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CONCEPTSin
BIOINFORMATICS
and GENOMICS
CONCEPTSin
BIOINFORMATICS
and GENOMICS
JAMIL MOMAND
CaliforniaState University, LosAngeles
ALISON McCURDY
CONTRIBUTORS
Silvia Heubach
Nancy Warter-Perez
New York Oxford

OXFORD UNIVERSITY PRESS
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Library of Congress Cataloging-in-Publication Data
Names: Momand,Jamil, author. I McCurdy, Alison , author.

Title : Concepts in bioinformatics and genomics / Jamil Momand, California
State University, Los Angeles , Alison McCurdy, California State
University , Los Angeles; contributors , Silvia Heubach, California State
University , Los Angeles , Nancy Warter-Perez, California State University ,
Los Angeles.
Description : New York : Oxford University Press, 2016. I Includes
bibliographical references and index.
Identifiers: LCCN 20150482001 ISBN 9780199936991 (alk. paper) I ISBN
9780199936984 (online material) I ISBN 9780190610531 (professor material)
I ISBN 9780190610548 (professor material)
Subjects : LCSH: Bioinformatics--Textbooks . I Genomics--Textbooks.
Classification: LCC QH324 .2 .M66 2016 I DDC 570.285--dc23
Printing number : 9 8 7 6 5 4 3 2 1
Printed in the United States of America

on acid-free paper
To our colleague Ray Garcia,

whose devotion to students willnever be forgotten.
BRIEFCONTENTS
Preface xiii
Acknowledgments xvii
About the Authors xix
Introduction xxi
CHAPTER 1 • REVIEWOF MOLECULAR BIOLOGY
CHAPTER 2 • INFORMATION ORGANIZATION AND SEQUENCEDATABASES 21
CHAPTER 3 • MOLECULAR EVOLUTION 38
CHAPTER 4 • SUBSTITUTIONMATRICES 66
CHAPTER 5 • PAIRWISESEQUENCEALIGNMENT 89
CHAPTER 6 • BASIC LOCAL ALIGNMENT SEARCHTOOL (BLAST) AND MULTIPLE

SEQUENCEALIGNMENT 106
CHAPTER 7 • PROTEINSTRUCTUREPREDICTION 129
CHAPTER 8 • PHYLOGENETICS 168
CHAPTER 9 • GENOMICS 210
CHAPTER 10 • TRANSCRIPTAND PROTEINEXPRESSIONANALYSIS 253
CHAPTER 11 • BASIC PROBABILITY 284
CHAPTER 12 • ADVANCED PROBABILITYFOR BIOINFORMATICSAPPLICATIONS 320
CHAPTER 13 • PROGRAMMING BASICSAND APPLICATIONSTO

BIOINFORMATICS 351
CHAPTER 14 • DEVELOPINGA BIOINFORMATICSTOOL 407
Glossary 433
Credits 443
Index 447
TABLEOF CONTENTS
Preface xiii The Gene Feature Key and FASTAFormat 29
Acknowledgments xvii Thought Question 2.1 30
About the Authors xix 2.5 LIMITATIONS OF GENBANK 31
Introduction xxi 2.6 REFERENCE SEQUENCE (REFSEQ) 31
Alternative Splicing 32
CHAPTER 1 • REVIEW OF MOLECULAR 2.7 PRIMARY AND SECONDARY
BIOLOGY DATABASES 33
UniProt Knowledge Base 34

LEARNING OUTCOMES
SUMMARY 35
1.1 INTRODUCTION
EXERCISES 35
1.2 GENES AND DNA
ANSWER TO THOUGHT QUESTION 37
1.3 RNA: THE INTERMEDIARY 4
REFERENCES 37
1.4 AMINO ACIDS: THE BUILDING BLOCKS
OF PROTEINS 5 BOX 2-1. SCIENTIST SPOTLIGHT: Walter Goad, Gen Bank
Founder 22
1.5 LEVELS OF PROTEIN STRUCTURE 8
BOX 2-2. A CLOSER LOOK: Gen Bank Is Critical to the
1.6 THE GENETIC CODE 9 Discovery of the MDM2 Oncoprotein, an Inhibitor
1.7 RELATIVE SIZES OF MATTER 12 ofp53 24
1.8 DNA ALTERATIONS 13
1.9 A CASE STUDY: SICKLE CELL ANEMIA 15

CHAPTER 3 • MOLECULAR EVOLUTION 38
What Are the Symptoms of Sickle Cell Anemia? 15
Sickle Cell Anemia Is the First Disease Linked LEARNING OUTCOMES 38

to a Specific Mutation 16 3.1 INTRODUCTION 38
1.10 INTRODUCTION TO p53 17 3.2 CONSERVED REGIONS IN PROTEINS 40
SUMMARY 18 3.3 MOLECULAR EVOLUTION 43
EXERCISES 19 Transformation of Normal Cells
REFERENCES 20 to Cancer Cells 43
BOX 1-1. A CLOSER LOOK: A Rare Inherited Cancer Is Are Mutations Inherited? 45
Caused by Mutated TP53 18 Natural Selection 46
Mechanisms of Mutation 48
CHAPTER 2 • INFORMATION ORGANIZATION
3.4 ANCESTRAL GENES AND PROTEIN
AND SEQUENCE DATABAS
ES 21 EVOLUTION 56
LEARNING OUTCOMES 21
3.5 MODULAR PROTEINS AND PROTEIN
EVOLUTION 60
2.1 INTRODUCTION 21
SUMMARY 62
2.2 PUBLIC DATABASES 23
EXERCISES 63
2.3 THE HEADER 26
REFERENCES 64
2.4 THE FEATURE KEYS 28
BOX 3-1. SCIENTIST SPOTLIGHT: Barbara
The CDS Feature Key and Gene Structure 28 McClintock 57
viii TABLE OF CONTENTS
CHAPTER 4 • SUBSTITUTIONMATRICES 66 5.3 THE NEEDLEMAN-WUNSCH GLOBAL

ALIGNMENT PROGRAM 94
Initialization and Mat rix Fill 94
4.1 INTRODUCTION 66
Traceback 97
4.2 IDENTITY SUBSTITUTION MATRIX 67
Gap Penalties 98
4.3 AMINO ACID SUBSTITUTION SYSTEM
5.4 MODIFIED NEEDLEMAN-WUNSCH GLOBAL
BASED ON NATURAL SELECTION 69
ALIGNMENT (N-Wmod) PROGRAM WITH
4.4 DEVELOPMENT OF THE MATRIX OF LINEAR GAP PENALTY 99
"ACCEPTED" AMINO ACID
N-Wmod Initialization 100
SUBSTITUTIONS 71
N-Wmod Matrix Fill 101
Thought Question 4-1 72
N-Wmod Traceback 101
4.5 RELATIVE MUTABILITY CALCULATIONS 74
5.5 ENDS-FREE GLOBAL ALIGNMENT 101
4.6 DEVELOPMENT OF THE PAM1 MUTATION
PROBABILITY MATRIX 74 5.6 LOCAL ALIGNMENT PROGRAM WITH LINEAR
GAP PENALTY 102
4.7 DETERMINATION OF THE RELATIVE
FREQUENCIES OF AMINO ACIDS 75 SUMMARY 104
4.8 CONVERSION OF THE PAM1 MUTATIONAL EXERCISES 104

