Medical Sciences Commons^™

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J. Krais, David J. Glass, Ilse Chudoba, Yifan Wang, Wanjuan Feng, Dennis Simpson, Pooja Patel, Zemin Liu, Ryan Neumann-Domer, Robert G. Betsch, Andrea J. Bernhardy, Alice M. Bradbury, Jason Conger, Wei-Ting Yueh, Joseph Nacson, Richard T. Pomerantz, Gaorav P. Gupta, Joseph R. Testa, Neil Johnson

Department of Biochemistry and Molecular Biology Faculty Papers

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq−/− cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were …

Multi-Ancestry Genome-Wide Association Analyses Improve Resolution Of Genes And Pathways Influencing Lung Function And Chronic Obstructive Pulmonary Disease Risk, Nick Shrine, Abril G. Izquierdo, Jing Chen, Richard Packer, Robert J. Hall, Anna L. Guyatt, Chiara Batini, Rebecca J. Thompson, Chandan Puvuluri, Vidhi Malik, Brian D. Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A. Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Sinjini Sikdar, Martin D. Tobin, Et Al.

Mathematics & Statistics Faculty Publications

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of …

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 and Presentations

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 …

Updated Genes, Lifestyles, And Their Interactions For Human Longevity, Brenda Bin Su, Alexis Villafranca, Chunxiang Mao, Stephanie Hernandez, Stephanie Lozano, Masoud M. Zarei, Kesheng Wang, Saraswathy Nair, Chun Xu

Health & Biomedical Sciences Faculty Publications and Presentations

Healthy aging is the prolonging of optimal wellbeing during the progressive decline in physiological functions that are necessary for survival. Two important components of aging include an individual’s genetic makeup and lifestyle choices such as diet and exercise. Genetic factors are responsible for the functional physiology of the body including cell maintenance, metabolism and apoptosis. The individual effects of genes and lifestyle choices on aging are reported mainly in Caucasian populations, with very limited studies in minority populations. In this review, we included the effects of genes and environment and the interaction between them on aging in Hispanic population in …

The Role Of Ifih1 Gene Rs1990760 And Rs2111485 Single-Nucleotide Polymorphisms In Generalized Vitiligo Predisposition, Duru Onan, Ahu Yorulmaz, Fati̇h Süheyl Ezgü, Kadi̇r Mutlu Hayran, Seray Külcü Çakmak, Refi̇ka Ferda Artüz, Başak Yalçin

Turkish Journal of Medical Sciences

Interferon-induced helicase (IFIH1) is a gene locus that has been recently defined as a candidate for susceptibility to generalized vitiligo (GV). The objectives of this study were to assess the association of IFIH1 gene, rs2111485, and rs1990760 single-nucleotide polymorphisms (SNP) with susceptibility to GV and the autoimmune diseases accompanying GV.Materials and methods: We prospectively studied GV patients and frequency-matched healthy controls by age and sex. The genotypes of the participants were determined for rs1990760 and rs2111485 SNPs of IFIH1. Dominant, recessive, and additive models were evaluated for each SNP adjusted for age and sex. Results: The patients and their controls …

The Zinc Transporter Zipt-7.1 Regulates Sperm Activation In Nematodes, Yanmei Zhao, Chieh-Hsiang Tan, Amber Krauchunas, Andrea Scharf, Nicholas Dietrich, Kurt Warnhoff, Zhiheng Yuan, Marina Druzhinina, Sam Guoping Gu, Long Miao, Andrew Singson, Ronald E Ellis, Kerry Kornfeld

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating …

Examining The Influence And Role Of Pharmacogenetics Among Children With Autism Spectrum Disorder, Nuha Shaker

Masters Theses & Specialist Projects

Pharmacogenetics is the study of genomic-guided individualized drug prescription that plays an important role in preventing the severe adverse effects of drugs, decreasing the time and cost of therapeutic choices, and directing healthcare professionals to choose medications that are effective and safe. It is noteworthy that this approach becomes highly beneficial in patients suffering from chronic diseases or disorders, since these conditions may require multiple and long term pharmacological therapies, as in children with autism spectrum disorder (ASD). However, public acceptance is a major challenge when implementation of pharmacogenetics merges into clinical practice. The purpose of this study is a) …

A Novel Genetic Variant In Long Non-Coding Rna Gene Nexn-As1 Is Associated With Risk Of Lung Cancer, Hua Yuan, Hongliang Liu, Zhensheng Liu, Kouros Owzar

Dartmouth Scholarship

Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wideassociation studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortiumin populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10−7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University anddeCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant(odds ratio = 1.17; 95% confidence interval = 1.11–1.24; P = 8.31 × 10−9). In further in silico analysis,rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.

