Genetics and Genomics Commons^™

The Regulation Of The Phosphatidate Phosphatase Gene Pah1 And Its Regulatory Role On Cell Homeostasis, Goldie Libby Sherr

Dissertations, Theses, and Capstone Projects

The Saccharomyces cerevisiae gene, PAH1, encodes a phosphatidate (PA) phosphatase that plays a fundamental role in lipid metabolism. PA phosphatases are key enzymes that catalyze the PA dephosphorylation reaction to form diacylglycerides, the first step in the synthesis of triacylglycerols. Pah1p, one of the main PA phosphatases in yeast, has not only emerged as a key player in lipid biosynthetic pathways, but also acts as an important regulator of nuclear membrane biogenesis, the transcriptional regulation of many inositol-sensitive upstream activating sequence (UAS_INO)containing genes needed for phospholipid synthesis, vacuole homeostasis, and lipid droplet formation. Due to its …

Machine Learning Meta-Analysis Of Large Metagenomic Datasets: Tools And Biological Insight, Edoardo Pasolli, Duy Tin Truong, Faizan Malik, Levi Waldron, Nicola Segata

Publications and Research

Shotgun metagenomic analysis of the human associated microbiome provides a rich set of microbial features for prediction and biomarker discovery in the context of human diseases and health conditions. However, the use of such high-resolution microbial features presents new challenges, and validated computational tools for learning tasks are lacking. Moreover, classification rules have scarcely been validated in independent studies, posing questions about the generality and generalization of disease-predictive models across cohorts. In this paper, we comprehensively assess approaches to metagenomics-based prediction tasks and for quantitative assessment of the strength of potential microbiome-phenotype associations. We develop a computational framework for prediction …

Epigenetic Profiles Signify Cell Fate Plasticity In Unipotent Spermatogonial Stem And Progenitor Cells, Ying Liu, Eugenia G. Giannopoulou, Duacheng Wen, Ilaria Falciatori, Oliver Elemento, C. David Allis, Shahin Rafii, Marco Seandel

Publications and Research

Spermatogonial stem and progenitor cells (SSCs) generate adult male gametes. During in vitro expansion, these unipotent murine cells spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here we investigate this conversion process through integrative transcriptomic and epigenomic analyses. We find in SSCs that promoters essential to maintenance and differentiation of embryonic stem cells (ESCs) are enriched with histone H3-lysine4 and -lysine 27 trimethylations. These bivalent modifications are maintained at most somatic promoters after conversion, bestowing MASCs an ESC-like promoter chromatin. At enhancers, the core pluripotency circuitry is activated partially in SSCs and completely in MASCs, concomitant with loss of …

The Implications Of Chromatin Remodelers' Acetylation In Ino1 Activation, Michelle M. Esposito

Dissertations, Theses, and Capstone Projects

It is known that histone acetylases (HATs) regulate gene expression, but only recently have new functional implications about remodelers’ acetylation emerged. For instance, the HAT, Gcn5p, is capable of acetylating the catalytic subunit of the nucleosome remodeling complex SWI/SNF, Snf2p, which results in the dissociation of the complex from chromatin. The implications of this acetylation and subsequent dissociation have yet to be explored with regard to transcriptional regulation and other possible mechanisms. To further understand the implications of remodeler acetylation, I used a yeast model system examining the expression of the inositol-3-phosphate synthase gene INO1. Through chromatin immunoprecipitation (ChIP) …

Role Of Bec-1/Beclin 1 And Autophagy Genes In C.Elegans Germline Cell Proliferation, Kristina Ames

Dissertations, Theses, and Capstone Projects

Autophagy is an evolutionary conserved process involved in the cellular adaptation to stress and basal levels of autophagy are crucial for cellular metabolism and homeostasis. Cellular recycling by autophagy is characterized by the formation of distinctive double-membrane vesicles (autophagosomes) that engulf unnecessary cytoplasmic components, such as organelles and long-lived proteins. Failure to remove protein aggregates and/or damaged organelles, via autophagy, has been implicated in various medical conditions such as liver disease, neurodegenerative diseases and cancer. Autophagy may suppress or promote cellular proliferation in tumors, depending on the type and metabolic state of the cell, where autophagy is generally believed to …

Cellmapper: Rapid And Accurate Inference Of Gene Expression In Difficult-To-Isolate Cell Types, Bradlee D. Nelms, Levi Waldron, Luis A. Barrera, Andrew W. Weflen, Jeremy A. Goettel, Guoji Guo, Robert K. Montgomery, Marian R. Neutra, David T. Breault, Scott B. Snapper, Stuart H. Orkin, Martha L. Bulyk, Curtis Huttenhower, Wayne I. Lencer

Publications and Research

We present a sensitive approach to predict genes expressed selectively in specific cell types, by searching publicly available expression data for genes with a similar expression profile to known cell-specific markers. Our method, CellMapper, strongly outperforms previous computational algorithms to predict cell type-specific expression, especially for rare and difficult-to-isolate cell types. Furthermore, CellMapper makes accurate predictions for human brain cell types that have never been isolated, and can be rapidly applied to diverse cell types from many tissues. We demonstrate a clinically relevant application to prioritize candidate genes in disease susceptibility loci identified by GWAS.

Phylogenomic Identification Of Regulatory Sequences In Bacteria: An Analysis Of Statistical Power And An Application To Borrelia Burgdorferi Sensu Lato, Che I. Martin, Tika Y. Sukarna, Saymon Akther, Girish Ramrattan, Pedro Pagan, Lia Di, Emmanuel F. Mongodin, Claire M. Fraser, Steven E. Schutzer, Benjamin J. Luft, Sherwood R. Casjens, Wei-Gang Qiu

Publications and Research

Phylogenomic footprinting is an approach for ab initio identification of genome-wide regulatory elements in bacterial species based on sequence conservation. The statistical power of the phylogenomic approach depends on the degree of sequence conservation, the length of regulatory elements, and the level of phylogenetic divergence among genomes. Building on an earlier model, we propose a binomial model that uses synonymous tree lengths as neutral expectations for determining the statistical significance of conserved intergenic spacer (IGS) sequences. Simulations show that the binomial model is robust to variations in the value of evolutionary parameters, including base frequencies and the transition-to-transversion ratio. We …

Improved Evidence-Based Genome-Scale Metabolic Models For Maize Leaf, Embryo, And Endosperm, Samuel M. D. Seaver, Louis M. T. Bradbury, Océane Frelin, Raphy Zarecki, Eytan Ruppin, Andrew D. Hanson, Christopher S. Henry

Publications and Research

There is a growing demand for genome-scale metabolic reconstructions for plants, fueled by the need to understand the metabolic basis of crop yield and by progress in genome and transcriptome sequencing. Methods are also required to enable the interpretation of plant transcriptome data to study how cellular metabolic activity varies under different growth conditions or even within different organs, tissues, and developmental stages. Such methods depend extensively on the accuracy with which genes have been mapped to the biochemical reactions in the plant metabolic pathways. Errors in these mappings lead to metabolic reconstructions with an inflated number of reactions and …

High-Throughput Comparison, Functional Annotation, And Metabolic Modeling Of Plant Genomes Using The Plantseed Resource, Samuel M. D. Seaver, Svetlana Gerdes, Océane Frelin, Claudia Lerma-Ortiz, Louis M. T. Bradbury, Rémi Zallot, Ghulam Hasnain, Thomas D. Niehaus, Basma El Yacoubi, Shiran Pasternak, Robert Olson, Gordon Pusch, Ross Overbeek, Valérie De Crécy-Lagarde, Doreen Ware, Andrew D. Hanson, Christopher S. Henry

Publications and Research

There is a growing demand for genome-scale metabolic reconstructions for plants, fueled by the need to understand the metabolic basis of crop yield and by progress in genome and transcriptome sequencing. Methods are also required to enable the interpretation of plant transcriptome data to study how cellular metabolic activity varies under different growth conditions or even within different organs, tissues, and developmental stages. Such methods depend extensively on the accuracy with which genes have been mapped to the biochemical reactions in the plant metabolic pathways. Errors in these mappings lead to metabolic reconstructions with an inflated number of reactions and …

Long-Term Cre-Mediated Retrograde Tagging Of Neurons Using A Novel Recombinant Pseudorabies Virus, Hysell V. Oviedo, Hassasna K. Oyibo, Petr Znamenskiy, Lynn W. Enquist, Anthony M. Zador

Publications and Research

Brain regions contain diverse populations of neurons that project to different long-range targets. The study of these subpopulations in circuit function and behavior requires a toolkit to characterize and manipulate their activity in vivo. We have developed a novel set of reagents based on Pseudorabies Virus (PRV) for efficient and long-term genetic tagging of neurons based on their projection targets. By deleting IE180, the master transcriptional regulator in the PRV genome, we have produced a mutant virus capable of infection and transgene expression in neurons but unable to replicate in or spread from those neurons. IE180-null mutants showed no cytotoxicity, …

Collective Behaviour Without Collective Order In Wild Swarms Of Midges, Alessandro Attanasi, Andrea Cavagna, Lorenzo Del Castello, Irene Giardina, Stefania Melillo, Leonardo Parisi, Oliver Pohl, Bruno Rossaro, Edward Shen, Edmondo Silvestri, Massimilano Viale

Publications and Research

Collective behaviour is a widespread phenomenon in biology, cutting through a huge span of scales, from cell colonies up to bird flocks and fish schools. The most prominent trait of collective behaviour is the emergence of global order: individuals synchronize their states, giving the stunning impression that the group behaves as one. In many biological systems, though, it is unclear whether global order is present. A paradigmatic case is that of insect swarms, whose erratic movements seem to suggest that group formation is a mere epiphenomenon of the independent interaction of each individual with an external landmark. In these cases, …

Fast Quantitative Real-Time Pcr-Based Screening For Common Chromosomal Aneuploidies In Mouse Embryonic Stem Cells, Charlotte D'Hulst, Irena Parvanova, Delia Tomoiaga, Maria L. Sapar, Paul Feinstein

Publications and Research

Chromosomal integrity has been known for many years to affect the ability of mouse embryonic stem cells (mESCs) to contribute to the germline of chimeric mice. Abnormal chromosomes are generally detected by standard cytogenetic karyotyping. However, this method is expensive, time consuming, and often omitted prior to blastocyst injection, consequently reducing the frequency of mESC-derived offspring. Here, we show a fast, accurate, and inexpensive screen for identifying the two most common aneuploidies (Trisomy 8 and loss of chromosome Y) in genetically manipulated mESCs using quantitative real-time PCR (qPCR). Screening against these two aneuploidies significantly increases the fraction of normal mESC …

Signatures Of Rapid Evolution In Urban And Rural Transcriptomes Of White-Footed Mice (Peromyscus Leucopus) In The New York Metropolitan Area, Stephen Edward Harris, Jason Munshi-South, Craig Oberfell, Rachel O'Neill

Publications and Research

Urbanization is a major cause of ecological degradation around the world, and human settlement in large cities is accelerating. New York City (NYC) is one of the oldest and most urbanized cities in North America, but still maintains 20% vegetation cover and substantial populations of some native wildlife. The white-footed mouse, Peromyscus leucopus, is a common resident of NYC’s forest fragments and an emerging model system for examining the evolutionary consequences of urbanization. In this study, we developed transcriptomic resources for urban P. leucopus to examine evolutionary changes in protein-coding regions for an exemplar “urban adapter.” We used Roche 454 …

Genome-Wide Analyses Of Shavenbaby Target Genes Reveals Distinct Features Of Enhancer Organization, Delphine Menoret, Marc Santolini, Isabelle Fernandes, Rebecca Spokony, Jennifer Zanet, Ignacio Gonzalez, Yvan Latapie, Pierre Ferrer, Hervé Rouault, Kevin P. White, Philippe Besse, Vincent Hakim, Stein Aerts, Francois Payre, Serge Plaza

Publications and Research

Background: Developmental programs are implemented by regulatory interactions between Transcription Factors (TFs) and their target genes, which remain poorly understood. While recent studies have focused on regulatory cascades of TFs that govern early development, little is known about how the ultimate effectors of cell differentiation are selected and controlled. We addressed this question during late Drosophila embryogenesis, when the finely tuned expression of the TF Ovo/Shavenbaby (Svb) triggers the morphological differentiation of epidermal trichomes.

Results: We defined a sizeable set of genes downstream of Svb and used in vivo assays to delineate 14 enhancers driving their specific expression in trichome …

Pten Regulation Of Local And Long-Range Connections In Mouse Auditory Cortex, Qiaojie Xiong, Hysell V. Oviedo, Lloyd C. Trotman, Anthony M. Zador

Publications and Research

Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression. Laser-scanning photostimulation showed …

Comparative Genomics Of The Pathogenic Ciliate Ichthyophthirius Multifiliis, Its Free-Living Relatives And A Host Species Provide Insights Into Adoption Of A Parasitic Lifestyle And Prospects For Disease Control, Robert S. Coyne, Linda Hannick, Dhanasekaran Shanmugam, Jessica B. Hostetler, Daniel Brami, Vinita S. Joardar, Justin Johnson, Diana Radune, Irtisha Singh, Jonathan H. Badger, Ujjwal Kumar, Milton Saier, Yufeng Wang, Hong Cai, Jianying Gu, Michael W. Mather, Akhil B. Vaidya, David E. Wilkes, Vidyalakshmi Rajagopalan, David J. Asai, Chad G. Pearson, Robert C. Findly, Harry W. Dickerson, Martin Wu, Cindy Martens, Yves Van De Peer, David S. Roos, Donna M. Cassidy-Hanley, Theodore G. Clark

Publications and Research

Background

Ichthyophthirius multifiliis, commonly known as Ich, is a highly pathogenic ciliate responsible for 'white spot', a disease causing significant economic losses to the global aquaculture industry. Options for disease control are extremely limited, and Ich's obligate parasitic lifestyle makes experimental studies challenging. Unlike most well-studied protozoan parasites, Ich belongs to a phylum composed primarily of free-living members. Indeed, it is closely related to the model organism Tetrahymena thermophila. Genomic studies represent a promising strategy to reduce the impact of this disease and to understand the evolutionary transition to parasitism.

Results

We report the sequencing, assembly and annotation …