PROBABILITY MATRIX TO THE PAM1
REFERENCES 105
LOG-ODDS SUBSTITUTION MATRIX 77
BOX 5-1. SCIENTIST SPOTLIGHT: Christian
4.9 CONVERSION OF THE PAM1 MUTATIONAL
D. Wunsch 96
PROBABILITY MATRIX TO OTHER PAM
SUBSTITUTION MATRICES 78
4.10 PRACTICAL USES FOR PAM SUBSTITUTION CHAPTER 6 • BASIC LOCAL ALIGNMENT
MATRICES 79
SEARCH TOOL (BLAST) AND MULTIPLE
4,11 BLOSUM SUBSTITUTION MATRIX 81
SEQUENCEALIGNMENT 106
4.12 PHYSICO-CHEMICAL PROPERTIES OF
AMINO ACIDS CORRELATE TO VALUES 6.1 INTRODUCTION 106
IN MATRICES 84
6.2 THE BLAST PROGRAM 107
4.13 PRACTICAL USAGE 86
Four Phases in the BLAST Program 109
SUMMARY 87
How Does BLASTAccount for Gaps? 111
EXERCISES 87
How Is the Hit Deemed to Be Statistically
ANSWERS TO THOUGHT QUESTIONS 88 Significant? 111
REFERENCES 88 Thought Question 6-1 113
BOX 4-1. SCIENTIST SPOTLIGHT: Margaret Belle Why Is the BLAST Program Faster Than the
Dayhoff 70 Smith-Waterman Program? 113
Low Complexity Regions and Masking 114
Usefulness of BLAST 114

CHAPTER 5 • PAIRWISE SEQUENCE PSI-BLAST 115
ALIGNMENT 89
LEARNING OUTCOMES 89 6.3 MULTIPLE SEQUENCE ALIGNMENT 118
5.1 INTRODUCTION 89 ClustalW 120
5.2 SLIDING WINDOW 90 SUMMARY 126
Dot Plots 92 EXERCISES 126
The Dotter Program 93 ANSWERS TO THOUGHT QUESTIONS 127

TABLE OF CONTENTS ix
REFERENCES 127 8.2 PHYLOGENY AND PHYLOGENETICS 170

BOX 6-1. SCIENTIST SPOTLIGHT: David Lipman, Molecular Clocks 171
NCBI Director 119
Phylogenetic Tree Nomenclature 178
How to Tell if Sequences in Two Lineages Are

CHAPTER 7 • PROTEINSTRUCTURE
Undergoing Sequence Substitution at Nearly
PREDICTION 129 Equal Rates 180
LEARNING OUTCOMES 129 DNA, RNA, and Protein-Based Trees 182
7.1 INTRODUCTION 129 8.3 TWO CLASSES OF TREE-GENERATION

METHODS 183
7.2 EXPERIMENTAL METHODS OF STRUCTURE
DETERMINATION 132 Unweighted Pair Group Method with Arithmetic
Mean (UPGMA) 183
X-ray Crystallography 132
NMR Spectroscopy 137
7.3 INFORMATION DEPOSITED INTO THE
PROTEIN DATA BANK 139 Thought Question 8-3 188
7.4 MOLECULAR VIEWERS 141 Thought Question 8-4 196
Thought Question 7-1 142 Bootstrap Analysis 196
7.5 PROTEIN FOLDING 143 Other Substitution Rate Models: Kimura

Two-Parameter Model and Gamma
Christian Anfinsen's Protein Unfolding Distance Model 198
and Refolding Experiment 143
Neighbor-Joining Method 199
Local Minimum Energy States 143
8.4 APPLICATION OF PHYLOGENETICS TO
Energy Landscape Theory 144 STUDIES OF THE ORIGIN OF MODERN
HUMANS 200
7.6 PROTEIN STRUCTURE PREDICTION
METHODS 14S 8.5 PHYLOGENETIC TREE OF LIFE 203
Prediction Method 1: Computational 8.6 TP53 GENE FAMILY MEMBERS IN
Methods 145 DIFFERENT SPECIES 203
Combining Computational Methods SUMMARY 206
and Knowledge-Based Systems 149
EXERCISES 206
Calculation of Accuracy of Structure Predictions 151
ANSWERS TO THOUGHT QUESTIONS 208
Prediction Method 2: Statistical
and Knowledge-Based Methods 153 REFERENCES 208
Prediction Method 3: Neural Networks 156 BOX 8-1. A CLOSER LOOK: What Do We know about
Neanderthal and Denisovan? 189
Prediction Method 4: Homology Modeling 160
BOX 8-2. SCIENTIST SPOTLIGHT: Svante Paabo 191
Prediction Method 5: Threading 163
SUMMARY 165
CHAPTER 9 • GENOMICS 210
EXERCISES 165
ANSWER TO THOUGHT QUESTION 166
REFERENCES 167
9.1 INTRODUCTION 210
BOX 7-1. A CLOSER LOOK: p53 Co-crystallized with

9.2 DNA SEQUENCING-DIDEOXY METHOD 211
DNA Reveals Insights into Cancer 135 Dideoxy Nucleotides 211
Step-by-Step Procedure of DNA Sequencing 213

CHAPTER 8 • PHYLOGENETICS 168
Electrophoresis 213
LEARNING OUTCOMES 168 Thought Question 9-1 213
8.1 INTRODUCTION 168 9.3 POLYMERASE CHAIN REACTION (PCR) 213

x TABLE OF CONTENTS
9.4 DNA SEQUENCING: NEXT-GENERATION 9.12 PRACTICAL APPLICATION OF TAG SNP, SNP
(NEXT-GEN) SEQUENCING AND MUTATION ANALYSES 246
TECHNOLOGIES 215
9.13 WHAT IS THE SMALLEST GENOME? 248
Common Themes in Next-Gen Sequencing
SUMMARY 249
Technologies 215
EXERCISES 249
Ion Semiconductor Sequencing 216
Nanopore-Based Sequencing 219
REFERENCES 251
9.5 THE PHIX174 BACTERIOPHAGE
GENOME 220 BOX 9-1. SCIENTIST SPOTLIGHT: J. Craig Venter 227
9.6 THE GENOME OF HAEMOPHJLUSINFLUENZAE BOX 9-2. A CLOSER LOOK: DNA Fingerprinting
Rd AND THE WHOLE GENOME SHOTGUN (DNA Profiling) 237
SEQUENCING APPROACH 221
Whole Genome Shotgun Approach 222
Thought Question 9-2 224 CHAPTER 10 • TRANSCRIPTAND PROTEIN

Haemophi/us fnf/uenzae Rd Genome 224 EXPRESSION
ANALYSIS 253
9.7 GENOME ASSEMBLY AND ANNOTATION 226
Contig N50 and Scaffold N50 226
Bacterial Genome Annotation Systems 228
10.2 BASIC PRINCIPLES OF GENE
9.8 GENOME COMPARISONS 228 EXPRESSION 254
Synteny Dot Plot 228 10.3 MEASUREMENT OF TRANSCRIPT LEVELS 258

