Bioinformatics: An Introduction

Preface to the Fourth Edition
Preface to the Third Edition
Preface to the Second Edition
Preface to the First Edition
Contents
1 Introduction
	1.1 What is Bioinformatics?
	1.2 What Can Bioinformatics Do?
	1.3 An Ontology of Bioinformatics
	1.4 The Organization of This Book
	References
Part I Overview
2 Genotype, Phenotype, and Environment
	References
3 Regulation and Control
	3.1 The Concept of Machine
	3.2 Regulation
	3.3 Cybernetics
	3.4 Adaptation
	3.5 The Integrating Rôle of Directive Correlation
	3.6 Timescales of Adaptation
	3.7 The Architecture of Functional Systems
	3.8 Autonomy and Heterarchical Architecture
	3.9 Biological Information Processing
	References
4 Evolution
	4.1 Phylogeny and Evolution
		4.1.1 Group and Kin Selection
		4.1.2 Models of Evolution
	4.2 Evolutionary Systems
	4.3 Evolutionary Computing
	4.4 Concluding Remarks on Evolution
	References
5 Origins of Life and Earth Prehistory
	References
Part II Information
6 The Nature of Information
	6.1 Structure and Quantity
		6.1.1 The Generation of Information
		6.1.2 Conditional and Unconditional Information
		6.1.3 Experiments and Observations
	6.2 Constraint
		6.2.1 The Value of Information
		6.2.2 The Quality of Information
	6.3 Accuracy, Meaning, and Effect
		6.3.1 Accuracy
		6.3.2 Meaning
		6.3.3 Effect
		6.3.4 Significs
	6.4 Further Remarks on Information Generation and Reception
	6.5 Summary
	References
7 The Transmission of Information
	7.1 The Capacity of a Channel
	7.2 Coding
	7.3 Decoding
	7.4 Compression
		7.4.1 Use of Compression to Measure Distance
		7.4.2 Ergodicity
	7.5 Noise
	7.6 Error Correction
	7.7 Summary
	References
8 Sets and Combinatorics
	8.1 The Notion of Set
	8.2 Combinatorics
		8.2.1 Ordered Sampling with Replacement
		8.2.2 Ordered Sampling Without Replacement
		8.2.3 Unordered Sampling Without Replacement
		8.2.4 Unordered Sampling With Replacement
	8.3 The Binomial Theorem
9 Probability and Likelihood
	9.1 The Notion of Probability
	9.2 Fundamentals
		9.2.1 Generalized Union
		9.2.2 Conditional Probability
		9.2.3 Bernoulli Trials
	9.3 Moments of Distributions
		9.3.1 Runs
		9.3.2 The Hypergeometric Distribution
		9.3.3 The Law of Large Numbers
		9.3.4 Additive and Multiplicative Processes
	9.4 Likelihood
	References
10 Statistics and Causation
	10.1 A Brief Outline of Statistics
	10.2 The Calculus of Causation
	References
11 Randomness and Complexity
	11.1 Random Processes
	11.2 Markov Chains
	11.3 Random Walks
	11.4 The Generation of Noise
	11.5 Complexity
	11.6 Biological Complexity
	References
12 Systems and Networks
	12.1 General Systems Theory
		12.1.1 Automata
		12.1.2 Cellular Automata
		12.1.3 Percolation
		12.1.4 Systems Biology
	12.2 Networks (Graphs)
		12.2.1 Trees
		12.2.2 Complexity Parameters of Networks
		12.2.3 Dynamical Properties
	12.3 Synergetics
	12.4 Self-organization
	References
13 Useful Algorithms
	13.1 Pattern Recognition
	13.2 Botryology
		13.2.1 Clustering
		13.2.2 Principal Component and Linear Discriminant Analyses
		13.2.3 Wavelets
	13.3 Multidimensional Scaling and Seriation
	13.4 Visualization
	13.5 The Maximum Entropy Method
	References
Part III Biology
14 The Nature of Living Things
	14.1 The Cell
	14.2 Mitochondria
	14.3 Metabolism
	14.4 The Cell Cycle
