Medicine and Health Sciences Commons^™

Leveraging Global Gene Expression Patterns To Predict Expression Of Unmeasured Genes, James Rudd, René A. Zelaya, Eugene Demidenko, Ellen L. Goode, Casey S. Greene S. Greene, Jennifer A. Doherty

Dartmouth Scholarship

BackgroundLarge collections of paraffin-embedded tissue represent a rich resource to test hypotheses based on gene expression patterns; however, measurement of genome-wide expression is cost-prohibitive on a large scale. Using the known expression correlation structure within a given disease type (in this case, high grade serous ovarian cancer; HGSC), we sought to identify reduced sets of directly measured (DM) genes which could accurately predict the expression of a maximized number of unmeasured genes.

Antioncogenic And Oncogenic Properties Of Nrf2 In Arsenic-Induced Carcinogenesis, Young-Ok Son, Poyil Pratheeshkumar, Ram Vinod Roy, Andrew Hitron, Lei Wang, Sasidharan Padmaja Divya, Mei Xu, Jia Luo, Gang Chen, Zhuo Zhang, Xianglin Shi

Center for Research on Environmental Disease Faculty Publications

Arsenic (As³⁺) is a carcinogen with considerable environmental and occupational relevancy. The present study shows that As³⁺-transformed human lung bronchial epithelial BEAS-2B cells (AsT cells) exhibit the property of apoptosis resistance. The level of basal reactive oxygen species (ROS) is very low in AsT cells in correlation with elevated expressions of both antioxidant enzymes and antiapoptotic proteins. Nuclear factor erythroid 2-related factor (Nrf2) and p62 are constitutively expressed. These two proteins up-regulate antioxidant enzymes and antiapoptotic proteins. The knockdown of Nrf2 or p62 by small interfering RNA (siRNA) enhanced both ROS levels and As³⁺-induced …

Segregation Of A Latent High Adiposity Phenotype In Families With A History Of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants With Large Effects In Diabetes-Related Obesity, Arthur B. Jenkins, Marijka Batterham, Dorit Samocha-Bonet, Katherine Tonks, Jerry R. Greenfield, Lesley V. Campbell

Dr Marijka Batterham

Background We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH−) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+. Methods Normoglycaemic participants were categorised either FH+ (≥1 1st degree relative with T2DM, 50F/30M, age 45±14 (SD) yr) or FH− (71F/51M, age 43±14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass …

Genestation 1.0: A Synthetic Resource Of Diverse Evolutionary And Functional Genomic Data For Studying The Evolution Of Pregnancy-Associated Tissues And Phenotypes, Mara Kim, Brian A. Cooper, Rohit Venkat, Julie B. Phillips, Haley R. Eidem, Jibril Hirbo, Sashank Nutakki, Scott M. Williams, Louis J. Muglia, J. Anthony Capra, Kenneth Petren, Patrick Abbot, Antonis Rokas, Kriston L. Mcgary

Dartmouth Scholarship

Mammalian gestation and pregnancy are fast evolving processes that involve the interaction of the fetal, maternal and paternal genomes. Version 1.0 of the GEneSTATION database (http://genestation.org) integrates diverse types of omics data across mammals to advance understanding of the genetic basis of gestation and pregnancy-associated phenotypes and to accelerate the translation of discoveries from model organisms to humans. GEneSTATION is built using tools from the Generic Model Organism Database project, including the biology-aware database CHADO, new tools for rapid data integration, and algorithms that streamline synthesis and user access. GEneSTATION contains curated life history information on pregnancy and …

Hereditary Sensory Autonomic Neuropathy Ii, A Rare Disease In A Large Pakistani Family, Fazal M. Arain, Prem Chand

Department of Paediatrics and Child Health

Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self-mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and …

The Dna Structure And Sequence Preferences Of Wrn Underlie Its Function In Telomeric Recombination Events, Deanna N. Edwards, Amrita Machwe, Li Chen, Vilhelm A. Bohr, David K. Orren

Toxicology and Cancer Biology Faculty Publications

Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome. Here we examine WRN's role in telomeric maintenance, by comparing its action on a variety of DNA structures without or with telomeric sequences. Our results show that WRN clearly prefers to act on strand invasion intermediates in a manner that favours strand invasion and exchange. Moreover, WRN unwinding of these recombination structures is further enhanced when the invading strand contains at least three G-rich single-stranded telomeric repeats. These selectivities are most pronounced at NaCl concentrations within …

