research project was completed in order to discuss the possible association with and connection between nutrition and fertility in both male and female individuals who have either of the two most common MTHFR gene polymorphisms, 677C>T and 1298A>C. These two polymorphisms are of particular interest because they are associated with the most decreased activity of the MTHFR …

The Assembled Genome Of The Stroke-Prone Spontaneously Hypertensive Rat, Theodore S Kalbfleisch, Nahla A Hussien Abouel Ela, Kai Li, Wesley A Brashear, Kelli J Kochan, Yaming Zhu, Eric J Kline, Elizabeth A Hudson, Terence D Murphy, Françoise Thibaud-Nissen, Melissa L Smith, Peter A Doris

Faculty, Staff and Student Publications

BACKGROUND: We report the creation and evaluation of a de novo assembly of the genome of the spontaneously hypertensive rat, the most widely used model of human cardiovascular disease.

METHODS: The genome is assembled from long read sequencing (PacBio HiFi and continuous long read data [CLR]) and scaffolded with long-range structural information obtained from Bionano optical maps and proximity ligation sequencing proximity analysis of the genome. The genome assembly was polished with Illumina short reads. Completeness of the assembly was investigated using Benchmarking Universal Single Copy Orthologs analysis. The genome assembly was also evaluated with the rat reference gene set, …

Novel Compound Heterozygous Variants In The Ush2a Gene Associated With Autosomal Recessive Retinitis Pigmentosa Without Hearing Loss, Xiong Deng

Faculty, Staff and Student Publications

Background: Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies characterized by the primary degeneration of rod photoreceptors and the subsequent loss of cone photoreceptors because of cell death. It is caused by different mechanisms, including inflammation, apoptosis, necroptosis, pyroptosis, and autophagy. Variants in the usherin gene (USH2A) have been reported in autosomal recessive RP with or without hearing loss. In the present study, we aimed to identify causative variants in a Han-Chinese pedigree with autosomal recessive RP.

Methods: A six-member, three-generation Han-Chinese family with autosomal recessive RP was recruited. A full clinical examination, whole exome …

Treatment Of Epilepsy Using A Targeted P38Γ Kinase Gene Therapy, Nicolle Morey, Magdalena Przybyla, Julia Van Der Hoven, Yazi D Ke, Fabien Delerue, Lars M Ittner

Faculty, Staff and Student Publications

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates …

Privacy-Aware Estimation Of Relatedness In Admixed Populations, Han Chen, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in third-party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization.

RESULTS: Here, we present SIGFRIED, which makes …

The Evolving Privacy And Security Concerns For Genomic Data Analysis And Sharing As Observed From The Idash Competition, Arif Harmanci, Miran Kim, Kai Post, Diyue Bu, Tyler Bath, Jihoon Kim, Weijie Liu, Hongbo Chen, Lucila Ohno-Machado

Faculty, Staff and Student Publications

Concerns regarding inappropriate leakage of sensitive personal information as well as unauthorized data use are increasing with the growth of genomic data repositories. Therefore, privacy and security of genomic data have become increasingly important and need to be studied. With many proposed protection techniques, their applicability in support of biomedical research should be well understood. For this purpose, we have organized a community effort in the past 8 years through the integrating data for analysis, anonymization and sharing consortium to address this practical challenge. In this article, we summarize our experience from these competitions, report lessons learned from the events …

A Multi-Omics Framework Reveals Strawberry Flavor Genes And Their Regulatory Elements, Zhen Fan, Denise M Tieman, Steven J Knapp, Philipp Zerbe, Randi Famula, Kevin M Folta, Manbo Lee, Youngjae Oh, Seonghee Lee, Vance M Whitaker

Faculty, Staff and Student Publications

Flavor is essential to consumer preference of foods and is an increasing focus of plant breeding programs. In fruit crops, identifying genes underlying volatile organic compounds has great promise to accelerate flavor improvement, but polyploidy and heterozygosity in many species have slowed progress. Here we use octoploid cultivated strawberry to demonstrate how genomic heterozygosity, transcriptomic intricacy and fruit metabolomic diversity can be treated as strengths and leveraged to uncover fruit flavor genes and their regulatory elements. Multi-omics datasets were generated including an expression quantitative trait loci map with 196 diverse breeding lines, haplotype-phased genomes of a highly-flavored breeding selection, a …