Requirements For Pseudomonas Aeruginosa Type I-F Crispr-Cas Adaptation Determined Using A Biofilm Enrichment Assay, Gary E. Heussler, Jon L. Miller, Courtney E. Price, Alan J. Collins

Dartmouth Scholarship

CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated protein) systems are diverse and found in many archaea and bacteria. These systems have mainly been characterized as adaptive immune systems able to protect against invading mobile genetic elements, including viruses. The first step in this protection is acquisition of spacer sequences from the invader DNA and incorporation of those sequences into the CRISPR array, termed CRISPR adaptation. Progress in understanding the mechanisms and requirements of CRISPR adaptation has largely been accomplished using overexpression of cas genes or plasmid loss assays; little work has focused on endogenous CRISPR-acquired immunity from viral predation. …

Elevated Mtss1 Expression Associated With Metastasis And Poor Prognosis Of Residual Hepatitis B-Related Hepatocellular Carcinoma, Xiu-Yan Huang, Zi-Li Huang, Bin Xu, Zi Chen

Dartmouth Scholarship

Background: Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear.

Methods: An orthotopic nude mice model with palliative HCC hepatectomy was performed in this study. Metastasis-related genes in tumor following resection were screened; HCC invasion, metastasis, and some molecular alterations were examined in vivo and in vitro. Clinical significance of key gene mRNA expression was also analyzed.

Variants In Cxcr4 Associate With Juvenile Idiopathic Arthritis Susceptibility., Terri H. Finkel, Jin Li, Zhi Wei, Wei Wang, Haitao Zhang, Edward M. Behrens, Emma L. Reuschel, Sophie Limou, Carol Wise, Marilynn Punaro, Mara L. Becker, Jane E. Munro, Berit Flatø, Øystein Førre, Susan D. Thompson, Carl D. Langefeld, David N. Glass, Joseph T. Glessner, Cecilia E. Kim, Edward Frackelton, Debra K. Shivers, Kelly A. Thomas, Rosetta M. Chiavacci, Cuiping Hou, Kexiang Xu, James Snyder, Haijun Qiu, Frank Mentch, Kai Wang, Cheryl A. Winkler, Benedicte A. Lie, Justine A. Ellis, Hakon Hakonarson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.

METHODS: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed …

Expression Of Complement And Toll-Like Receptor Pathway Genes Is Associated With Malaria Severity In Mali: A Pilot Case Control Study, Rafal S. Sobota, Antoine Dara, Jessica E. Manning, Amadou Niangaly

Dartmouth Scholarship

Background: The host response to infection by Plasmodium falciparum, the parasite most often responsible for severe malaria, ranges from asymptomatic parasitaemia to death. The clinical trajectory of malaria is influenced by host genetics and parasite load, but the factors determining why some infections produce uncomplicated malaria and some proceed to severe disease remain incompletely understood.

Methods: To identify molecular markers of severe falciparum malaria, human gene expression patterns were compared between children aged 6 months to 5 years with severe and uncomplicated malaria who were enrolled in a case–control study in Bandiagara, Mali. Microarrays were used to obtain expression …

Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib

Dartmouth Scholarship

Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic …

Iron-Dependent Gene Expression In Actinomyces Oris, Matthew P. Mulé, David Giacalone, Kayla Lawlor, Alexa Golden, Caroline Cook, Thomas Lott, Elizabeth Aksten, George A. O'Toole, Lori J. Bergeron

Dartmouth Scholarship

Actinomyces oris is a Gram-positive bacterium that has been associated with healthy and diseased sites in the human oral cavity. Most pathogenic bacteria require iron to survive, and in order to acquire iron in the relatively iron-scarce oral cavity A. oris has been shown to produce iron-binding molecules known as siderophores. The genes encoding these siderophores and transporters are thought to be regulated by the amount of iron in the growth medium and by the metal-dependent repressor, AmdR, which we showed previously binds to the promoter of proposed iron-regulated genes.