Comparison of E.coli Substrain DH10B to E. coli Thought Question 10-1 260
Substrain MG1655 229
10.4 TRANSCRIPTOME AND MICROARRAYS 260
9.9 THE HUMAN GENOME 229
Stages of a Microarray Experiment 260
General Characteristics of the Human
Heatmaps 264
Genome 230
Comparison of the Human Genome to the
Chimpanzee Genome 231 Cluster Analysis 265
Thought Question 9-3 232 Thought Question 10-3 266
Detailed Analysis of the Human Genome Practical Applications of Microarray Data 266
Landscape 233
Considerations to Take in the Interpretation
9.10 REGION OF THE HUMAN GENOME THAT of Microarray Data 267
ENCOMPASSES THE TP53 GENE 239
Protein Levels Can Be Controlled by Regulation
General Comments on the Region Encoding the of Degradation Rate 267
TP53Gene 239
10.5 RNA-Seq (RNA SEQUENCING) 268
Tracks That Display Information about the TP53
Advantages of RNA-Seq 268
Region of the Genome 240
Overview of RNA-Seq Steps 269
9.11 THE HAPLOTYPE MAP 243
Bridge Amplification 271
What Is a Haplotype? 243
Analysis of an Experiment Using RNA-Seq 272
Haplotypes Can Be Specified by Markers Derived
from SNPs,lndels, and CNVs 243 10.6 THE PROTEOME 273
Tag SNPs 244 Separation of Proteins and Quantification of Their
Steady-State Levels: Two-Dimensional (20) Gel
Electrophoresis 273
How Did Haplotypes Originate? 244
Identification of Proteins: Liquid Chromatography-
The HapMap Database 246 Mass Spectrometry (LC-MS) 275
TABLE OF CONTENTS xi
Advantages and Challenges of Current Proteome 12.2 EXTREME VALUE DISTRIBUTION 322
Analysis Techniques 277
Right-Tail P-value 326
10.7 REGULATION OF p53-CONTROLLED
GENES 278 12.3 SIGNIFICANCE OF ALIGNMENTS 326
SUMMARY 280 12.4 STOCHASTIC PROCESSES 331
EXERCISES 280 Markov Chains 332
ANSWERS TO THOUGHT QUESTIONS 282 Thought Question 12-1 333
REFERENCES 282 Hidden Markov Models 335
BOX 10-1. SCIENTIST SPOTLIGHT: Patrick 0. Brown 262 Poisson Process and Jukes-Cantor Model 344
SUMMARY 348
CHAPTER 11 • BASICPROB
ABILITY 284 EXERCISES 348

REFERENCES 350
BOX 12-1. SCIENTIST SPOTLIGHT:
11.2 THE BASICS OF PROBABILITY 284 Michael Waterman 321
Definitions and Basic Rules 284
Counting Methods When Order Matters 287 CHAPTER 13 • PROGRAMM

ING BASICS
Counting Methods When Order Does Not AND APPLICATIONSTO BIOINFORMA
TICS 351
Matter 290
Independence 291
Dependence 292
13.2 DEVELOPERS AND USERS WORK
11.3 BAYES' LAW IN PROBABILITY TOGETHER TO MAKE NEW
AND STATISTICS 294
DISCOVERIES 353
The Law ofTotal Probability and Bayes' Law 294
13.3 WHY PYTHON? 355
13.4 GETTING STARTED WITH PYTHON 356
Bayesian Inference 298
13.5 DATA FLOW: REPRESENTING
Thought Question 11-2 301 AND MANIPULATING DATA 358
11.4 RANDOM VARIABLES 303 Variable Names 359
Discrete Random Variables 303 Data Types and Operators 359
Thought Question 11-3 304 Strings 361
Thought Question 11-4 308 13,6 PUTTING IT TOGETHER: A SIMPLE PROGRAM

TO LOOK UP THE HYDROPHOBICITY OF
Continuou s Random Variables 310 AN AMINO ACID 368
SUMMARY 315 13.7 DECISION MAKING 369
EXERCISES 316 Operations for Decision Making 370
ANSWERS TO THOUGHT QUESTIONS 318 If-Tests 371
REFERENCES 319 Conditional Expressions 376
Loops 376
CHAPTER 12 • ADVANCEDPROBABILITY FOR Thought Question 13-1 377
BIOINFORMATICSAPPLICATIONS 320
LEARNING OUTCOMES 320 Thought Question 13-3 379
12.1 INTRODUCTION 320 13.8 INPUT AND OUTPUT 379

xii TABLE OF CONTENTS
13.9 PROGRAM DESIGN: DEVELOPING KYTE- 14.2 ANALYSIS OF AN EXISTING TOOL:

DOOLITTLE'S HYDROPATHY SLIDING EMBOSS WATER LOCAL ALIGNMENT
WINDOW TOOL 381 TOOL 408
Step 1: Understanding the Problem 382 Thought Question 14-1 411
Steps 2 Through 4: Develop and Refine 14.3 OVERVIEW OF SPA: A SIMPLE PAIRWISE
Algorithm 383 ALIGNMENT TOOL 411
Step 5: Code in Target Language (Python) 385 14.4 ALGORITHMS 412
Steps 6 and 7: Program Verification (Testing and 14.5 ALGORITHMS FOR SPA 413
Debugging) 385
Input Sequences 415
Create Substitution Matrix 416
13.10 HIERARCHICAL DESIGN: FUNCTIONS
Input Gap Penalties 419
AND MODULES 390
Output Alignment 425
Python Functions 390
14.6 ALGORITHM COMPLEXITY 426
14.7 EXTENSIONS TO SIMPLE PAIRWISE
Python Modules and Packages 400
ALIGNMENT TOOL 428
SUMMARY 402
SUMMARY 429
EXERCISES 402
EXERCISES 430
PROJECT 431
REFERENCES 406
BOX 13-1. SCIENTIST SPOTLIGHT: Russell
REFERENCES 432
F. Doolittle 353
BOX 14-1. SCIENTIST SPOTLIGHT: Richard Karp 428
CHAPTER 14 • DEVELOPING A Glossary 433