Complement Component C4 Structural Variation And Quantitative Traits Contribute To Sex-Biased Vulnerability In Systemic Sclerosis, Shervin Assassi, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K De Vries-Bouwstra, Gisela Orozco, Anne Barton, Ariane L Herrick, Chikashi Terao, Yannick Allanore, Carmen Fonseca, Marta Eugenia Alarcón-Riquelme, Timothy R D J Radstake, Lorenzo Beretta, Christopher P Denton, Maureen D Mayes, Javier Martin

Faculty, Staff and Student Publications

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its …

Svat: Secure Outsourcing Of Variant Annotation And Genotype Aggregation

Faculty, Staff and Student Publications

BACKGROUND: Sequencing of thousands of samples provides genetic variants with allele frequencies spanning a very large spectrum and gives invaluable insight into genetic determinants of diseases. Protecting the genetic privacy of participants is challenging as only a few rare variants can easily re-identify an individual among millions. In certain cases, there are policy barriers against sharing genetic data from indigenous populations and stigmatizing conditions.

RESULTS: We present SVAT, a method for secure outsourcing of variant annotation and aggregation, which are two basic steps in variant interpretation and detection of causal variants. SVAT uses homomorphic encryption to encrypt the data at …

Genome-Wide Association Analyses Of Physical Activity And Sedentary Behavior Provide Insights Into Underlying Mechanisms And Roles In Disease Prevention, Daiane Hemerich, Siacia Broos, Tarunveer S Ahluwalia, Traci M Bartz, Amy R Bentley, Lawrence F Bielak, Mike Chong, Audrey Y Chu, Diane Berry, Rajkumar Dorajoo, Nicole D Dueker, Elisa Kasbohm, Bjarke Feenstra, Mary F Feitosa, Christian Gieger, Mariaelisa Graff, Leanne M Hall, Toomas Haller, David A Hillis, Ville Huikari, Nancy Heard-Costa, Christina Holzapfel, Anne U Jackson, Åsa Johansson, Anja Moltke Jørgensen, Marika A Kaakinen, Robert Karlsson, Kathleen F Kerr, Boram Kim, Chantal M Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Penelope A Lind, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Massimo Mangino, Christoph Metzendorf, Kristine R Monroe, Alexander Pacolet, Louis Pérusse, Rene Pool, Rebecca C Richmond, Natalia V Rivera, Sebastien Robiou-Du-Pont, Katharina E Schraut, Christina-Alexandra Schulz, Heather M Stringham, Toshiko Tanaka, Alexander Teumer, Constance Turman, Peter J Van Der Most, Mathias Vanmunster, Frank J A Van Rooij, Jana V Van Vliet-Ostaptchouk, Xiaoshuai Zhang, Jing-Hua Zhao, Wei Zhao, Zhanna Balkhiyarova, Marie N Balslev-Harder, Sebastian E Baumeister, John Beilby, John Blangero, Dorret I Boomsma, Soren Brage, Peter S Braund, Jennifer A Brody, Marcel Bruinenberg, Ulf Ekelund, Ching-Ti Liu, John W Cole, Francis S Collins, L Adrienne Cupples, Tõnu Esko, Stefan Enroth, Jessica D Faul, Lindsay Fernandez-Rhodes, Alison E Fohner, Oscar H Franco, Tessel E Galesloot, Scott D Gordon, Niels Grarup, Catharina A Hartman, Gerardo Heiss, Jennie Hui, Thomas Illig, Russell Jago, Alan James, Peter K Joshi, Taeyeong Jung, Mika Kähönen, Tuomas O Kilpeläinen, Woon-Puay Koh, Ivana Kolcic, Peter P Kraft, Johanna Kuusisto, Lenore J Launer, Aihua Li, Allan Linneberg, Jian'an Luan, Pedro Marques Vidal, Sarah E Medland, Yuri Milaneschi, Arden Moscati, Bill Musk, Christopher P Nelson, Ilja M Nolte, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Christine Power, Olli T Raitakari, Mägi Reedik, Alex P Reiner, Paul M Ridker, Igor Rudan, Kathy Ryan, Mark A Sarzynski, Laura J Scott, Robert A Scott, Stephen Sidney, Kristin Siggeirsdottir, Albert V Smith, Jennifer A Smith, Emily Sonestedt, Marin Strøm, E Shyong Tai, Koon K Teo, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Andre G Uitterlinden, Jagadish Vangipurapu, Natasja Van Schoor, Uwe Völker, Gonneke Willemsen, Kayleen Williams, Quenna Wong, Huichun Xu, Kristin L Young, Jian Min Yuan, M Carola Zillikens, Alan B Zonderman, Adam Ameur, Stefania Bandinelli, Joshua C Bis, Michael Boehnke, Claude Bouchard, Daniel I Chasman, George Davey Smith, Eco J C De Geus, Louise Deldicque, Marcus Dörr, Michele K Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Vilmundur Gudnason, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo L Horta, Elina Hyppönen, Marjo-Riitta Jarvelin, W Craig Johnson, Sharon L R Kardia, Lambertus A Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik K E Magnusson, Nicholas G Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari E North, Claes Ohlsson, Albertine J Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda W J H Penninx, Tune H Pers, Ozren Polasek, Inga Prokopenko, Charles N Rotimi, Nilesh J Samani, Xueling Sim, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Nicholas J Timpson, Rob M Van Dam, Nathalie Van Der Velde, Cornelia M Van Duijn, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gérard Waeber, Nicholas J Wareham, David R Weir, Heinz-Erich Wichmann, James F Wilson, Andrea L Hevener, Anna Krook, Juleen R Zierath, Martine A I Thomis, Ruth J F Loos, Marcel Den Hoed