		14.4.1 The Chromosome
		14.4.2 The Structures of Genome and Genes
		14.4.3 The C-Value Paradox
		14.4.4 The Structure of the Chromosome
	14.5 Cancer
	14.6 The Immune System
	14.7 Molecular Mechanisms
		14.7.1 Replication
		14.7.2 Proofreading and Repair
		14.7.3 Recombination
		14.7.4 Summary of Sources of Genome Variation
	14.8 Gene Expression
		14.8.1 Transcription
		14.8.2 Regulation of Transcription
		14.8.3 Prokaryotic Transcriptional Regulation
		14.8.4 Eukaryotic Transcriptional Regulation
		14.8.5 mRNA Processing
		14.8.6 Translation
	14.9 Ontogeny (Development)
		14.9.1 Stem cells
		14.9.2 Epigenesis
		14.9.3 The Epigenetic Landscape
		14.9.4 ps: [/EMC pdfmark [/objdef Equ /Subtype /Span /ActualText (r) /StPNE pdfmark [/StBMC pdfmarkto.ps: [/EMC pdfmark [/Artifact <> /BDC pdfmark rps: [/EMC pdfmark [/StBMC pdfmark ps: [/EMC pdfmark [/StPop pdfmark [/StBMC pdfmark and ps: [/EMC pdfmark [/objdef Equ /Subtype /Span /ActualText (upper K) /StPNE pdfmark [/StBMC pdfmarkto.ps: [/EMC pdfmark [/Artifact <> /BDC pdfmark Kps: [/EMC pdfmark [/StBMC pdfmark ps: [/EMC pdfmark [/StPop pdfmark [/StBMC pdfmark Selection
		14.9.5 Homeotic Genes
	References
Chapter15TheMoleculesofLife
	15.1MoleculesandSupramolecularStructure
	15.1MoleculesandSupramolecularStructure
	thletterofthealphabet.Thenextstageofcomplexityistoconsidermolecules(Table15.2)andmacromolecules(Table15.3).Thisisstillhighlyreductionist,however,itcorrespondstocalculatingShannonentropyfromthevocabularyofMacbeth.Wordsare,however,groupedintosentences,which,inturn,arearrangedintoparagraphs.Thecellisanalogouslyhighlystructured—moleculesaregroupedintosupramolecularcomplexes,which,inturn,areassembledintoorganelles.Thisstructure,someofwhichisvisibleintheopticalmicroscope,butwhichmostlyneedsthehigherresolutionoftheelectronmicroscope,isoftencalledultrastructure.Itisdifficulttoquantify—thatis,assignnumericalparameterstoit,withwhichdifferentsetsofobservationscanbecompared.Thehumaneyecanreadilyperceivedrasticchangesinultrastructurewhenacellissubjectedtoexternalstress,butgenerallythesechangeshavetobedescribedinwords.
	.
	15.1MoleculesandSupramolecularStructure
	Element
	500
	Notypes
	Element
	1600
	H
	Element
	.
	15.2Water
	10nm
	.
	Density
	.
	.
	15.3DNA
	.
	TheO–Hinfraredspectrum(ofHODinliquidD
	Bondedandnonbondedionsareinequilibrium:
	atroomtemperatureorabout2.4kJ/mol)
	.
	Fig.15.2PolymerizedDNA.Theso-called
	Fig.15.2PolymerizedDNA.Theso-called
	endisatthelowerright(afterAgeno,1967;reproducedwithpermissionoftheAccademiadeiLincei)
	to
	Fig.15.2PolymerizedDNA.Theso-called
	Fig.15.3Thehydrogen-bondingpatternsofcomplementarybases(thymine[T],adenine[A],gua-nine[G],cytosine[C],movingroundclockwisefromtheupperleft)(afterAgeno,1967;reproducedwithpermissionoftheAccademiadeiLincei).InRNA,uracil(U)replacesthymine(i.e.,themethylgrouponthebaseisreplacedbyhydrogen)andtheribosehasahydroxylgroup.ThelowerpairisdenotedbyCpG(Sect.14.8.4)
	Fig.15.3Thehydrogen-bondingpatternsofcomplementarybases(thymine[T],adenine[A],gua-nine[G],cytosine[C],movingroundclockwisefromtheupperleft)(afterAgeno,1967;reproducedwithpermissionoftheAccademiadeiLincei).InRNA,uracil(U)replacesthymine(i.e.,themethylgrouponthebaseisreplacedbyhydrogen)andtheribosehasahydroxylgroup.ThelowerpairisdenotedbyCpG(Sect.14.8.4)
	.