BIOINFORMATICSTOOL 407 Credits 443
LEARNING OUTCOMES 407 Index 447

In 2001, in a massive collaborative effort of scientists, probability as they lead up to the concept of Expect value
working from a multitude of disciplines, including biol- (E-value) and its use in sequence alignment programs.
ogy, biochemistry, chemistry, genetics, engineering, and Concepts in Bioinformatics and Genomics also describes,
computer science, one of the tremendous feats in the his- from a mathematical perspective, the development of the
tory of science was accomplished: the sequencing of the hidden Markov model and how it can be used to align
human genome. sequences in multiple sequence alignment programs.
Today, we can imagine a not-too-distant future in Finally, it introduces students to programming exercises
which our personal genomes are entirely known to us. directly related to bioinformatics problems. Thought-
We will download our genetic data and know by our se- provoking exercises stretch the students' imaginations
quences whether we are susceptible to particular dis- and learning, giving them a deeper understanding of
eases such as diabetes, cancer, and stroke. We'll modify software programs, molecular biology, basic probability,
our behaviors and mitigate these risks-our lives will and program-coding methodology underpinning the
change. For some of us, a poor genetic profile will affect discipline. The material covered in this book provides
our outlook on life, or the economics of our lives. How students with the fundamental tools necessary to ana-
will medicine adapt to common knowledge of the lyze biological data.
genome? We do not quite know yet what this world looks
like, but some of its weightiest questions are already
being asked and debated-and studied by a rapidly ex- ORGANIZATION
panding field of genomics and bioinformatics research.
These are questions about the modern world, the modern Introduction to Bioinformatics: Chapters 1-5
person, and the future ofbiological science.
Welcome to the world ofbioinformatics. CHAPTER 1 is an overview of molecular biology. It will
provide the essential biology vocabulary for understand-
ing bioinformatics. Chapter 2 introduces GenBank, the
database that stores the vast amounts of DNA and RNA
THE APPROACH
sequence data crucial for bioinformatics research.
Concepts in Bioinformatics and Genomicstakes a concep- CHAPTER 3 discusses molecular evolution, which ex-
tual approach to its subject, balancing biology, mathe- plains the diversity of sequences and how mutations get
matics, and programming, while highlighting relevant passed to progeny. Chapter 4 delves into the derivation
real-world applications. Topics are developed from the of amino acid substitution matrices, the basis of se-
fundamentals up, like in an introductory textbook. This quence comparison programs, which help us connect
is a comprehensive book for students enrolled in their molecular evolution to protein structure and function.
first course in bioinformatics. A compelling case study Chapter 5 discusses amino acid substitution matrices
gene, the TP53 gene, a human tumor suppressor with and pairwise sequence comparison programs. Here, we
strong clinical applications, runs throughout, engag- begin to get into the nuts and bolts of algorithms that use
ing students with a continuously relevant example. data from evolution and protein domain conservation to
The textbook thoroughly describes basic principles of infer whether two genes are homologs.
xiv PREFACE
Biology: Chapters 6-10 three to four years. Similarly, databases that are bulwarks
of the field will not vanish in the foreseeable future. Un-
CHAPTER 6 further develops the topic of pairwise se-
derstanding the rationale for the basis of these bioinfor-
quence comparison by describing the Basic Local Align- matics tools is critical for students pursuing molecular
ment Search Tool (BLAST) and discusses multiple life science or bioinformatics careers.
sequence alignment programs with an emphasis on the
first popular program of this class-ClustalW. Chap-
ter 7 is devoted to protein structure prediction programs. Flexible Organization
This chapter provides strong foundational knowledge of Overall, biology, mathematics, and computer science are
protein structures and the Protein Data Bank. Chapter 8 presented in an order that systematically develops a stu-
introduces phylogenetics with a discussion of DNA, pro- dent's understanding of the area. To highlight relevant
tein sequence information, and the construction of phy- connections between the three, we include cross-
logenetic trees. Chapter 9 presents genomics analysis references in the main text and in footnotes. Those who
with an emphasis on next-generation sequencing (NGS), wish to teach the course with the biology-heavy chapters
and annotation of bacterial genomes. Chapter 10 is all in the beginning may consider presenting the chapters in
about gene expression. Approximately half of this chap- the order listed in the table of contents. In this order, the
ter is devoted to methods to measure transcript levels biology-heavy chapters (Chapters 1 through 10) are fol-
with an emphasis on microarrays and RNA-seq. The lowed by two mathematics-heavy chapters ( Chapters 11
other half is devoted to proteomics, where we describe and 12) and two computer science-heavy chapters
how mass spectrometry is used to identify proteins iso- (Chapters 13 and 14).
lated from 2D-gels. If instructors wish to integrate computer program-
ming early into the course, they may want to consider
Mathematics: Chapters 11-12 presenting the chapters in the following order: 1-5, 13,
CHAPTER 11 introduces you to probability, a requisite 14, and 6-12. Chapters 1 through 5 provide the biologi-
component ofbioinformatics research, with an emphasis cal rationale for pairwise sequence alignment and Chap-
on counting methods, dependence, Bayesian inference, ters 13 and 14 provide the computer programming
and random variables. In Chapter 12 the subject of a con- background so that students can create their own soft-
tinuous random variable, introduced in the previous ware tools to align sequences. The programming con-
chapter, will be further developed into a discussion of cepts in Chapters 13 and 14 reinforce the biological
the extreme value distribution and its use in analyzing principles covered in Chapters 1 through 5. To provide
the significance of an alignment. We conclude the chap- students with more time to learn the Python program-
ter with stochastic processes, specifically Markov chains ming basics, instructors may wish to intersperse topics
and hidden Markov models, as well as a mathematical from Chapters 13 and 14 among topics covered in Chap-
derivation of the Jukes-Cantor model. ters 1 through 5. After covering Chapters 1 through 5, 13
and 14, material from the more biology-heavy chapters
Programming: Chapters 13-14 (Chapters 6-10) and the mathematics-heavy chapters
(Chapters 11-12) can be covered.
CHAPTER 13 focuses on Python, a popular bioinformat- Some bioinformatics and genomics courses are taught
ics programming language. The Kyte-Doolittle Hydrop- in a format consisting of a lecture section and a separate
athy sliding window program (one of the first popular computer lab section. If this is the case, the lecture sec-
bioinformatics programs) is used to illustrate Python tion can focus on Chapters 1 through 12, the lab section
fundamentals and to introduce you to the program on Chapters 13 and 14. The lab section may allow more
design process. Chapter 14 follows this design process time for students to work through small coding assign-
and steps you through the development of a pairwise ments that together provide a foundation for a more ex-
sequence alignment tool. tensive programming project (described in Chapter 14)
to be completed by the end of the lab course. Another
way of dividing the material between lecture and lab sec-
FOR PROFESSORS tions is to focus the lecture on the biology-heavy chapters
(Chapters 1-10) and include Chapters 11-14 in the lab.
If instructors would like to integrate mathematics
Approach and Rationale
earlier in the course they may consider covering Chap-
The bioinformatics discipline has matured to the point ters 11 and 12 just prior to Chapter 6. The introductory
where there is general agreement on the software pro- basic probability segment of Chapter 11, followed by the
grams and databases that are standards in the field. The explicit derivation of extreme value distribution in
algorithms that form the foundations of these software Chapter 12, provide a strong foundation for the discus-
programs will not significantly change within the next sion of E-value, an important component of the BLAST
PREFACE xv
SUGGESTEDALTERNATIVE PRESENTATIONS OF TEXTBOOK
PRESENTATIONORDEROF ALTERNATECHAPTER TYPE OF INTEGRATION