Cyclic Di-Gmp-Mediated Repression Of Swarming Motility By Pseudomonas Aeruginosa Pa14 Requires The Motab Stator, S. L. Kuchma, N. J. Delalez, L. M. Filkins, E. A. Snavely, J. P. Armitage, G. A. O'Toole

Dartmouth Scholarship

The second messenger cyclic diguanylate (c-di-GMP) plays a critical role in the regulation of motility. In Pseudomonas aeruginosa PA14, c-di-GMP inversely controls biofilm formation and surface swarming motility, with high levels of this dinucleotide signal stimulating biofilm formation and repressing swarming. P. aeruginosa encodes two stator complexes, MotAB and MotCD, that participate in the function of its single polar flagellum. Here we show that the repression of swarming motility requires a functional MotAB stator complex. Mutating the motAB genes restores swarming motility to a strain with artificially elevated levels of c-di-GMP as well as stimulates swarming in the wild-type strain, …

Meta-Gsa: Combining Findings From Gene-Set Analyses Across Several Genome-Wide Association Studies, Albert Rosenberger, Stefanie Friedrichs, Christopher I. Amos, Paul Brennan, Gordon Fehringer, Joachim Heinrich, Rayjean J. Hung, Thomas Muley, Martina Müller-Nurasyid, Angela Risch, Heike Bickeböller

Dartmouth Scholarship

Gene-set analysis (GSA) methods are used as complementary approaches to genome-wide association studies (GWASs). The single marker association estimates of a predefined set of genes are either contrasted with those of all remaining genes or with a null non-associated background. To pool the p-values from several GSAs, it is important to take into account the concordance of the observed patterns resulting from single marker association point estimates across any given gene set. Here we propose an enhanced version of Fisher’s inverse χ²-method META-GSA, however weighting each study to account for imperfect correlation between association patterns.

Testing Multiple Hypotheses Through Imp Weighted Fdr Based On A Genetic Functional Network With Application To A New Zebrafish Transcriptome Study, Jiang Gui, Casey S. Greene, Con Sullivan, Walter Taylor, Jason H. Moore, Carol Kim

Dartmouth Scholarship

In genome-wide studies, hundreds of thousands of hypothesis tests are performed simultaneously. Bonferroni correction and False Discovery Rate (FDR) can effectively control type I error but often yield a high false negative rate. We aim to develop a more powerful method to detect differentially expressed genes. We present a Weighted False Discovery Rate (WFDR) method that incorporate biological knowledge from genetic networks. We first identify weights using Integrative Multi-species Prediction (IMP) and then apply the weights in WFDR to identify differentially expressed genes through an IMP-WFDR algorithm. We performed a gene expression experiment to identify zebrafish genes that change expression …

Clustered Regularly Interspaced Short Palindromic Repeat-Dependent, Biofilm-Specific Death Of Pseudomonas Aeruginosa Mediated By Increased Expression Of Phage-Related Genes, Gary E. E. Heussler, Kyle C. Cady, Katja Koeppen, Sabin Bhuju, Bruce A. Stanton, George A. O’Toole

Dartmouth Scholarship

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (CRISPR/Cas) system is an adaptive immune system present in many archaea and bacteria. CRISPR/Cas systems are incredibly diverse, and there is increasing evidence of CRISPR/Cas systems playing a role in cellular functions distinct from phage immunity. Previously, our laboratory reported one such alternate function in which the type 1-F CRISPR/Cas system of the opportunistic pathogen Pseudomonas aeruginosa strain UCBPP-PA14 (abbreviated as P. aeruginosa PA14) inhibits both biofilm formation and swarming motility when the bacterium is lysogenized by the bacteriophage DMS3. In this study, we demonstrated that the presence of just the DMS3 …

Nonreplicating, Cyst-Defective Type Ii Toxoplasma Gondii Vaccine Strains Stimulate Protective Immunity Against Acute And Chronic Infection, Barbara Andrea Fox, David J. Bzik