	Asexpectedfromtheiraromaticstructure,thebasesareplanar.Figure15.4showstheformationofthedoublehelix.Thegenesofmostorganismsareformedbysuchadoublehelix.ThemeltingoftheH-bondsasthetemperatureisraisedishighly coöperative(duetotherepulsiveelectrostaticforcebetweenthechargedphosphategroups).Onaverage,theseparationintosinglestrandedDNAoccursatabout80
	Fig.15.3Thehydrogen-bondingpatternsofcomplementarybases(thymine[T],adenine[A],gua-nine[G],cytosine[C],movingroundclockwisefromtheupperleft)(afterAgeno,1967;reproducedwithpermissionoftheAccademiadeiLincei).InRNA,uracil(U)replacesthymine(i.e.,themethylgrouponthebaseisreplacedbyhydrogen)andtheribosehasahydroxylgroup.ThelowerpairisdenotedbyCpG(Sect.14.8.4)
	Table15.5summarizessomesignificantdiscoveriesrelatingtoDNA.
	Discoveryorevent
	Example:UCSCGenomeBrowser
	Crick
	Discoveryorevent
	Atetranucleotidestructureelucidated
	1944
	Principalworker(s)
	Discoveryorevent
	where
		(15.4)
		isBoltz-mann’sconstant,and
		.
	15.4RNA
	.
	15.4RNA
	.Theconceptcanbeillustratedbyfocusingonloopclo-sure,consideredtobethemostimportantfoldingevent.Thepotentialenergyistheenthalpy(i.e.,thenumber
	RNAhasfivemainfunctions:asamessenger(mRNA),actingasanintermediaryinproteinsynthesis;asanenzyme(ribozymes);aspart(about60%byweight,therestbeingprotein)oftheribosome(rRNA);asthecarrierfortransferringaminoacidstothegrowingpolypeptidechainsynthesizedattheribosome(tRNA);andasamodulatorofDNA4andmRNAinteractions—smallinterferingRNA(siRNA;seeSect.14.8.4).
	15.4RNA
	Fig.15.5ApieceofRNA(fromtheQ
	Fig.15.5ApieceofRNA(fromtheQ
	15.5Proteins
	Globularproteins
	Fig.15.5ApieceofRNA(fromtheQ
	whichmaybeverylarge,suchthattheyformgelsbyentanglement.Thepolypeptidebackboneisextensivelydecoratedwithrelativelyshortpolysac-charides.Typicallytheyactaslubricantsandengulfers(example:mucin);
	.
	.
	whichmaybeverylarge,suchthattheyformgelsbyentanglement.Thepolypeptidebackboneisextensivelydecoratedwithrelativelyshortpolysac-charides.Typicallytheyactaslubricantsandengulfers(example:mucin);
	.
	whicharealsoglobular,butpermanentlyembedded(transversally)inalipidbilayermembrane.Theymainlyfunctionaschannels,energyandsignaltransducers,andmotors(examples:ATPase,bacteriorhodopsin,andporin).
	whichmaybeverylarge,suchthattheyformgelsbyentanglement.Thepolypeptidebackboneisextensivelydecoratedwithrelativelyshortpolysac-charides.Typicallytheyactaslubricantsandengulfers(example:mucin);
	.
	4.4
	.
	.
	denotesabenzenering.Squarebracketsdenotearingstructure
	.
	Fig.15.6Hydrogen-bondingcapabilitiesofthepeptidebackboneandthepolarresidues(afterBakerandHubbard).Residuesnotshownareincapableofhydrogenbondformation
	Fig.15.6Hydrogen-bondingcapabilitiesofthepeptidebackboneandthepolarresidues(afterBakerandHubbard).Residuesnotshownareincapableofhydrogenbondformation
	10AsshowninFig.15.6,someresiduescanalsoparticipateinhydrogen-bonding,butthebackbonepeptideH-bonds(orpotentialH-bonddonorsandacceptors)areofcoursemorenumerousand,hence,moresignificant.11Fernández(2012a,
	.
	Fig.15.6Hydrogen-bondingcapabilitiesofthepeptidebackboneandthepolarresidues(afterBakerandHubbard).Residuesnotshownareincapableofhydrogenbondformation
	integrityrequiresthatthebackboneH-bondsbekeptdry.TheenergeticimportanceofH-bondwrapping(i.e.,protectionfromwater)canbeseenbynotingthattheenergyofahydrogenbondisstronglycontext-dependent.Inwater,itisabout2kJ/mol;invacuo,itincreaseseightfoldtotenfold.Wrappingwillthereforegreatlycontributetotheenthalpicstabilizationofglobularproteinconformation.
		.
		;mostsolublemonomericglobularproteinshavea
		.
		and
		.
	odictableoftheelementsinchemistry.Indeed,thedehydronconceptisneededtocomputationallyfoldapeptidechainabinitio.
		.
		.
		15.5.3ProteinStructureDetermination
		2.
		isonlyabout11).
		.
	Crystallizetheprotein(oftenunusualsaltconditionsarerequired)andrecordtheX-raydiffractogram,15orcarryoutnuclearmagneticresonancespectroscopy(oneormoreof
	Crystallizetheprotein(oftenunusualsaltconditionsarerequired)andrecordtheX-raydiffractogram,15orcarryoutnuclearmagneticresonancespectroscopy(oneormoreof
	C,
	7.
	Crystallizetheprotein(oftenunusualsaltconditionsarerequired)andrecordtheX-raydiffractogram,15orcarryoutnuclearmagneticresonancespectroscopy(oneormoreof
	hands.Thisgivesafairimpressionoftypicalproteinstructureatverylowresolution.
		.
		15.6Polysaccharides
		.
	Problem.Examinewhetherpolysaccharidescouldbeusedastheprimaryinforma-tioncarrierinacell.
	Problem.Examinewhetherpolysaccharidescouldbeusedastheprimaryinforma-tioncarrierinacell.
	15.7Lipids
	Problem.Examinewhetherpolysaccharidescouldbeusedastheprimaryinforma-tioncarrierinacell.
	Fig.15.8Somenaturallyoccurringlipidsandmembranecomponents:1,afattyacid;2,phos-phatidicacid;3,phosphatidylethanolamine;4,phosphatidylcholine;5,cardiolipin(diphosphatidyl- glycerol);6,cholesterol
	Fig.15.8Somenaturallyoccurringlipidsandmembranecomponents:1,afattyacid;2,phos-phatidicacid;3,phosphatidylethanolamine;4,phosphatidylcholine;5,cardiolipin(diphosphatidyl- glycerol);6,cholesterol
	Fig.15.8Somenaturallyoccurringlipidsandmembranecomponents:1,afattyacid;2,phos-phatidicacid;3,phosphatidylethanolamine;4,phosphatidylcholine;5,cardiolipin(diphosphatidyl- glycerol);6,cholesterol
	thelipidsprobablyplayafarmoreactiverôlethanmerelyfunctioningasapassivematrixfortheprotein—whichmayconstitutemorethan50%ofthemembrane.Thecovalentattachmentofalipidmoleculetoaprotein,typicallyataterminalaminoacid,isasignificantformofpost-translationalmodification.Itisnowknownthattheeukaryoticlipidometypicallycomprisesmanyhun-dredsofdifferentmolecules,andtheirglobalanalysisrequireshigh-throughput techniques.Animportantdevelopmenthasbeen“shotgun”massspectrometryofthelipidsextractedbysolvents,20whichnotonlyenablesthedifferentlipidstobeidentified,butalsoquantifiestheirabundances.Thehighthroughputisachievedby considerableautomationoftheprocessandthedatahandlingiscomputationallyheavy.21
		References
		References
		FernándezA(2012a)Epistructuraltensionpromotesproteinassociations.PhysRevLett108:188102
		FernándezA,SosnickTR,ColubriA(2002)Dynamicsofhydrogenbonddesolvationinproteinfolding.JMolBiol321:659–675
		AgenoM(1967)Lineediricercainfisicabiologica.AccadNazLincei102:3–50
		References
	SchwudkeD,SchuhmannK,HerzogR,BornsteinSR,ShevchenkoA(2011)Shotgunlipidomicsonhighresolutionmassspectrometers.ColdSpringHarbourPerspectBiol3:a004614
		YetukuriL,EkroosK,Vidal-PuigA,OrešiˇcM(2008)Informaticsandcomputationalstrategiesforthestudyoflipids.MolBioSystems4:121–127
		YetukuriL,EkroosK,Vidal-PuigA,OrešiˇcM(2008)Informaticsandcomputationalstrategiesforthestudyoflipids.MolBioSystems4:121–127
		YetukuriL,EkroosK,Vidal-PuigA,OrešiˇcM(2008)Informaticsandcomputationalstrategiesforthestudyoflipids.MolBioSystems4:121–127
16 Environment and Ecology
	16.1 Susceptibility to Disease
	16.2 Toxicogenomics
	16.3 Ecosystems Management
	References
Part IV Omics
17 Genomics
	17.1 DNA Sequencing
		17.1.1 Extraction of Nucleic Acids
		17.1.2 The Polymerase Chain Reaction
		17.1.3 Sequencing
		17.1.4 Expressed Sequence Tags
		17.1.5 Next Generation Sequencing
	17.2 DNA Methylation Profiling
	17.3 Gene Identification
	17.4 Extrinsic Methods
		17.4.1 Database Reliability
		17.4.2 Sequence Comparison and Alignment
		17.4.3 Trace, Alignment, and Listing
		17.4.4 Dynamic Programming Algorithms
	17.5 Intrinsic Methods
		17.5.1 Signals
		17.5.2 Hidden Markov Models
	17.6 Minimalist Approaches to Deciphering DNA
	17.7 Phylogenies
	17.8 Metagenomics
	References
18 Transcriptomics and Proteomics
	18.1 Transcriptomics
	18.2 Proteomics
		18.2.1 Two-Dimensional Gel Electrophoresis
		18.2.2 Column Chromatography
		18.2.3 Other Kinds of Electrophoresis
	18.3 Protein Identification
	18.4 Isotope-Coded Affinity Tags
	18.5 Protein Microarrays
	18.6 Protein Expression Patterns—Temporal and Spatial
	18.7 The Kinome
	References
19 Microbiomics
	References
20 Viruses
	20.1 Virus Structure and Life Cycle
	20.2 Viruses as Pathogens
	20.3 Virus Genome Sequencing
	References
21 Single Cell Analysis and Multiomics
	21.1 Experimental Methods
	21.2 Applications to Disease and Other Phenomena
	21.3 Beyond Sequence
	References
22 Biological Signalling
	22.1 The Complexity of Signal Transduction
	22.2 Anatomy of Signal Transduction
	22.3 Signalling Channel Capacities
	22.4 Molecular Mechanism of Recognition and Actuation
	22.5 Overcoming Noise
	References
23 Regulatory Networks
	23.1 Interactomics
	23.2 Network Modelling
	23.3 A Simple Example—Operons
	23.4 Inference of Regulatory Networks
	23.5 The Physical Chemistry of Interactions
	23.6 Intermolecular Interactions
	23.7 In Vivo Experimental Methods for Interactions
		23.7.1 The Yeast Two-Hybrid Assay
		23.7.2 Crosslinking
		23.7.3 Correlated Expression
		23.7.4 Other Methods
	23.8 In Vitro Experimental Methods
		23.8.1 Chromatography
		23.8.2 Direct Affinity Measurement
		23.8.3 Protein Chips
	23.9 Interactions from Sequence
	23.10 Global Statistics of Interactions
	23.11 Metabolomics and Metabonomics
	23.12 Data Collection
	23.13 Data Analysis
	23.14 Metabolic Regulation
		23.14.1 Metabolic Control Analysis
		23.14.2 The Metabolic Code
	23.15 Metabolic Networks
	References
24 The Nervous System
	24.1 The Neuron and Neural Networks
	24.2 Outstanding Problems
	24.3 Artificial Neural Networks
	24.4 Neurocomputation
	References
25 Phenomics
	25.1 Enzyme Activity-Based Protein Profiling
	25.2 Phenotype Microarrays
	25.3 Ethomics
	25.4 Actimetry
	25.5 Modeling Life
	References
Part V Applications
26 Medicine and Disease
	26.1 Infectious Diseases
	26.2 Noninfectious Diseases
	26.3 Personalized Medicine
	26.4 Toward Automated Diagnosis
	References
27 Drug Discovery
	27.1 Routes to Discovery
	27.2 Protein–Protein Interactions
	27.3 Enhancing Control of Specificity
	27.4 Drug–Drug Interactions
	27.5 Nanodrugs
	27.6 High-Throughput Experimental Approaches
	27.7 Behaviour-Based Testing
	References
28 Forensic Investigation
	28.1 DNA Forensics in Criminal Investigations
	28.2 Tracing Genetically Modified Ingredients in Food
	References
29 Pandemics
	References
30 Domestication
	References
31 The Organization of Knowledge
	31.1 Ontology
	31.2 The Classification of Knowledge
	31.3 Knowledge Representation
	31.4 Data Mining
	31.5 Text Mining
	31.6 The Automation of Research
	31.7 Big Data
	References
Appendix  Bibliography
Index