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GENOMICS AND PROTEOMICS Functional and Computational Aspects guoxingzhong and huangzhiman www.dnathink.org 2003.3.5 GENOMICS AND PROTEOMICS Functional and Computational Aspects Editedby Sándor Suhai Deutsches Krebsforschungszentrum Heidelberg, Germany KLUWER ACADEMIC PUBLISHERS New York, Boston, Dordrecht, London, Moscow eBook ISBN: 0-306-46823-9 Print ISBN: 0-306-46312-1 ©2002 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: http://www.kluweronline.com and Kluwer's eBookstore at: http://www.ebooks.kluweronline.com PREFACE Genome research will certainly be one of the most important and exciting scien- tificdisciplines of the 21st century. Deciphering the structure of the human genome, as wellasthatof severalmodel organisms,is the keytoourunderstandinghowgenesfunc- tioninhealth anddisease.Withthecombined developmentof innovativetools,resources, scientificknow-how, and an overall functional genomic strategy, the origins of human andother organisms’geneticdiseasescan betraced. Scientificresearch groupsanddevel- opmentaldepartmentsof severalmajor pharmaceuticaland biotechnologicalcompanies are using new, innovative strategiesto unravel how genes function, elucidating the gene protein product, understanding how genes interact with others-both in health and in the disease state. Presently, the impact of the applications of genome research on our society in medicine, agriculture and nutrition will be comparable only to that of communication technologies. In fact, computational methods, including networking, have been playing a substantialrole even in genomics and proteomics from the beginning. Wecan observe, however, a fundamental change of the paradigm in life sciences these days: research focused until now mostly on the study of single processes related to a fewgenes or gene products, but due to technical developments of the last years we can now potentially identifyand analyzeall genes and geneproducts of an organism and clarify their role in the network of life processes.This breakthrough in life sciencesis gaining speed world- wide and its impact on biology is comparable only to that ofmicrochips on information technology. Themain purpose of the International Symposium on Genomics and Proteomics: Functional and Computational Aspects, held October 4–7, 1998 at the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg, was to give an overview of the present state of the unique relationship between bioinformatics and experimental genome research. The five main sessions, under the headings: expression analysis; functional gene identification; functional aspects of higher order DNA-structure; from protein sequenceto structure and function; and genetic and medical aspects of genomics, com- prised both computational work and experimental studies to synergetically unify both approaches. The content of this volume was presented mostly as plenary lectures. The confer- .. ence was held at the same time as the Annual Meeting of the Gesellschaft fur Genetik (GfG). It is a great pleasure to thank Professor Harald zur Hausen and the coworkers ofDKFZ fortheir help and hospitality extended to the lecturers andparticipants during the meeting.We would also liketo thank the European Commission and the companies BASF AG, BASF-LYNX Bioscience AG, Bayer AG, BIOMEVA GmbH, Boehringer v vi Preface Mannheim GmbH, Hoffmann-La Roche Ltd., Knoll AG, Merck KGaA, and Schering AG for the funding of the symposium. The organizers, Annemarie Poustka, Hermann Bujard, and Sándor Suhai, profited greatly from the help of the scientificcommittee, ClausBartram,Jörg Hoheisel, FotisKafatos, Jörg Langowski,Peter Lichter,JensReich, Manfred Schwab,Peter Seeburg,and Martin Vingron. Furthermore, theeditor isdeeply indebted to Anke Retzmann and Michaela Knapp-Mohammady for their help in orga- nizing the meeting and preparing this volume. Sá'ndor Suhai CONTENTS 1. ... and Counting: DNA-Microarrays ........................... 1 Jörg D. Hoheisel 2. Obtaining and Evaluating Gene Expression Profiles with cDNA Microarrays .............................................. 5 Michael Bittner, Yidong Chen, Sally A. Amundson, Javed Khan, Albert J. Fornace Jr., Edward R. Dougherty, Paul S. Meltzer, and Jeffrey M. Frent 3. Large Scale Expression Screening Identifies MolecularPathways and Predicts Gene Function ................................... 27 Nicolas Pollet, Volker Gawantka, Hajo Delius, and Christof Niehrs 4. The Glean Machine: What Can We Learn from DNA Sequence Polymorphisms? .......................................... 37 Daniel L. Hartl, E. Fidelma Boyd, Carlos D. Bustamante, and Stanley A. Sawyer 5. Automatic Assembly and Editing of Genomic Data .................. 51 B. Chevreux, T. Pfisterer, and S. Suhai 6. QUEST: An Iterated Sequence Databank Search Method ............... 67 William R. Taylor and Nigel P. Brown 7. A n Essay on Individual Sequence Variatio nin Expressed Sequence Tags (ESTs) ......................................................... 83 Jens Reich, David Brett, and Jens Hanke 8. Sequence Similarity Based Gene Prediction ............................. 95 Roderic Guigó, Moisés Burset, Pankaj Agarwal, Josep E Abril, Randall F. Smith and James W. Fickett 9. Functional Proteomics ............................................. 107 Joachim Klose vii viii Contents 10. The Genome As a Flexible Polymer Chain: Recent Results from Simulations and Experiments .................................... 121 Jörg Langowski, Carsten Mehring, Markus Hammermann, Konstantin Klenin, Christian Münkel, Katalin Tóth, and Gero Wedemann 1 1. Analysis of Chromosome Territory Architecture in the Human Cell Nucleus: Overview of Data from a Collaborative Study ........... 