Faculty, Staff and Student Publications

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle …

Whole Genome Sequence Association Analysis Of Fasting Glucose And Fasting Insulin Levels In Diverse Cohorts From The Nhlbi Topmed Program, Daniel Dicorpo, Sheila M. Gaynor, Emily M. Russell, Kenneth E. Westerman, Laura M. Raffield, Marcio Almeida, Juan M. Peralta, John Blangero, Joanne E. Curran, Ravindranath Duggirala

School of Medicine Publications

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well …

Genetic Origins Of Polycystic Ovarian Syndrome (Pcos): An Analysis Of The Genetic Correlation Between Pcos And Insulin Receptor Mutations, Lauren Henry

Undergraduate Theses

Polycystic Ovarian Syndrome (PCOS) remains an extremely common, yet understudied syndrome experienced by 6-12% of females of reproductive age. Not only does it cause painful side effects manifesting both physically and mentally, but it also poses a threat to the fertility of those affected. For this reason, a more in-depth analysis to better understand how to detect this condition early and prevent fertility complications later is certainly warranted. PCOS is suspected to be primarily genetic due to correlations among immediate female family members. Based on previous research, a good starting point for analysis is the INSR gene. Various mutations within …

Plasma Proteome Analyses In Individuals Of European And African Ancestry Identify Cis-Pqtls And Models For Proteome-Wide Association Studies, Pascal Schlosser, Ckdgen Consortium, Bing Yu, Eric Boerwinkle, Josef Coresh, Nilanjan Chatterjee

Faculty, Staff and Student Publications

Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative …

Accessory Genomes Drive Independent Spread Of Carbapenem-Resistant Klebsiella Pneumoniae Clonal Groups 258 And 307 In Houston, Tx, Diana Panesso, Hongyu Miao, Carol Hill, Liang Chen, Robin Patel, Bettina C Fries, Lilian Abbo, Eric Cober, Sara Revolinski, Courtney L Luterbach, Henry Chambers, Vance G Fowler, Robert A Bonomo, Samuel A Shelburne, Barry N Kreiswirth, David Van Duin, Blake M Hanson, Cesar A Arias

Faculty, Staff and Student Publications

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is an urgent public health threat. Worldwide dissemination of CRKp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CRKp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 …