Expression Of The Il-11 Gene In Metastatic Cells Is Supported By Runx2-Smad And Runx2-Cjun Complexes Induced By Tgfβ1., Xuhui Zhang, Hai Wu, Jason R. Dobson, Gillian Browne, Deli Hong, Jacqueline Akech, Lucia R. Languino, Gary S. Stein, Jane B. Lian

Department of Cancer Biology Faculty Papers

In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes …

Maternal Psychiatric Disease And Epigenetic Evidence Suggest A Common Biology For Poor Fetal Growth, Timothy H. Ciesielski, Carmen J. Marsit, Scott M. Williams

Dartmouth Scholarship

We sought to identify and characterize predictors of poor fetal growth among variables extracted from perinatal medical records to gain insight into potential etiologic mechanisms. In this process we reevaluated a previously observed association between poor fetal growth and maternal psychiatric disease. We evaluated 449 deliveries of >36 weeks gestation that occurred between 9/2008 and 9/2010 at the Women and Infants Hospital in Providence Rhode Island. This study group was oversampled for Small-for-Gestational-Age (SGA) infants and excluded Large-for-Gestational-Age (LGA) infants. We assessed the associations between recorded clinical variables and impaired fetal growth: SGA or Intrauterine Growth Restriction (IUGR) diagnosis. After …

Ace And Ucp2 Gene Polymorphisms And Their Association With Baseline And Exercise-Related Changes In The Functional Performance Of Older Adults, Justin W. Keogh, Barry Palmer, Denise Taylor, Andrew Kilding

Justin Keogh

Maintaining high levels of physical function is an important aspect of successful ageing. While muscle mass and strength contribute to functional performance in older adults, little is known about the possible genetic basis for the heterogeneity of physical function in older adults and in how older adults respond to exercise. Two genes that have possible roles in determining levels of muscle mass, strength and function in young and older adults are angiotensin-converting enzyme (ACE) and mitochondrial uncoupling protein 2 (UCP2). This study examined whether polymorphisms in these two individual genes were associated with baseline functional performance levels and/or the training-related …

Chromatin To Clinic: The Molecular Rationale For Parp1 Inhibitor Function., Felix Y. Feng, Johann S. De Bono, Mark A. Rubin, Karen E Knudsen

Department of Cancer Biology Faculty Papers

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.

Network-Based Stratification Analysis Of 13 Major Cancer Types Using Mutations In Panels Of Cancer Genes., Xue Zhong, Hushan Yang, Shuyang Zhao, Yu Shyr, Bingshan Li

Department of Medical Oncology Faculty Papers

BACKGROUND: Cancers are complex diseases with heterogeneous genetic causes and clinical outcomes. It is critical to classify patients into subtypes and associate the subtypes with clinical outcomes for better prognosis and treatment. Large-scale studies have comprehensively identified somatic mutations across multiple tumor types, providing rich datasets for classifying patients based on genomic mutations. One challenge associated with this task is that mutations are rarely shared across patients. Network-based stratification (NBS) approaches have been proposed to overcome this challenge and used to classify tumors based on exome-level mutations. In routine research and clinical applications, however, usually only a small panel of …

Plasminogen Activator Inhibitor-1 In Cigarette Smoke Exposure And Influenza A Virus Infection-Induced Lung Injury, Yashodhar P. Bhandary, Shwetha K. Shetty, Amarnath S. Marudamuthu, Krishna K. Midde, Hong-Long Ji, Homoyoun Shams, Renuka Subramaniam, Jian Fu, Steven Idell, Sreerama Shetty

Center for Research on Environmental Disease Faculty Publications

Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC …

Obstetrician And Gynecologist Utilization Of The Nipt Expanded Testing Option, Sarah Mayes Ba

Dissertations & Theses (Open Access)

Noninvasive prenatal testing (NIPT) enables the detection of common fetal aneuploidies such as trisomy 21, trisomy 18, trisomy 13, and sex chromosome abnormalities via analysis of cell-free fetal DNA circulating in maternal serum. Although the accuracy of NIPT for fetal aneuploidy is expected to be higher than that of currently available alternative maternal serum screening options, the implications of results are not straight forward. In October 2013, the option to screen for additional trisomies and select microdeletion syndromes, such as 22q11.2 deletion syndrome and 5 p- syndrome, became clinically available. Due to this rapidly evolving prenatal screening technology, clinicians must …