133 H. Bornfleth, C. Cremer, T. Cremer, S. Dietzel, P. Edelmann, R. Eils, W.Jäger,D. Kienle,G. Kreth,P. Lichter, G. Little, C. Münkel, J. Langowski, I. Solovei, E. H. K. Stelzer, and D. Zink 12. From Sequence to Structure and Function: Modelling and Simulation of Light-Activated Membrane Proteins .................................. 141 Jerome Baudry, Serge Crouzy, Benoit Roux, and Jeremy C. Smith 13. SHOX Homeobox Gene and Turner Syndrome .......................... 149 E. Rao and G. A. Rappold 14. A Feature-Based Approach to Discrimination and Prediction of Protein Folding ................................................ 157 Boris Mirkin and Otto Ritter 15. Linking Structural Biology with Genome Research: The Berlin “Protein Structure Factory” Initiative ....................................... 179 Udo Heinemann, Juergen Frevert, Klaus-Peter Hofmann, Gerd Illing, Hartmut Oschkinat, Wolfram Saenger, and Rolf Zettl 16. G Protein-coupled Receptors, or the Power of Data ..................... 191 Florence Horn, Mustapha Mokrane, Johnathon Weare, and Gerrit Vriend 17. Distributed Application Management in Bioinformatics .................. 215 M. Senger, P. Ernst, and K.-H. Glatting 18. Is Human Genetics Becoming Dangerous to Society? .................... 231 Charles J. Epstein Contributors ............................................................ 243 Index ................................................................... 249 1 ... AND COUNTING DNA-Microarrays Jörg D. Hoheisel* Functional Genome Analysis Deutsches Krebsforschungszentrum Im Neuenheimer Feld 506 D-69 120 Heidelberg Germany In recent years, emphasis in genome research has moved away from the more descriptive presentation of the rather static sequence fundaments of an organism toward the evaluation of the dynamic processes taking place within a living cell on the level of nucleic acids (and beyond). This adds another dimension of complexity, since the entire organism has to be re-analysed very many times over with probes generated under different environmental conditions or taken from different (tissue) parts. The observed scale of fluctuation is somewhat surprising although this is not news as such. The genomic approaches only bring home this message more clearly and convincingly, because it is reflected in the puzzling composition of the information obtained. Toward a compre- hensive understanding, rather elaborate and fast methods are therefore essential and accurate numbers need to be determined. The last issue is critical, since already subtle variations can precipitate enormous consequences, especially in regulative processes. Many presentations at the recent Symposium on Genomics and Proteomics dealt with methodologies capable to perform this sort of analyses, at least in principle, and high- lighted the perspectives and challenges ahead. The term “DNA-microarray” stands for the currently most prominent and promis- ing type of technology in this respect. By simultaneously analysing the hybridisation behaviour of probe molecules at very many different sequences, it combines simplicity * Tel.:+49-6221-424680, Fax: -424682. e-mail: [email protected] Genomics and Proteomics, edited by Sándor Suhai. Kluwer Academic / Plenum Publishers, New York, 2000. 1 2 J.D.Hoheisel of the assaywith the high throughput required for genomic approaches. A simple look at the numbers of relevant publications (Figure 1)published during the last few years illustrates both the increased awareness of the array-based approaches and the actual start of data production by such means (for review see Nature Biotechnol. 17, 1999), although a considerable number of relevant publications is missing because of search- intrinsic restrictions to only certain types of manuscripts andjournals. Also, there are currently indeed still more reviews and forecasts on the subject than reports on actual data, yet this is bound tochangevery soon. The potential range of microarray applications isaswide as isthe field of lifesci- encesandcommerce.Thus, there isnot a singleone technique for all applications-nor will there ever be one-but a rather wide spectrum of array types, adapted to the par- ticular needs. Rather than decrease, this variety will increase with the number of applications (andcompaniesgettinginvolved)at least for sometime,sincecertain techniques are well suited for one kind of analysis while less fitting another. Also, there are many newareasofapplicationout thereeithernotyetbeingworked ator, mostlikely,noteven thought of today, in a development similar to PCR, when from a single basic principle very many derivatives evolved. One field, for example, yet virtually unexplored by microarray techniques is the analysis of the information encoded in the DNA structure rather than sequence. It has been demonstrated that not only functional information is geneticallyencoded that way but, in addition, that even short term memory effectsare possible (e.g., Pohl, 1987).Another example is the determination of the methylation statusof DNA, important for both structureand function (Olek et al., 1996). As with many scientific developments during their initial phases, the microarray techniques arestillfullof pitfalls andproblems.Ithasbeenshownthat mutationalanaly- sesof thep53-genecanbecarriedoutathigher accuracythan bysequencing, thecurrent gold standard (Ahrendt et al., 1999), but this does not hold true for many other Figure 1. Number of hits when searching Medline for manuscripts dealing with applications of DNA-arrays, microarraysandDNA-chips. Thevaluefor 1999isanextrapolationbasedonthenumberpublishedintheperiod January to March and probably an underestimate of the eventual total.