Retrospective Genomics Highlights Changes In Genetic Composition Of Tiger Sharks (Galeocerdo Cuvier) And Potential Loss Of A South-Eastern Australia Population, Alice Manuzzi, Belen Jiménez-Mena, Romina Henriques, Bonnie J Holmes, Julian Pepperell, Janette Edson, Mike B Bennett, Charlie Huveneers, Jennifer R Ovenden, Einar E Nielsen

Staff and Researcher Publications

Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark (Galeocerdo cuvier) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in …

Ancestral Diversity Improves Discovery And Fine-Mapping Of Genetic Loci For Anthropometric Traits–The Hispanic/Latino Anthropometry Consortium, Heather M Highland, Hung-Hsin Chen, Kristin L Young, Kaustubh Adhikari, Nicholette D Palmer, Jennifer E Below, Jonathan Bradfield, Alexandre C Pereira, Láshauntá Glover, Daeeun Kim, Adam G Lilly, Poojan Shrestha, Alvin G Thomas, Xinruo Zhang, Minhui Chen, Charleston W K Chiang, Sara Pulit, Andrea Horimoto, Marta Guindo-Martínez, Michael Preuss, Claudia Schumann, Roelof A J Smit, Gabriela Torres-Mejía, Victor Acuña-Alonzo, Gabriel Bedoya, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Rolando González-José, Giovanni Poletti, Francisco Rothhammer, Hakon Hakonarson, Robert Igo, Sharon G Adler, Sudha K Iyengar, Susanne B Nicholas, Stephanie M Gogarten, Carmen R Isasi, George Papnicolaou, Adrienne M Stilp, Qibin Qi, Minjung Kho, Jennifer A Smith, Carl D Langefeld, Lynne Wagenknecht, Roberta Mckean-Cowdin, Xiaoyi Raymond Gao, Darryl Nousome, David V Conti, Ye Feng, Matthew A Allison, Zorayr Arzumanyan, Thomas A Buchanan, Yii-Der Ida Chen, Pauline M Genter, Mark O Goodarzi, Yang Hai, Willa Hsueh, Eli Ipp, Fouad R Kandeel, Kelvin Lam, Xiaohui Li, Jerry L Nadler, Leslie J Raffel, Kathryn Roll, Kevin Sandow, Jingyi Tan, Kent D Taylor, Anny H Xiang, Jie Yao, Astride Audirac-Chalifour, Jose De Jesus Peralta Romero, Fernando Hartwig, Bernando Horta, John Blangero, Joanne E Curran, Ravindranath Duggirala, Donna E Lehman, Sobha Puppala, Laura Fejerman, Esther M John, Carlos Aguilar-Salinas, Noël P Burtt, Jose C Florez, Humberto García-Ortíz, Clicerio González-Villalpando, Josep Mercader, Lorena Orozco, Teresa Tusié-Luna, Estela Blanco, Sheila Gahagan, Nancy J Cox, Craig Hanis, Nancy F Butte, Shelley A Cole, Anthony G Comuzzie, V Saroja Voruganti, Rebecca Rohde, Yujie Wang, Tamar Sofer, Elad Ziv, Struan F A Grant, Andres Ruiz-Linares, Jerome I Rotter, Christopher A Haiman, Esteban J Parra, Miguel Cruz, Ruth J F Loos, Kari E North

Faculty, Staff and Student Publications

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS …

Meta-Analysis Of Genome-Wide Association Studies Identifies Ancestry-Specific Associations Underlying Circulating Total Tau Levels, Myriam Fornage, Alexa S Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L Adrienne Cupples, Vincent Damotte, Charles S Decarli, Anita L Destefano, Luc Djoussé, Alison E Fohner, Carol E Franz, Tiffany F Kautz, Jean-Charles Lambert, Michael J Lyons, Thomas H Mosley, Kenneth J Mukamal, Matthew P Pase, Robert A Rissman, Claudia L Satizabal, Ramachandran S Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J Launer, William S Kremen, William T Longstreth, M Arfan Ikram, Sudha Seshadri

Faculty, Staff and Student Publications

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Mendelian Randomization Supports Bidirectional Causality Between Telomere Length And Clonal Hematopoiesis Of Indeterminate Potential, Tetsushi Nakao, Alexander G. Bick, Margaret A. Taub, Seyedeh M. Zekavat, Md M. Uddin, Abhishek Niroula, Juan M. Peralta, Joanne E. Curran, John Blangero

School of Medicine Publications

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies …

Assessing Identification Of Newly Diagnosed Breast Cancer Patients For Referral To Genetic Counseling, Corinne Marie Locke

Theses and Dissertations

Since 1998, the National Comprehensive Cancer Network (NCCN) guidelines have specified clinical indications for genetic testing for breast cancer susceptibility genes, but retrospective studies have shown that, despite meeting the NCCN criteria, patients are not always advised of the option of genetic testing. Further compounding this issue, studies have shown that cancer family history intake and documented family history can be incomplete even when taken by oncology providers. At this study site and other cancer centers in the country, patients with a new diagnosis of breast cancer are referred for genetic counseling by their cancer care team if they are …

Vitamin C Reduces Igf-1 And Vegf Signaling In Retinal Endothelial Cells, Jonathon Reynolds

Annual Research Symposium

No abstract provided.

Crosstalk Between Hippo And Rb Tumour Suppressor Pathways In Ovarian Cancer, Fatmata Sesay

Theses and Dissertations

The cell cycle is a highly regulated process that ensures the timely and accurate division of cells. Events of the normal cell cycle fall under two categories - positive and negative regulatory mechanisms. The first category, positive regulatory machinery, includes active protein complexes of cyclins in association with their partnering cyclin-dependent kinases (cyclin/CDK), which mediate series of phosphorylation events that relay a cell cycle progression from one stage to the next. The second category, the negative regulatory mechanisms, include the checkpoint controls consisting of the retinoblastoma (RB) family of proteins, some of which can form a transcriptional repressor complex DREAM. …

Single-Cell Rna Sequencing Reveals Intratumoral Heterogeneity And Potential Mechanisms Of Malignant Progression In Prostate Cancer With Perineural Invasion, Lin Yang, Jie Xiong, Siyao Liu, Jiali Zhang, Junyan Su, Jing Chen, Mengyuan Liu, Beifang Niu

Faculty, Staff and Student Publications

Background: Prostate cancer (PCa) is the second most common cancer among men worldwide. Perineural invasion (PNI) was a prominent characteristic of PCa, which was recognized as a key factor in promoting PCa progression. As a complex and heterogeneous disease, its true condition is difficult to explain thoroughly with conventional bulk RNA sequencing. Thus, an improved understanding of PNI-PCa progression at the single-cell level is needed.

Methods: In this study, we performed scRNAseq on tumor tissues of three PNI-PCa patients. Principal component analysis (PCA) and Uniform manifold approximation and projection (UMAP) were used to reduce dimensionality and visualize the cellular composition …

Nrf1 Association With Auts2-Polycomb Mediates Specific Gene Activation In The Brain, Sanxiong Liu, Kimberly A Aldinger, Chi Vicky Cheng, Takae Kiyama, Mitali Dave, Wukui Zhao, Nicolas Descostes, Pedro Lee, Stefano G Caraffi, Ivan Ivanovski, Edoardo Errichiello, Christiane Zweier, Orsetta Zuffardi, Michael Schneider, Antigone S Papavasiliou, M Scott Perry, Jennifer Humberson, Megan T Cho, Astrid Weber, Andrew Swale, Tudor C Badea, Chai-An Mao, Livia Garavelli, William B Dobyns, Danny Reinberg

Faculty, Staff and Student Publications

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its …

How Opportune Is Multigene Testing In Metastatic Colorectal Cancer? A Review, Cristina Orlov-Slavu, Andreea Parosanu, Mihaela Olaru, Dragos Serban, Ioana Paunica, Cornelia Nitipir

Journal of Mind and Medical Sciences

Personalized treatment in oncology is the most innovative method of care. The best method to establish personalized treatment is by genetic characterization of the malignant cell.

Theoretically, the more detailed the characterization, the more effective the choice of treatment becomes. Currently, there are fast and relatively low-cost options that allow such genetic characterization. However, test results sometimes do not detect targetable alterations and, even if they do detect, the use of the treatment-alteration combination does not always generate a satisfactory oncological response.

The present paper aims to answer two questions. First, how targetable can the most common gene alterations in …

The Onset Of Exercise-Associated Hyponatremia And Individual Differences In Inappropriate Arginine Vasopressin Excretion: A Review Of Proposed Mechanisms, Michelle Stehman, Stephen A. Maris

Topics in Exercise Science and Kinesiology

Topics in Exercise Science and Kinesiology Volume 2: Issue 1, Article 10, 2021. Exercise-associated hyponatremia (EAH) has been reported to develop during endurance events such as triathlons and marathons. As these events become more popular, the incidence of developing EAH also increases. The development of EAH is commonly associated with the overconsumption of hypotonic fluids such as water and tends to be more prevalent in females. There is also evidence to suggest the inappropriate secretion of arginine vasopressin (AVP) leading to water retention may predispose an individual for developing EAH, especially when coupled with the overconsumption of fluids. Recent research …

Whole Genome Sequence Analysis Of Platelet Traits In The Nhlbi Trans-Omics For Precision Medicine Initiative, Amarise Little, Yao Hu, Quan Sun, Deepti Jain, Jai G. Broome, Ming-Huei Chen, Florian Thibord, Caitlin Mchugh, John Blangero, Joanne E. Curran

School of Medicine Publications

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet …

Gene Expression Profiling Of Mapk Pathway Inhibitor Resistance In Cutaneous Melanoma: Can Bioinformatics Be Used To Select Better Melanoma Cell Lines?, Stephen Luebker

Theses & Dissertations

Melanoma is the deadliest form of skin cancer, and incidence has continued to increase. Half of all melanomas have a BRAF V600E mutation and respond to MAPK pathway inhibitors, including BRAF inhibitor therapy or BRAF/MEK inhibitor combination therapy, but nearly all patients develop treatment resistance. Melanoma cell lines produce variable results as models of MAPK pathway inhibitor resistance. To better understand how the genomic similarity of a melanoma cell line to patient-derived tumors affects resistance mechanisms, differences in DNA mutations and copy-number alterations were compared between melanoma cell lines profiled by the Cancer Cell Line Encyclopedia and cutaneous melanoma tumors …

Muc13 Enhances Colorectal Cancer Metastasis, Kyle Doxtater

Theses and Dissertations (ETD)

Colorectal cancer (CRC) is one of the most prevalent cancer worldwide with a 5% lifetime incidence in developed countries. It is third most common cause of cancer related death in the United States and the second deadliest when men and women are combined. Encouragingly due to changes in dietary lifestyle, screening colonoscopy, and advancement in treatments the mortality has decreased in recent years. Most sporadic CRCs develop from polyploid adenomas and are preceded by intramucosal carcinomas (stage 0), which can progress into more malignant forms. This developmental process is known as the adenoma-carcinoma sequence. Early detection and endoscopic removal are …

Ciliary Extracellular Vesicles Are Distinct From The Cytosolic Extracellular Vesicles, Ashraf M. Mohieldin, Rajasekharreddy Pala, Richard Beuttler, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Extracellular vesicles (EVs) are cell‐derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid‐shear flow, but many proteins encapsulated in these vesicles have never been identified. Primary cilia are ubiquitous mechanosensory organelles that protrude from the apical surface of almost all human cells. Primary cilia also serve as compartments for signalling pathways, and their defects have been associated with a wide range of human genetic diseases called ciliopathies. To better understand the mechanism of ciliopathies, it is imperative to know …

Genetic Mechanisms Of Transcriptional Regulation In Childhood Acute Lymphoblastic Leukemia, Xujie Zhao

Theses and Dissertations (ETD)

Introduction. Advances in genomic profiling and sequencing studies have identified germline and somatic variations that are associated with childhood ALL, improving our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL). Recent genome-wide association studies (GWAS) have identified germline genetic variations of ARID5B and, more recently, IGF2BP1 that are associated with susceptibility to ALL. Genome-wide sequencing studies also discovered a new ALL subtype characterized of ZNF384-mediated chromosomal translocations, providing new insights into genetic heterogeneity in childhood ALL. However, the underlying mechanism by which these genetic variants contribute to the transcriptional regulatory circuitries of ALL is still poorly understood. …