Madness: Schizophrenia, Then And Now, Diane W. Aldrich

Senior Theses

In examining the subject of mental illness, it is clear that diseases and disorders of the brain have not received the same degree of attention in the United States, over the years, as have acute and infectious diseases of the body. This thesis discusses the history of research and treatment of brain disorders, generally, with particular emphasis on schizophrenia, the most serious of mental disorders. The narrative includes the story of my aunt, who was schizophrenic. The objective of this thesis is to add another voice to the many who have asked that the bar on mental health research and …

Lipid-Induced Epigenomic Changes In Human Macrophages Identify A Coronary Artery Disease-Associated Variant That Regulates Ppap2b Expression Through Altered C/Ebp-Beta Binding, Michael E. Reschen, Kyle J. Gaulton, Da Lin, Elizabeth J. Soilleux, Andrew J. Morris, Susan S. Smyth, Christopher A. O'Callaghan

Gill Heart & Vascular Institute Faculty Publications

Genome-wide association studies (GWAS) have identified over 40 loci that affect risk of coronary artery disease (CAD) and the causal mechanisms at the majority of loci are unknown. Recent studies have suggested that many causal GWAS variants influence disease through altered transcriptional regulation in disease-relevant cell types. We explored changes in transcriptional regulation during a key pathophysiological event in CAD, the environmental lipid-induced transformation of macrophages to lipid-laden foam cells. We used a combination of open chromatin mapping with formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and enhancer and transcription factor mapping using chromatin immuno-precipitation (ChIP-seq) in primary human macrophages before …

Like Father, Like Son, Katrina Bramstedt

Katrina A. Bramstedt

This is a review of the Japanese film, Like Father, Like Son. The movie tells the story of two families attempting to resolve the dilemma of learning that their 6-year old sons are actually not their biological children, but rather children swapped at birth by a nurse with malicious intent.

Sparcoc: A New Framework For Molecular Pattern Discovery And Cancer Gene Identification, Shiqian Ma, Daniel Johnson, Cody Ashby, Donghai Xiong, Carole L. Cramer, Jason H. Moore, Shuzhong Zhang, Xiuzhen Huang

Dartmouth Scholarship

It is challenging to cluster cancer patients of a certain histopathological type into molecular subtypes of clinical importance and identify gene signatures directly relevant to the subtypes. Current clustering approaches have inherent limitations, which prevent them from gauging the subtle heterogeneity of the molecular subtypes. In this paper we present a new framework: SPARCoC (Sparse-CoClust), which is based on a novel Common-background and Sparse-foreground Decomposition (CSD) model and the Maximum Block Improvement (MBI) co-clustering technique. SPARCoC has clear advantages compared with widely-used alternative approaches: hierarchical clustering (Hclust) and nonnegative matrix factorization (NMF). We apply SPARCoC to the study of lung …

Disrupting Sumoylation Enhances Transcriptional Function And Ameliorates Polyglutamine Androgen Receptor-Mediated Disease., Jason P Chua, Satya L Reddy, Zhigang Yu, Elisa Giorgetti, Heather L Montie, Sarmistha Mukherjee, Jake Higgins, Richard C Mceachin, Diane M Robins, Diane E Merry, Jorge A Iñiguez-Lluhí, Andrew P Lieberman

Department of Biochemistry and Molecular Biology Faculty Papers

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that …

Fungal Mediator Tail Subunits Contain Classical Transcriptional Activation Domains, Zhongle Liu, Lawrence C. Myers

Dartmouth Scholarship

Classical activation domains within DNA-bound eukaryotic transcription factors make weak interactions with coactivator complexes, such as Mediator, to stimulate transcription. How these interactions stimulate transcription, however, is unknown. The activation of reporter genes by artificial fusion of Mediator subunits to DNA binding domains that bind to their promoters has been cited as evidence that the primary role of activators is simply to recruit Mediator. We have identified potent classical transcriptional activation domains in the C termini of several tail module subunits of Saccharomyces cerevisiae, Candida albicans, and Candida dubliniensis Mediator, while their N-terminal domains are necessary and sufficient for their …