Dartmouth Scholarship

Live attenuated vaccine strains, such as type I nonreplicating uracil auxotroph mutants, are highly effective in eliciting lifelong immunity to virulent acute infection by Toxoplasma gondii. However, it is currently unknown whether vaccine-elicited immunity can provide protection against acute infection and also prevent chronic infection. To address this problem, we developed nonreverting, nonreplicating, live attenuated uracil auxotroph vaccine strains in the type II Δku80 genetic background by targeting the deletion of the orotidine 5′-monophosphate decarboxylase (OMPDC) and uridine phosphorylase (UP) genes. Deletion of OMPDC induced a severe uracil auxotrophy with loss of replication, loss of …

Early Inflammatory Mediator Gene Expression In Two Models Of Traumatic Brain Injury: Ex Vivo Cortical Slice In Mice And In Vivo Cortical Impact In Piglets, David J. Graber, Beth A. Costine, William F. Hickey

Dartmouth Scholarship

Background: The immunological response during the first 24 hours after traumatic brain injury (TBI) may be a critical therapeutic interval for limiting the secondary neuronal damage that is influenced by enhanced inflammatory mediator expression.

Methods: To gain further insight of the early injury response, we examined the expression of several inflammatory genes by real-time qPCR as a function of time or distance from injury in two distinct mammalian models: an ex vivo mouse cortical slice injury system and an in vivo piglet model of brain injury.

Influence Of Environmental Exposure On Human Epigenetic Regulation, C. J. Marsit

Dartmouth Scholarship

Environmental toxicants can alter epigenetic regulatory features such as DNA methylation and microRNA expression. As the sensitivity of epigenomic regulatory features may be greatest during the in utero period, when critical windows are narrow, and when epigenomic profiles are being set, this review will highlight research focused on that period. I will focus on work in human populations, where the impact of environmental toxicants in utero, including cigarette smoke and toxic trace metals such as arsenic, mercury and manganese, on genome-wide, gene-specific DNA methylation has been assessed. In particular, arsenic is highlighted, as this metalloid has been the focus …

Expression Of Enteropathogenic Escherichia Coli Map Is Significantly Different Than That Of Other Type Iii Secreted Effectors In Vivo., Mai Nguyen, Jason Rizvi, Gail Hecht

Department of Medicine Faculty Papers

The enteropathogenic Escherichia coli (EPEC) locus of enterocyte effacement (LEE)-encoded effectors EspF and Map are multifunctional and have an impact on the tight junction barrier while the non-LEE-encoded proteins NleH1 and NleH2 possess significant anti-inflammatory activity. In order to address the temporal expression of these important genes in vivo, their promoters were cloned upstream of the luxCDABE operon, and luciferase expression was measured in EPEC-infected mice by bioluminescence using an in vivo imaging system (IVIS). Bioluminescent images of living mice, of excised whole intestines, and of whole intestines longitudinally opened and washed were assessed. The majority of bioluminescent bacteria localized …

Correlation Between Antibiotic Resistance And Virulence Ofpseudomonas Aeruginosa Clinical Isolates, Fatma Ibrahim Sonbol, Maha Abd El Fattah Khalil, Abdelfattah Badr Mohamed, Sameh Samir Ali

Turkish Journal of Medical Sciences

Background/aim: Virulent Pseudomonas aeruginosa is frequently life-threatening and often challenging to treat, and the emergence of multidrug-resistant isolates presents a critical problem for patients. The aim of the study was concerned with molecular analysis of the virulence factors and antimicrobial resistance profile of multidrug-resistant P. aeruginosa (MDRPA). Materials and methods: Out of 44 MDRPA isolates, 12 isolates representing different resistance profiles and sources of samples were selected for further molecular studies. Polymerase chain reaction (PCR) approaches were applied to identify the genes implicated in antimicrobial resistance or virulence factors in the selected MDRPA isolates. Results: Multidrug-resistance (pstS), ß-lactamase (IMP7, IMP10, …

Analysis Of Clock-Regulated Genes In Neurospora Reveals Widespread Posttranscriptional Control Of Metabolic Potential, Jennifer M. M. Hurley, Arko Dasgupta, Jillian M. Emerson, Xiaoying Zhou, Carol S. Ringelberg, Nicole Knabe

