Inferring hypotheses from complex profile data [Elektronische Ressource] : by means of CSB.DB, a comprehensive systems-biology database / by Dirk Steinhauser

Steinhauser

Sujets

• Biologie

Informations

• Publié par: universitat_potsdam
• Publié le: 01 janvier 2005
• Nombre de lectures: 4
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Max Planck Institute of Molecular Plant Physiology
Department: Molecular Physiology
Research Group: Root Metabolism



Inferring Hypotheses from Complex Profile Data
- By Means of CSB.DB, a Comprehensive Systems-Biology Database -


Dissertation

A thesis submitted to the
Mathematisch-Naturwissenschaftliche Fakultät
of the
Universität Potsdam
for the degree of

‘doctor rerum naturalium’
(Dr. rer. nat.)






by
Dirk Steinhauser

Potsdam, October 2004























The work presented in this thesis was carried out between October 2001 and September 2004 at the
Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm.
st1 Examiner: Prof. Dr. Lothar Willmitzer
Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany

nd2 Examiner: Prof. Dr. Joachim Selbig
Institute of Biochemistry and Biology, Potsdam University, Germany

th3 Examiner: Prof. Dr. Dierk Scheel
Leibnitz Institute of Plant Biochemistry, Halle, Germany

rd4 Examiner: Prof. Dr. Uwe Sonnewald
Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany

This Ph.D. thesis is the account of work done between October 2001 and September 2004 in the
department of Prof. Willmitzer at the Max Planck Institute of Molecular Plant Physiology, Golm,
Germany. It is result of my own work and has not been submitted for any degree or Ph.D. at any other
university.












Eidesstattliche Erklärung

Diese Dissertation ist das Ergebnis praktischer Arbeit, welche von Oktober 2001 bis September 2004
durchgeführt wurde in der Abteilung von Prof. Willmitzer im Max-Planck-Institut für Molekulare
Pflanzenphysiologie, Golm. Ich versichere, die vorliegende Arbeit selbständig und ohne unerlaubte
Hilfe angefertigt und keine anderen als die angegebenen Quellen und Hilfsmittel benutzt zu haben. Ich
versichere ebenfalls, dass die Arbeit an keiner anderen Hochschule als der Universität Potsdam
eingereicht wurde.



Potsdam-Golm, im Oktober 2004


Dirk Steinhauser
Abstract
Abstract
The past decades are characterized by various efforts to provide complete sequence information of
genomes regarding various organisms. The availability of full genome data triggered the development
of multiplex high-throughput assays allowing simultaneous measurement of transcripts, proteins and
metabolites. With genome information and profiling technologies now in hand a highly parallel
experimental biology is offering opportunities to explore and discover novel principles governing
biological systems. Understanding biological complexity through modelling cellular systems
represents the driving force which today allows shifting from a component-centric focus to integrative
and systems level investigations. The emerging field of systems biology integrates discovery and
hypothesis-driven science to provide comprehensive knowledge via computational models of
biological systems.
Within the context of evolving systems biology, investigations were made in large-scale
computational analyses on transcript co-response data through selected prokaryotic and plant model
organisms. CSB.DB - a comprehensive systems-biology database - (http://csbdb.mpimp-
golm.mpg.de/) was initiated to provide public and open access to the results of biostatistical analyses
in conjunction with additional biological knowledge. The database tool CSB.DB enables potential
users to infer hypothesis about functional interrelation of genes of interest and may serve as future
basis for more sophisticated means of elucidating gene function. The co-response concept and the
CSB.DB database tool were successfully applied to predict operons in Escherichia coli by using the
chromosomal distance and transcriptional co-responses. Moreover, examples were shown which
indicate that transcriptional co-response analysis allows identification of differential promoter
activities under different experimental conditions. The co-response concept was successfully
transferred to complex organisms with the focus on the eukaryotic plant model organism Arabidopsis
thaliana. The investigations made enabled the discovery of novel genes regarding particular
physiological processes and beyond, allowed annotation of gene functions which cannot be accessed
by sequence homology. GMD - the Golm Metabolome Database - was initiated and implemented in
CSB.DB to integrated metabolite information and metabolite profiles. This novel module will allow
addressing complex biological questions towards transcriptional interrelation and extent the recent
systems level quest towards phenotyping.
Page - 1 - Table of Contents
Table of Contents
ABSTRACT........................................................................................................................................................... 1
TABLE OF CONTENTS....... 2
CHAPTER I - GENERAL INTRODUCTION: - GENOMICS & POST-GENOMICS -............................. 3
CHAPTER II - IMPLEMENTATION & DEVELOPMENT: - CSB.DB: A COMPREHENSIVE
SYSTEMS-BIOLOGY DATABASE -............................................................................................................... 19
CHAPTER III - PROOF OF CONCEPT: - HYPOTHESIS-DRIVEN APPROACH TO PREDICT
TRANSCRIPTIONAL UNITS FROM GENE EXPRESSION DATA - ........................................................ 27
CHAPTER IV - APPLICATION TO A.THALIANA: - IDENTIFICATION OF BRASSINOSTEROID-
RELATED GENES BY MEANS OF TRANSCRIPT CO-RESPONSE ANALYSES -................................ 45
CHAPTER V - APPLICATION TO A.THALIANA: - INFERRING HYPOTHESES FOR GENE
FUNCTIONS: THE ARABIDOPSIS THALIANA SUBTILASE GENE FAMILY -..................................... 67
CHAPTER VI - FROM GENOME TO METABOLOME: - [e-mail]: THE GOLM
METABOLOME DATABASE -........................................................................................................................ 90
CHAPTER VII - GENERAL DISCUSSION & OUTLOOK: - SYSTEMS BIOLOGY: FROM INSIDE
TO OUTSIDE - ................................................................................................................................................... 99
DEUTSCHE ZUSAMMENFASSUNG ........................................................................................................... 112
ACKNOWLEDGEMENTS.............................................................................................................................. 113
CURRICULUM VITAE.... 114
LIST OF PUBLICATIONS 115
APPENDIX........................................................................................................................................................ 117

Page - 2 - Chapter I: General Introduction


Chapter I - General Introduction:
- Genomics & Post-Genomics -
Abstract
The past decades have seen a growing number of organisms with available complete genome
sequences. The accessibility of those resources triggered the development and recent maturation of
high-throughput assays. Multi-parallel analyses of transcripts, proteins and metabolites are central for
functional genomics. This highly parallel experimental biology is offering opportunities to explore and
discover underlying governing principles of biological systems. The following sections give a brief
overview of past and recent developments of high-throughput approaches and bioinformatics which
take advantage from the availability of entire genome sequences and multi-parallel techniques.

Introduction
Recent biological research is characterized by a noteworthy alteration which is mainly driven by the
massive increase of sequence information and the development of high-throughput assays.
Consequently, new types of experiments are made possible and allow scientists discoveries and
explorations of biological processes and functions on an unprecedented scale. In the past decades
various multinational coordinated efforts have focused on genome sequencing and initial gene
analyses. Recently, theses large investments led to a public release of more than 30 entire or partial
genome sequences (see http://www.ncbi.nlm.nih.gov/Genomes/index.html). Those breakthroughs have
been made for Escherichia coli (Blattner et al., 1997), Saccharomyces cerevisiae (Goffeau et al.,
1996), Arabidopsis thaliana (The Arabidopsis Genome Initiative, 2000), Oryza sativa (Yo et al.,2002),
Drosophila melangolaster (Adams et al, 2000), Caenorhabditis elegans (The C. elegans Sequencing
Consortium, 1998), Homo sapiens (The International Human Genome Sequencing Consortium, 2001),
and many other species. Further progress of genome sequencing, in both public and private efforts,
will be made for at least another hundreds of organisms in the near future (see
http://www.ncbi.nlm.nih.gov/Genomes/index.html), e.g. Lycopersicon esculentum [Solanaceae
Genome Network, (http://www.sgn.cornell.edu/index.html)]. The limitations of large-scale EST
(expressed