Bridged Filaments Of Histone-Like Nucleoid Structuring Protein Pause Rna Polymerase And Aid Termination In Bacteria., Matthew V. Kotlajich, Daniel R. Hron, Beth A. Boudreau, Zhiqiang Sun, Yuri L. Lyubchenko, Robert Landick

Journal Articles: Pharmaceutical Sciences

Bacterial H-NS forms nucleoprotein filaments that spread on DNA and bridge distant DNA sites. H-NS filaments co-localize with sites of Rho-dependent termination in Escherichia coli, but their direct effects on transcriptional pausing and termination are untested. In this study, we report that bridged H-NS filaments strongly increase pausing by E. coli RNA polymerase at a subset of pause sites with high potential for backtracking. Bridged but not linear H-NS filaments promoted Rho-dependent termination by increasing pause dwell times and the kinetic window for Rho action. By observing single H-NS filaments and elongating RNA polymerase molecules using atomic force microscopy, we …

Cohort Of Birth Modifies The Association Between Fto Genotype And Bmi, James Niels Rosenquist, Steven F. Lehrer, A. James O'Malley, Alan M. Zaslavsky, Jordan W. Smoller, Nicholas A. Christakis

Dartmouth Scholarship

A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this …

Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes …

Genetic Network Properties Of The Human Cortex Based On Regional Thickness And Surface Area Measures, Anna R. Docherty, Chelsea K. Sawyers, Matthew S. Panizzon, Michael C. Neale, Lisa T. Eyler, Christine Fennema-Notestine, Carol E. Franz, Chi-Hua Chen, Linda K. Mcevoy, Brad Verhulst, Ming T. Tsuang, William S. Kremen

Psychiatry Publications

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques—biometrical genetic modeling, cluster analysis, and graph theory—to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several …

De Novo Mutations In Congenital Heart Disease With Neurodevelopmental And Other Congenital Anomalies, J. Homsy, S. Zaidi, Y. Shen, J. S. Ware, K. E. Samocha, K. J. Karczewski, S. R. Depalma, D. Mckean, A. Romano-Adesman, W. K. Chung, +31 Additional Authors

Journal Articles

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, …

Genome-Wide Scans Detect Adaptation To Aridity In A Widespread Forest Tree Species [Dataset], Dorothy A. Steane, Brad M. Potts, Elizabeth Mcclean, Suzanne M. Prober, William D. Stock, René E. Vaillancourt, Margaret Byrne

Research Datasets

Patterns of adaptive variation within plant species are best studied through common garden experiments, but these are costly and time-consuming, especially for trees that have long generation times. We explored whether genome-wide scanning technology combined with outlier marker detection could be used to detect adaptation to climate and provide an alternative to common garden experiments. As a case study, we sampled nine provenances of the widespread forest tree species, Eucalyptus tricarpa, across an aridity gradient in southeastern Australia. Using a Bayesian analysis we identified a suite of 94 putatively adaptive (outlying) sequence-tagged markers across the genome. Population-level allele frequencies of …

Genetic Network Properties Of The Human Cortex Based On Regional Thickness And Surface Area Measures, Anna R. Docherty, Chelsea K. Sawyers, Matthew S. Panizzon, Michael C. Neale, Lisa T. Eyler, Christine Fennema-Notestine, Carol E. Franz, Chi-Hua Chen, Linda K. Mcevoy, Brad Verhulst, Ming T. Tsuang, William S. Kremen

Psychiatry Publications

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques—biometrical genetic modeling, cluster analysis, and graph theory—to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several …

De Novo Assembly Of The Chimpanzee Transcriptome From Nextgen Mrna Sequences, Mnirnal D. Maudhoo, Jacob D. Madison, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: Common chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) are the species most closely related to humans. For this reason, it is especially important to have complete and accurate chimpanzee nucleotide and protein sequences to understand how humans evolved their unique capabilities. We provide transcriptome data from four untransformed cell types derived from the reference Pan troglodytes, "Clint", to better annotate the chimpanzee genome and provide empirical validation for proposed gene models of this important species.

FINDINGS: RNA was extracted from primary cells cultured from four tissues: skin, adipose stroma, vascular smooth muscle and skeletal muscle. These four RNA samples …