Dartmouth Scholarship

Neurospora crassa has been for decades a principal model for filamentous fungal genetics and physiology as well as for understanding the mechanism of circadian clocks. Eukaryotic fungal and animal clocks comprise transcription-translation-based feedback loops that control rhythmic transcription of a substantial fraction of these transcriptomes, yielding the changes in protein abundance that mediate circadian regulation of physiology and metabolism: Understanding circadian control of gene expression is key to understanding eukaryotic, including fungal, physiology. Indeed, the isolation of clock-controlled genes (ccgs) was pioneered in Neurospora where circadian output begins with binding of the core circadian transcription factor WCC to a subset …

Chip-Seq And In Vivo Transcriptome Analyses Of The Aspergillus Fumigatus Srebp Srba Reveals A New Regulator Of The Fungal Hypoxia Response And Virulence, Dawoon Chung, Bridget M. Barker, Charles C. Carey, Brittney Merriman

Dartmouth Scholarship

The Aspergillus fumigatus sterol regulatory element binding protein (SREBP) SrbA belongs to the basic Helix-Loop-Helix (bHLH) family of transcription factors and is crucial for antifungal drug resistance and virulence. The latter phenotype is especially striking, as loss of SrbA results in complete loss of virulence in murine models of invasive pulmonary aspergillosis (IPA). How fungal SREBPs mediate fungal virulence is unknown, though it has been suggested that lack of growth in hypoxic conditions accounts for the attenuated virulence. To further understand the role of SrbA in fungal infection site pathobiology, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) was …

Inpp4b Suppresses Prostate Cancer Cell Invasion, Myles C. Hodgson, Elena I. Deryugina, Egla Suarez, Sandra M. Lopez, Dong Lin, Hui Xue, Ivan P. Gorlov

Dartmouth Scholarship

INPP4B and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease. We and others have previously shown that loss of INPP4B expression correlates with poor prognosis in multiple malignancies and with metastatic spread in prostate cancer.

We demonstrate that de novo expression of INPP4B in highly invasive human prostate carcinoma PC-3 cells suppresses their invasion both in vitro and in vivo. Using global gene expression analysis, we found that INPP4B regulates a number of genes associated with cell adhesion, the extracellular matrix, and the cytoskeleton. Importantly, de novo expressed INPP4B suppressed the proinflammatory chemokine …

The Association Of The Vanin-1 N131s Variant With Blood Pressure Is Mediated By Endoplasmic Reticulum-Associated Degradation And Loss Of Function, Ya-Juan Wang, Bamidele O. Tayo, Anupam Bandyopadhyay, Heming Wang, Tao Feng, Nora Franceschini, Hua Tang, Jianmin Gao, Yun Ju Sung, The Cogent Bp Consortium, Robert C. Elston, Scott M. Williams, Richard S. Cooper, Ting-Wei Mu, Xiaofeng Zhu

Dartmouth Scholarship

High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 …

Lineage-Specific Interface Proteins Match Up The Cell Cycle And Differentiation In Embryo Stem Cells, Angela Re, Christopher T. Workman, Levi Waldron, Alessandro Quattrone, Søren Brunak

Publications and Research

The shortage of molecular information on cell cycle changes along embryonic stem cell (ESC) differentiation prompts an in silico approach, which may provide a novel way to identify candidate genes or mechanisms acting in coordinating the two programs. We analyzed germ layer specific gene expression changes during the cell cycle and ESC differentiation by combining four human cell cycle transcriptome profiles with thirteen in vitro human ESC differentiation studies. To detect cross-talk mechanisms we then integrated the transcriptome data that displayed differential regulation with protein interaction data. A new class of non-transcriptionally regulated genes was identified, encoding proteins which interact …

Predicting Targeted Drug Combinations Based On Pareto Optimal Patterns Of Coexpression Network Connectivity, Nadia M. Penrod, Casey S. Greene, Jason H. Moore

Dartmouth Scholarship

Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets. We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced …

Brain White Matter Development Is Associated With A Human-Specific Haplotype Increasing The Synthesis Of Long Chain Fatty Acids, B. D. Peters, A. N. Voineskos, P. R. Szeszko, T. A. Lett, P. Derosse, S. Guha, K. H. Karlsgodt, M. John, T. Lencz, A. K. Malhotra, +4 Additional Authors

Journal Articles

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with omega-3 and omega-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = …