Table Of ContentFFIRS.qxd 6/16/04 8:37 AM Page iv Quark03 Quark03:Desktop Folder:Chapter-FM:
January29,2004 2:46 WSPC/TrimSize:9inx6inforReviewVolume practical-bioinformatician
THE PRACTICAL
BIOINFORMATICIAN
Edited by
Limsoon Wong
Institute for Infocomm Research
Singapore
Published by
World Scientific Publishing Co. Pte. Ltd.
5 Toh Tuck Link, Singapore 596224
USA office: Suite 202, 1060 Main Street, River Edge, NJ 07661
UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
THE PRACTICAL BIOINFORMATICIAN
Copyright © 2004 by World Scientific Publishing Co. Pte. Ltd.
All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means,
electronic or mechanical, including photocopying, recording or any information storage and retrieval
system now known or to be invented, without written permission from the Publisher.
For photocopying of material in this volume, please pay a copying fee through the Copyright
Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to
photocopy is not required from the publisher.
ISBN 981-238-846-X
Printed in Singapore.
January29,2004 2:46 WSPC/TrimSize:9inx6inforReviewVolume practical-bioinformatician
DEDICATION
This book is dedicated to the memoryof Dr. G. Christian Overton,a pioneerin
thefieldofbioinformaticsandaresearcherwithunparalleledvisionfortheuseof
computationalapproachestosolvebiologicalproblems.
Dr. Overton received his Bachelor of Science degree in mathematics and
physicsfromtheUniversityofNewMexicoin1971andhisPh.D.inbiophysics
fromtheJohnsHopkinsUniversityin1978.HethendidapostdocwithDr.Davor
SolterattheWistarInstitute,duringwhichtimehebecameincreasinglydrawnto
computers,andinparticulartothepromiseofartificialintelligence.Hetherefore
returnedto schoolpart-time,andtookaMaster’sdegreeinComputerandInfor-
mation Science at the Universityof Pennsylvania.After receivingthisdegreein
1986,hebrieflyleftacademiatoworkforBurroughs(latertobecomeUnisys)and
returnedto the Universityof Pennsylvaniain 1991to lead the informaticscom-
ponent of the Center for Chromosome 22, a collaboration between researchers
attheUniversityofPennsylvania,Children’sHospitalofPhiladelphia,andother
local institutions. During this time, he developedstrong ties with researchersin
computer science, statistics and biology. These collaborations eventually led in
1997 to the establishment of the Center for Bioinformatics at the University of
Pennsylvania, of which Dr. Overton was the founding Director. The Center for
Bioinformaticsis an interdisciplinaryventurebetweenthe Schoolsof Medicine,
ArtsandSciences,andEngineeringandAppliedScience.
Dr. Overton was an Associate Professor in the Departmentof Genetics, and
held a secondary appointment in the Department of Computer and Information
Science.Dr.Overton’suniquetraininginbiophysics,developmentalbiologyand
computer science, and his deep understandingof biomedicaland computational
problems, enabled him to establish many exciting research projects, effectively
bridgingthegapbetweencollaboratorsinnumerousfields.Dr.Overton’sownre-
searchinterestsfocusedonproblemsassociatedwithdatabaseintegration,genome
annotation,geneprediction,andtherecognitionofregulatoryelementswithinthe
seaofnucleotidesthatcomprisethehumangenome.Throughhisuseofadvanced
computational techniques to help in the construction of genomic databases, Dr.
v
January29,2004 2:46 WSPC/TrimSize:9inx6inforReviewVolume practical-bioinformatician
vi Dedication
Overtonalsogainedconsiderablerecognitionincomputerscience.Inadditionto
hisresearch,Dr.OvertonwasanEditorfortheJournalofComputationalBiology,
Bioinformatics, and Gene/Gene-COMBIS, as well as a Member of the Board of
DirectorsfortheInternationalSocietyforComputationalBiology.
PeterBuneman
UniversityofEdiburgh
SusanB.Davidson
UniversityofPennsylvania
LimsoonWong
InstituteforInfocommResearch
26November2003
January29,2004 2:46 WSPC/TrimSize:9inx6inforReviewVolume practical-bioinformatician
PREFACE
Over the past decade, computer scientists have increasingly been enlisted as
“bioinformaticians”to assist molecularbiologistsin their research.This bookis
conceivedasapracticalintroductiontobioinformaticsforthesecomputerscien-
tists.Whileitisnotpossibletobeexhaustiveincoverage,thechaptersarein-depth
discussions by expert bioinformaticianson both generaltechniquesand specific
approachestoarangeofselectedbioinformaticsproblems.Letusprovideabrief
overviewofthesechaptershere.
A practical bioinformatician must learn to speak the language of biology.
We thus begin with Chapter 1 by Ng and Chapter 2 by Scho¨nbachthat form an
overviewofmodernmolecularbiologyandoftheplanningandexecutionofbioin-
formaticsexperiments.At the same time, a practicalbioinformaticianmust also
be conversantin a broad spectrum of topics in computer science—data mining,
machinelearning,mathematicalmodeling,sequencealignment,dataintegration,
database management,workflow development,and so on. These diversedtopics
aresurveyedinthreeseparatechapters,viz.Chapter3byLietal.whichprovides
an in-depth review of data mining techniquesthat are amongstthe key comput-
ing technologiesfor the analysis of biologicaldata; Chapter 10 by Brown et al.
whichdiscussestheadvancesthroughthepastthirtyyearsinbothglobalandlo-
calalignment,andpresentmethodsforgeneralpurposehomologythatarewidely
adopted;and Chapter 17 by Wong which reviews some of the requirementsand
technologiesrelevanttodataintegrationandwarehousing.
DNAsequencescontainanumberoffunctionalandregulatorysites, suchas
the site where the transcription of a gene begins, the site where the translation
of a gene begins, the site where an exon of a gene ends and an intron begins,
and so on. The next several chapters of the book deal with the computational
recognitionofthesesites, viz.Chapter4byLietal.whichisanin-depthsurvey
spanningtwodecadesofresearchofmethodsforcomputationalrecognizationof
translation initiation sites from mRNA, cDNA, and DNA sequences;and Chap-
ters5–7byBajic´ etal.whichdiscussgeneralframeworks,conceptualissues,and
performancetuningrelatedto theuseofstatisticalandneuralnetworkmodeling
vii
January29,2004 2:46 WSPC/TrimSize:9inx6inforReviewVolume practical-bioinformatician
viii Preface
forcomputationalrecognitionofpromotersandregulatorysites.Therecognition
of translation initiation sites is among the simplest problems in the recognition
offunctionalsitesfromDNAsequences.Ontheotherhand,amongthetoughest
problemsintherecognitionoffunctionalsitesfromDNAsequencesisthedeter-
minationoflocationsofpromotersandrelatedregulatoryelementsandfunctional
sites. Thuswe hopethesefourchapterstogethercanbringoutclearlythewhole
rangeofapproachestothisgroupofproblems.
WenextmovetoanalysisofRNAsequences.Weconsidertheproblemofpre-
dicting the secondary structure of RNAs, which is relevant to applications such
as function classification, evolution study, and pseudogene detection. Chapter 8
bySungprovidesadetailedreviewofcomputationalmethodsforpredictingsec-
ondarystructurefromRNAsequences.Unlikethepredictionmethodsintroduced
inearlierchaptersforrecognitionoffunctionalsitesfromDNAsequences,which
aremostlydataminingandmachinelearningmethods,themethodsdescribedin
thischaptercomefromtherealmofmathematicalmodeling.
AfterlookingatRNAsequences,wemoveontoproteinsequences,andlook
ataspectsrelatingtoproteinfunctionprediction.Forexample,eachcompartment
in a cell has a unique set of functions, and it is thus reasonable to assume that
the compartmentor membranein which a proteinresides is a determinantof its
function. So we have Chapter 9 by Horton et al. to discuss various aspects of
protein subcellular localization in the context of bioinformatics and review the
twentyyearsofprogressinpredictingproteinsubcellularlocalization.Asanother
example,thehomologyrelationshipbetweenaproteinandanotherproteinisalso
suggestiveofthefunctionofthatprotein.SowehaveChapter12byKaplanetal.
todescribetwobioinformaticstools,ProtoNetandPANDORA.ProtoNetusesan
approachofproteinsequencehierarchicalclusteringtodetectremoteproteinrela-
tives.PANDORAusesagraph-basedmethodtointerpretcomplexproteingroups
throughtheirannotations.Asathirdexample,motifsarecommonlyusedtoclas-
sifyproteinsequencesandtoprovidefunctionalcluesonbindingsites, catalytic
sites,andactivesites,orstructure/functionsrelations.SowehaveChapter16by
Scho¨nbach and Matsuda to present a case study of a workflow for mining new
motifsfromtheFANTOM1mousecDNAclonecollectionbyalinkage-clustering
method, with an all-to-all sequence comparison, followed by visual inspection,
sequence,topological,andliteratureanalysisofthemotifcandidates.
Nextwesamplethefascinatingtopicofphylogenetics—thestudyoftheori-
gin, development,and death of a taxon—basedon sequence and other informa-
tion.Chapter11byMengisanintroductiontophylogeneticsusingacasestudyon
Saururaceae.In contrast to earlier chapters, which emphasize the computational
aspect,thischapteriswrittenfromtheperspectiveofaplantmolecularbiologist,
January29,2004 2:46 WSPC/TrimSize:9inx6inforReviewVolume practical-bioinformatician
Preface ix
and emphasizes instead the care that must be exercised in the use of computa-
tional tools and the analysis that must be performedon the results producedby
computationaltools.
The genomics and proteomics efforts have helped identify many new genes
andproteinsinlivingorganisms.However,simplyknowingtheexistenceofgenes
and proteinsdoes not tell us much aboutthe biologicalprocesses in which they
participate.Manymajorbiologicalprocessesarecontrolledbyproteininteraction
networksandgeneregulationnetworks.ThuswehaveChapter13byTanandNg
togiveanoverviewofthevariouscurrentmethodsfordiscoveringprotein-protein
interactionsexperimentallyandcomputationally.
Thedevelopmentofmicroarraytechnologyinthelast decadehasmadepos-
sible the simultaneousmonitoringof the expressionofthousandsof genes.This
developmentoffersgreatopportunitiesinadvancingthediagnosisofdieases,the
treatmentofdiseases,andtheunderstandingofgenefunctions.Chapter14byLi
andWongisanin-depthsurveyofseveralapproachestosomeofthegeneexpres-
sion analysischallengesthat accompanythese opportunities.On the otherhand,
Chapter15byLinetal.presentsamethodforselectingprobesinthedesignofa
microarraytoprofilegenome-widegeneexpressionofagivengenome.
Biological data is being created at ever-increasing rates as different high-
throughput technologies are implemented for a wide variety of discovery plat-
forms.It is crucialfor researchersto be able to notonly accessthis information
but also to integrateit well and synthesize new holistic ideas aboutvarioustop-
ics.Soitisappropriatethatwedevotetheremainingchaptersofthisbooktothe
issuesofintegratingdatabases,cleansingdatabases,andlarge-scaleexperimental
andcomputationalanalysisworkflowsasfollows.Chapter18byKolatkarandLin
demonstratestheconstructionofapurpose-builtintegrateddatabasePPDBusing
thepowerfulgeneraldataintegrationengineKleisli.Chapter19byWuandBarker
presentstheclassification-drivenrule-basedapproachinPIRdatabasetothefunc-
tional annotation of proteins. Wu and Barker also provide two case studies: the
firstlooksaterrorpropagationtosecondarydatabasesusingtheexampleofIMP
Dehydrogenase;thesecondlooksattransitiveidentificationerrorusingtheexam-
ple of His-I bifunctional proteins. Finally, Chapter 20 by Scheetz and Casavant
describesthe sophisticatedinformaticstoolsandworkflowunderlyingthe large-
scaleeffortinEST-basedgenediscoveryinRat,Human,Mouse,andotherspecies
beingconductedattheUniversityofIowa.
LimsoonWong
11December2003