FIRSTFIVE CHAPTERS PRESENTATIONORDER
1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Biology-heavy chapters first with cross-references to
mathematics- and computer science-heavy chapters.
1,2, 3,4, 5, 13, 14, 6, 7, 8, 9, 10, 11, 12 Biology-foundation chapters first with computer
science-heavy chapters more integrated.
1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12-lecture Biology-heavy and mathematics-heavy lecture section
13, 14-lab with a lab focused on computer science.
1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12-lecture Biology-heavy lecture section with a lab focused on
11, 12, 13, 14-lab mathematics and computer science.
1,2, 3,4, 5, 11, 12,6,7, 8, 9, 10, 13, 14 Biology-foundation chapters first with mathematics-
heavy chapters more integrated .
program discussed in Chapter 6. The segment of Chapter 9 ("Genomics") and Chapter 10 ("Transcript
Chapter 12 that introduces hidden Markov models will and Protein Expression Analysis").
strengthen the students' understanding of multiple se-
quence alignment discussed in Chapter 6. Case studies of TP53,the Tumor
The table above shows our suggestions for alterna- Suppressor Gene
tive sequences of the textbook chapters that can be tai-
The TP53 tumor suppressor is mutated in virtually all
lored to your particular needs.
cancer types, and there is wide interest in using this
knowledge to develop better cancer therapies. In Chap-
ter 1, we discuss how p53 was discovered as a protein
THE FEATURES bound to a monkey virus oncoprotein, and in the last
chapter, we show students how to create sequence align-
Balance of Biology, Mathematics, ment programs that quantify the similarities between
and Programming p53 and its paralogs , p63 and p73. By the end of this text-
book, students and instructors will have a deep under-
Concepts in Biochemistry and Genomics strikes a balance
standing of the molecular biology of this gene and how
of topics for all students, no matter their background. Bi-
bioinformatics can be used to further research progress
ology students will appreciate the reinforcement of the
in the fight against cancer .
molecular life science topics and the gradual introduc-
tion to basic probability and programming concepts.
Scientist Spotlight
Basic probability and programming use examples in biol-
ogy to help biology students see the relevance of these Scientists who made significant contributions to the bio-
concepts to molecular life science. Mathematics is ex- informatics field are highlighted in "Scientist Spotlight "
pertly interwoven with bioinformatics concepts. Stu- boxed sections. The scientists who created the first
dents with a background in computer programming will widely applicable amino acid substitution matrices
appreciate the basic biology primer in the first chapter. (Margaret Dayhoff), the first global sequence alignment
For students who already know how to program in an- program (Christian Wunsch) , the first local sequence
other language, this textbook offers the opportunity to alignment program (Michael Waterman) , and the first
learn the fundamentals of a new language, Python. program that successfully predicted protein membrane
spanning regions (Russell Doolittle)-these are just a
Genomics few of the brilliant discoveries and minds featured.
Genomics is a field that studies the entire sequenced

A Closer Look
genomes of organisms. Bioinformatics programs and
databases are highly applicable to genomics because of From the TP53 gene to DNA fingerprinting and the
the critical need to analyze and store a large amount of Neanderthal genome , this boxed material examines in
sequence data. Without bioinformatics, we cannot fully detail some of the most important elements of Con-
assess the genomics data we have collected. Chapters cepts in Bioinformatics and Genomics. Replete with fig-
that emphasize genomics are Chapter 8 ("Phylogenetics "), ures, photographs , and excerpts from published texts,
xvi PREFACE
"A Closer Look" provides the background and clarity For Students
needed to fully grasp the relevance ofbioinformatics.
Companion website (www.oup.com/us/momand):
Thought Questions Resources and links to bioinformatics software, tools,
and databases are available on the companion website.
Interspersed throughout the text, "Thought Q}Iestions" These are stable resources, such as Dotter, BLAST,
ask the important conceptual questions and prompt stu- GenBank, and many more, that have matured with the
dents to problem-solve and apply their knowledge on the discipline into the essential tools for the bioinformati-
fly. These questions provide students opportunities to cian. The companion site also provides downloadable
self-test and better engage with their reading. Answers programming tools that are necessary for students to
are found at the end of the chapter. complete the programming projects and end-of-chapter
exercises.
End-of-Chapter Exercises
Additionally, a robust list of end-of-chapter exercises For Instructors
encourages students to apply their bioinformatics knowl- The Ancillary Resource Center (ARC), located at www
edge holistically. Exercises are qualitative and quantita- .oup-arc.com/momand, contains the following teach-
tive, specific and comprehensive. ing tools:
GlossaryTerms • Digital Image Library includes electronic files in

Glossary terms are highlighted and defined the first time Power Point format of every illustration, photo,
they appear in the text. Concise explanations of the graph, figure caption, and table from the text-both
terms are also provided in the glossary section at the end labeled and unlabeled versions.
of the book. • Answers to End-of-Chapter Questions includes
detailed solutions to all of the many exercises pro-
vided at the end of each chapter.
SUPPORTPACKAGE • Editable Lecture Notes in PowerPoint format for
each chapter help make preparing lectures faster and
Oxford University Press offers a comprehensive ancil- easier than ever. Each chapter's presentation includes
lary package for instructors and students using Concepts a succinct outline of key concepts and incorporates
in Bioinformatics and Genomics. the graphics from the chapter.
When writing a textbook for the first time it is difficult to years. This project, called the Southern California Bioin-
foresee the amount of time it will require. For this proj- formatics Summer Institute, created an environment of
ect we resorted to carving out time between academic collegiality that made us realize how to use our respec-
terms, during summers, on weekends, and late at night. tive fields to complement each other to create a rigorous
Time usually spent with our families was, instead, dedi- bioinformatics training curriculum. Finally, we thank
cated to Concepts in Bioinformatics and Genomics. We our Cal State LA students who, over the many years of
would not have persevered without the encouragement enrolling in our bioinformatics course, collectively
and sacrifices of our spouses and families. For this we guided us to effectively convey the multidisciplinary
owe them tremendous gratitude. concepts in this rapidly evolving field.
We would also like to express our appreciation to
Jason Noe, senior editor at Oxford University Press, who
five years ago listened to our pitch and read our proposal MANUSCRIPTREVIEWERS
to create a new textbook. His combination of patience,
encouragement, and optimism moved the project along More than 70 reviewers were commissioned to read
to its favorable conclusion. Working with Jason were as- draft manuscript chapters. We are grateful to each one
sistant editor Andrew Heaton and editorial assistant Ben for sharing insights and suggestions, which contributed
Olcott, who were very responsive to our long lists of greatly to the published work. We thank Oxford Univer-
questions. Jason also selected Dragonfly Media Group, sity Press for locating and commissioning top reviewers.
whose team of Craig Durant, Caitlin Duckwall, and Rob To these reviewers we give a big thank you for your
Duckwall did a superb job refining our rough drafts of insightful comments and suggestions. We hope you find
the illustrations. In production, art director Michele much in the book that will captivate and benefit your
Laseau, designer Renata De Oliveira, and production students.
manager Lisa Grzan produced an accurate and beautiful
printed work. We would also like to thank Patrick Lynch,
editorial director; John Challice, vice president and pub- Preston Aldrich, Benedictine University
lisher; Frank Mortimer, director of marketing; David Stephane Aris-Brosou, Ottawa University
Jurman, marketing manager; Ileana Paules-Bronet, mar- Erich Baker, Baylor University
keting assistant; and Bill Marting, national sales man-
ager, along with the Oxford University Press sales force Guy F. Barbato, Richard Stockton College
for their support. Serdar Bozdag, Marquette University
We also thank our colleagues at California State Claudio Casola, Saint Louis University
University, Los Angeles (Cal State LA), Sandra Sharp
and Kirsten Fisher, who read early drafts of chapters and Kari L. Clase, Purdue University
offered invaluable advice on how to improve them. We Soochin Cho, Creighton University
acknowledge the National Science Foundation and Na- Tin-Chun Chu, Seton Hall University
tional Institutes of Health, which jointly funded a proj-
ect at Cal State LA; it gave us the opportunity to train Garrett Dancik, Eastern Connecticut State University
more than 100 undergraduate and graduate students in Heather Dehlin, Carroll University, Medical College
bioinformatics and genomics over the course of several of Wisconsin
xviii ACKNOWLEDGMENTS
Justin DiAngelo, Hofstra University Murlidharan T. Nair, Indiana University South Bend
Qynfeng Dong, University of North Texas Michael Persans, University of Texas Pan-American
Derek Dube, University of Saint Joseph Helen Piontkivska, Kent State University
Bert Ely, University of South Carolina Sarah Prescott, University of New Hampshire
Matthew Escobar, California State University San Marcos Catherine Putonti, Loyola University Chicago Lakeshore
Chester S. Fornari, DePauw University Srebrenka Robie, Agnes Scott College
Karl Fryxell, George Mason University Michael Rosenberg, Arizona State University Tempe
Arezou A. Ghazani, Harvard Medical School Eric Rouchka, University of Louisville
Eugenia Giannopoulou, CUNY City College Elizabeth Ryder, Worcester Polytechnic Institute
Cynthia Gibas, University of North Carolina at Charlotte Eva Sapi, University of New Haven
Santhosh Girirajan, Pennsylvania State University- Scott C . Schaefer, Lenoir-Rhyne University

University Park Amarda Shehu, George Mason University
James Godde, Monmouth College Kim Simons, Emporia State University
Michael Gribskov, Purdue University Malathi Srivatsan, Arkansas State University
Karen Guzman, Campbell University Aurelien Tartar, Nova Southeastern University
Jeremiah Hackett, University of Arizona Bryan Thines, Claremont Colleges
Xiyi Hang, California State University, Northridge Vladimir Uversky, University of South Florida
Barry Hoopengardner, Central Connecticut State University Virginia Oberholzer Vandergon, California State University
Yasha Karant, California State University San Bernardino Northridge
Anuj Kumar, University of Michigan Sabrina Walthall, Mercer University
SathishA . P. Kumar, Coastal Carolina University Xiaofei Wang, Tennessee State University
Stephen Levene, University of Texas at Dallas David Weisman, University of Massachusetts,
Zhijun Li, University of the Sciences in Philadelphia Boston
Li Liao, University of Delaware Amy Wiles, Mercer University
David A . Lightfoot, Southern Illinois University, Carbondale Zhenyu Xuan, University of Texas at Dallas
Ping Ma, University of Illinois Urbana-Champaign Mai Zahran, CUNY New York City College of Technology
Padmanabhan Mahadevan, University of Tampa

Jamil Momand
Shaun Mahony, Penn State University
Alison Mc Curdy
Susan McDowell, Ball State University
Silvia Heubach
Brett McKinney, University of Tulsa
Nancy Warter-Perez
Vida Mingo, Columbia College
JAMIL MOMAND has been a professor of biochemistry from University of Chicago in 1988 and her Ph.D. in
at Cal State LA since 1999. In 2000, he and Dr. Nancy chemistry at California Institute of Technology in 1995,
Warter-Perez (contributing author and professor of elec- she was a Camille and Henry Dreyfus Postdoctoral
trical and computer engineering) created a course that Fellow. She has been enjoying teaching chemistry-
introduces bioinformatics to students. The philosophy general, organic, bioorganic, and biochemistry-courses
of the course is to appeal to students with a background first at Harvey Mudd College and currently at Cal State
in either the mathematics/computer science area or the LA. She strives to improve her pedagogy as an ongoing
molecular life science area. The two professors designed process and is active in securing funding for curriculum
the course to help students be intelligent users of exist- development in science courses. She has been heavily
ing databases and software programs as well as to help involved in the development of innovative curriculum
them become developers of new bioinformatics soft- and educational policies at all levels of the university.
ware programs. The experience of teaching this course Dr. McCurdy collaborates and publishes on externally
for many years was harnessed to write Chapters 1-6 funded research projects with her research students,
and Chapters 13-14 in Concepts in Bioinformatics and applying the techniques of chemistry to tackle challeng-
Genomics. Dr. Momand also created the Bioinformatics ing biological questions. Most recently, her laboratory
and Computational Biology Minor Program at Cal State students have been working with her to develop an or-
LA, and he is the student advisor for students in this ganic chemical photoswitchable tool that may be used to
program. He received his Ph.D. in biochemistry at UCLA help understand aspects of oscillatory calcium signaling.
studying the metabolism of aged proteins in Dr. Steven She was the recipient of the 2009 Cal State LA Distin-
Clarke's laboratory. Dr. Momand was awarded a postdoc- guished Woman Award. Outside of work, she enjoys
toral fellowship at Princeton University in molecular bi- good meals, good books, and long, hilly bicycle rides
ology, where, in the laboratory of Dr. Arnold J. Levine, he with her husband Kerry.
demonstrated that the MDM2 proto-oncoprotein forms
a complex with the p53 tumor suppressor protein. At the SILVIA HEU BACH is a professor of mathematics at Cal
City of Hope National Medical Center Dr. Momand con- State LA. Since she joined the faculty in 1994, she has
tinued to study p53 and MDM2. He showed that p53 is been very active in interdisciplinary curricular develop-
susceptible to cysteine residue oxidation and that the oxi- ment. She taught the mathematics component in the bio-
dation destroys p53's ability to bind to DNA. Dr. Mo- informatics summer institute jointly run by Dr. Jamil
mand's research remains focused on the molecular Momand and Dr. Nancy Warter-Perez, which led to her
mechanisms of cell growth control and cancer. One line involvement in this book project. She was also the princi-
of investigation his laboratory is currently pursuing is un- pal investigator on a National Science Foundation grant
derstanding how cancer cells become resistant to chemo- to develop a general education modeling course for
therapy agents. Dr. Momand received the Cal State LA non-mathematics majors. In this course, students use the
Outstanding Professor Award for the 2014-2015 aca- computer-algebra system Mathematica to explore the
demic year. His hobbies include camping, hiking, jog- modeling process without the advanced background
ging, and ultimate Frisbee. needed to create and analyze mathematical models. More
recently, she was the driving force for the redesign of the
ALISON MCCURDY is a professor of chemistry at Cal mathematics sequence for life sciences majors, a major
State LA. After earning her B.S. in biological chemistry part of a project funded by the National Institutes of
xx ABOUT THE AUTHORS
Health to improve quantitative skills of life-science underrepresented minorities, and has been actively
majors at Cal State LA. The newly created courses now involved in academic governance , currently serving as
form the required mathematics course sequence and have the Academic Senate chair. In 1994 Dr. Warter-Perez
been taught since fall 2011. Dr. Heubach holds a master's established the Cal State LA Compiler Research Group
degree in mathematics and economics from the Univer- to study advanced compiler techniques for high-
sity of Ulm, Germany, and both master 's and Ph.D. de- performance processors. She has developed and taught
grees in applied mathematics from the University of a broad range of computer engineering courses and since
Southern California. Her current research areas are enu- 2000 has co-developed curricula for training biologists
merative combinatorics and combinatorial games, and and computer scientists in the field of bioinformatics.
she is the coauthor of a graduate text titled Combinatorics She has published widely on collaborative project based
of Compositions and Words. She also served as the chair of learning, an active learning strategy designed to help
her department for four years and as a vice-chair of the students persist and succeed in engineering. As direc-
Southern California / Nevada Section of the Mathemati- tor of the IMPACT LA NSF GK-12 Program from 2008
cal Association of America. Her accomplishments have to 2014 , she has worked to promote STEM by teaching
been recognized by the 2013 Cal State LA Distinguished graduate students how to communicate their research
Woman Award and the 1999 Cal State LA Outstanding to a broad audience and by providing a wide range of
Professor Award. She received several research travel opportunities for local middle and high school students
grants and was several times an invited researcher at the to explore science and engineering careers. Dr. Warter-
University of Haifa, Israel. Dr. Heubach enjoys watching Perez holds a B.S. in electrical engineering from Cornell
foreign movies , dancing , hiking , camping, traveling to in- University and an M.S. and Ph.D. in electrical engi-
teresting places, and spending time with her husband and neering from the University of Illinois at Urbana-
family at large. Champaign. She is the recipient of the 2013 Cal State
LA Outstanding Professor Award , the 2010 Cal State
NANCY WARTER-PEREZ is a professor of electrical LA Distinguished Woman Award, and the NSF Young
and computer engineering at Cal State LA. Since joining Investigator Award. She is also an avid supporter and
Cal State LA in 1993 , she has been dedicated to im- cheerleader of her husband and four children and is
proving STEM education and outreach, particularly for always up for a game of ultimate Frisbee.
In our time and for the foreseeable future, biology data is Because bioinformatics depends on the collection
being collected at an astounding rate. Whether the data and availability of biological data, the question that
is a new DNA sequence from an exotic animal or the 3D emerges is why there is so much interest in the analysis
structure of a novel protein, the information is invariably and storage of this data. A few examples of the applica-
stored in a database-some of which is accessible tion of biological data to our society may help answer this
through the Internet. In parallel, software tools to ana- broad question. In 1985, Alec Jeffreys discovered that it
lyze this data have been developed steadily. It is essential was possible to distinguish two individuals on the basis
for those who wish to perform research in life sciences to of their "DNA fingerprints." He found regions in the
be aware of the databases and software programs com- human genome that are highly variable and are called
monly used by scientists. Bioinformatics is the field that minisatellites. The lengths of the minisatellites could be
has emerged from this information explosion. used to identify individuals, much like traditional finger-
Before delving into bioinformatics, let's review its prints. Fast forward several decades, and the United
formal definition. Bioinformatics is the research, devel- States passed a law that requires individuals convicted
opment, or application of computational tools and ap- of felonies to submit their DNA to a national database
proaches for expanding the use of biological, medical, (the Combined DNA Index System) for DNA finger-
behavioral or health data, including those tools and ap- print (or profile) analysis. Today, the database of DNA
proaches to acquire, store, organize, archive, analyze or fingerprints from felons provides critical evidence to the
visualize such data. The origin of the term "bioinformat- criminal justice system.
ics" is obscure. In the late 1970s, a bioinformatics group Another example of the application ofbioinformat-
was established at the University of Utrecht. Paulien ics to our society is the discovery of how related humans
Hogeweg published the first paper from this group on a are to Neanderthals (also written as Neandertals). Ne-
program that graphically represents the predictions of anderthals belong to a species of hominids that, for a
different models for simulating real systems. Although time, cohabited the earth with humans (Homo sapiens)
she did not explicitly use the term "bioinformatics" in up until 30,000 years ago, after which Neanderthals
her paper, because of her affiliation with the bioinfor- died out. Fossil data had long suggested that Neander-
matics group, it was the first time the term appeared in thals constituted a species distinct from humans, mean-
print. Perhaps independently,Jean-Michel Claverie used ing they could not mate. Recently, the genome of
the French word "bioinformatique" in the 1980s and Neanderthals was sequenced from bones and compared
translated it to English during one of his lectures. In to- to the human genome using bioinformatics software
day's usage, bioinformatics overlaps with a number of tools. Although these tools were essential to this study,
other interdisciplinary subjects including, but not lim- the feasibility of the sequencing and assembling the
ited to, systems biology, computational biology, and ge- entire Neanderthal genome is largely attributed to the
nomics. Although nothing in the formal definition of advances in the field of genomics. Genome comparison
bioinformatics limits it to molecular data, the bioinfor- reveals that humans and Neanderthals shared a
matics field expanded rapidly in this area when the common ancestor 500,000 years ago. Interestingly, the
human genome sequence was published in 2001. Many comparison data shows that humans and Neanderthals
software programs and databases have been developed had some degree of genetic mixing between 50,000 and
to analyze molecular data; it is from this perspective that 100,000 years ago. In fact, humans in Europe and Asia
this textbook is written. carry 1 to 4% Neanderthal DNA! These are just a few
xxii INTRODUCTION
examples of the transformative power ofbioinformatics Transcript and Protein Expression Analysis (Chap-
and genomics. ter 10). These topics are crucial because it is likely that
In academia and in the workplace , it is generally ac- the cost of sequencing the human genome will fall to the
cepted that those who practice bioinformatics can be point where it is affordable for most people to have their
placed in one of two camps: users or developers. Users own genomes sequenced. If used properly, personal ge-
access databases and software programs to answer bio- nomes could be used in targeted preventative care and
logical problems. For example, a researcher may want to incentivize people to maintain a healthy lifestyle. The
know if a new drug might have toxic effects on the body . future ofbioinformatics and its application to genomics
Ifit is known precisely how the drug binds to its intended will undoubtedly be surprising and exciting.
protein target, then one approach is to search for similar
regions on other potential unintended protein targets.
The program s and databases required to identify similar REFERENCES
regions are readily available through the Internet. On
the other hand, developers create new programs and Altschul , S. F.,T. L. Madden, A. A. Schaffer, J. Zhang, Z. Zhang ,
databases that add to the repertoire of tools that increase W. Miller, and D. J. Lipman . 1997. "Gapped BLAST and PSI-
our knowledge of molecular life sciences. For example , a BLAST:A New Generation of Protein Database Search
Programs." Nucleic Acids Research 25: 3389-3402.
group of developers at the National Center for Biotech-
nology Information (NCBI) created a software program Bioinformatics Definition Committee. 2000. "NIH Working
called PSI-BLAST , which allows mining of databases for Definition of Bioinformatics and Computational Biology, July
17,2000 ."http: // www .bisti.nih.gov /docs / compubiodef.pdf.
similar genes in widely different organisms. PSI-BLAST
has been extensively used to determine the function of Claverie, J.M. and C. Notredame. 2007. Bioinformatics for
newly discovered genes. This book will cover areas es- Dummies, 2nd ed. Hoboken, NJ: Wiley Publishing.
sential for the user as well as the developer. The user will Green, R. E,J. Krause, S. E. Ptak, M. T. Ronan, J. F. Simons,
gain insight into how bioinformatics algorithms and da- L. Du, M. Egholm, J. M. Rothberg, M. Paunovic, and S. Paabo.
tabases operate ; the developer will gain insight into the 2006. "Analysis of One Million Base Pairs of Neanderthal
DNA." Nature 444: 330-336.
biological problems that are solved through bioinfor-
matics tool s. Green, R. E. et al. 2010. "A Draft Sequence of the Neandertal
Another field related to bioinformatics is genomics, Genome." Science 328: 710-722 .
which is the study of whole genomes from organisms . Hogeweg, P.and B. Hesper. 1978. "Interactive Instruction on
Bioinformatics tools are required for the scientific dis- Population Interactions." Computers and Biology in Medicine 8:
coveries made in genomics. We will devote three chap- 319-327.
ters to specialized topics within the genomics field: Jeffreys, A. J., V. Wilson, and S. L. Thein. 1985. "Individual-
Phylogenetics (Chapter 8), Genomics (Chapter 9), and Specific 'Fingerprints' of Human DNA." Nature 316: 76-79 .
1
AFTER STUDYING THIS CHAPTER,
YOU WILL:
Understand the relationship

between genes, transcripts,
proteins, and some functions
carried out by proteins.
Know that genes are composed of

DNA,transcripts are composed of
RNA,and proteins are composed
of amino acid residues.
Be familiar with the one-letter

code for nucleotides and
amino acids.
Appreciate the chemical nature of

nucleotides and proteins.
1.1 INTRODUCTION Understand the term "sequence

alignment."
In this chapter,we review basicconcepts in molecular biology
necessaryfor comprehending bioinformatics.You will then be intro- Be familiar with the chemical
properties of amino acid side
duced to an important molecule, p53 protein (sometimesreferredto chains.
as "p53,"for short),that playsa significant role in preventing cancer.

Know that there are four levels of
This molecule, as well as others,will be used to demonstrate the protein structure, each with a
higher degree of complexity.
utility and power of bioinformatics researchthroughout this book.
Understand that there exists a
universal genetic code that creates
a correspondence between an
order of nucleotides in DNAto
an order of amino acid residues
1.2 GENES AND DNA in proteins.
The genome is the DNA (deoxyribonucleic acid) that is found in an organ-
Appreciate that DNAalterations
ism. Each cell in the organism contains a complete genome. 1 Part of the
can lead to protein alterations that
genome is devoted to making proteins. The segments of the genome that affect protein function.
encode proteins are called genes. 2 Each protein has at least one function that
it carries out for the cell, and, ultimately, for the organism. Figure 1-1 shows Understand how the first
the hierarchy of genome, genes, proteins, and functions. Proteins carry out experiment demonstrating the
the many functions or tasks that collectively allow the organism to live and relationship between a mutation
reproduce. A single function could be repairing damaged DNA or it could and a disease was carried out.
be a step in the breakdown of glucose for the generation of energy. We are
just beginning to appreciate the fact that some proteins have more than one Be familiar with the TP53 tumor
suppressor gene and its protein
product p53.
1
There are a few exceptions. For example, in some mammals, red blood cells, also known
as erythrocytes, lose their DNA once they reach maturity, whereupon they fail to divide
further and have a very limited lifespan.
2
A small minority of genes express functional RNAs such as transfer RNA, ribosomal RNA,
small nuclear RNA, and other types of RNA. These RNAs do not produce proteins but they
perform important functions in the cell.
2 CHAPTER 1 Review of Molecular Biology
function , but we will not explore this complexity further

Genome here. Note that although they have the same genome, not
all cells express the same proteins. These differences in
! ! i protein expression occur because different cell types have
different specialized functions , and it is the repertoire of
Gene 1 Gene 2 Gene 3 Gene4
expressed proteins that gives each cell its specialized func-
tion. There is a subset of proteins unique to every cell type
Protein 2 Protein 4 and there is a subset of proteins common to all cells. Pro-
teins unique to a cell type are called specialized proteins,
and proteins common to all cells are called housekeeping
[ Function 1 [ Function 2 [ Function 3 [ Function X
J
proteins. Figure 1-1 shows that a kidney cell produces pro-
tein 1 and protein 2, but not protein 3. A skin cell produces
protein 2 and protein 3, but not protein 1. Proteins 1 and 3
are therefore specialized proteins and protein 2 is a house-
keeping protein .
There are estimated to be 20,000 - 25,000 genes in the
human genome, but they constitute only approximately
2 % of the total DNA found in each cell. 3 The non-gene part
of the genome remains a mystery and its exact function is
Expressed in Expressed in
kidney cell skin cell an active area of research. All DNA , whether it is consti-
tuted of genes or not, is composed of paired nucleotides
FIG. 1-1. The relationships between the genome, genes, proteins, (sometimes called base pairs). It is important to know the
functions , and cell types . structures and abbreviations associated with nucleotides.
These abbreviations are crucial in bioinformatics, for they
allow efficient storage and manipulation of the information contained in these fairly
complex molecular structures. As you will see later in this chapter, abbreviations
have been developed for other biomolecules as well.
A B Nitrogenous bases of DNA
Pyrimidines
Cytosine (C)
Purines
Adenine (A) Guanine (G)

Sugar (ribose)
FIG. 1-2. Structure of a nucleotide

within DNA.
A. The yellow-bordered atoms form the
3
phosphate, the brown-bordered atoms Here, we are referring to the genome that resides in the cell nucleus, sometimes referred to as the
form the sugar (deoxyribose), and the nuclear genome . Outside the cell nucleus there are much smaller genomes that reside in organelles
base (bordered in blue) can be any one of called mitochondria (found in all eukaryotes) and chloroplasts (found in eukaryotes that undergo
four types . B.The four types of bases are photosynthesis). Compared to the nuclear genome , these smaller genomes produce relative ly few
thymine, cytosine, adenine , and guanine. proteins.
GENESAND DNA 3
Nucleotides are composed of three parts: a phosphate , a sugar, and a base . The protein One or more chains of amino
parts of nucleotides that distinguish them from one another are called bases, and acid residues where each chain is a
there are four bases found in DNA. Figure 1-2 shows the chemical structures of DNA minimum of 50 residues long. Proteins
nucleotides . perform most of the biochemical
functions in the organism .
DNA is composed of two strands of nucleotides that are joined together. Be-
tween the strands of DNA, thymine associates specifically with adenine and cytosine
associates specifically with guanine. The two strands are complementary if all of
their bases can associate with each other . Figure l-3A shows the chemical structure
A B
S'end
o-
1 Adenine (A) Thymine (T)
-o- P= O
I -0 FH3 3'end
0 \: - c
~to
I
c-- c
I
~
\: - J
0
//
RH I
~C~
fa"--
"'-o/
c
/H
C
~H
/ I
0 H / 2 Minor
0 groove
-o-J=o HzN\ H O= P- o-
I
~ HC ,c:::N c- c I Phosphate
I I /, ~ H 0
)1/0 C,,,/N
N
\: J CH I
C -- C
/ -------- deoxyribose
backbone
-------
C
C C
I ..d "---
i /
C
/ I 0/ ~H 2
0 H /
-o- IJ=o ct 3 // 0
c- c
···· ··· ···N H2
\ CH
I
o= p- o- Major
o HC/; \ /.C - c / / groove
I \ / NH . ···· ··N C J'°N H 0
~?"o c/N-c,6 "~-J~ rl d

\ c -- c
I c'-... /
}c1
1 turn=
/ I ~ CH2
o H Cytosine (C) / 10 base pairs=
0
-o-P 1-- o
3.4 nanometers
H NHz .. Guanine (G) /
I c-/ ······o o= p- o-
o/ H e°
\
\
N.
\\
C
N H ~I
cc
1H 1/o N- c/ c fH I
( c/ \\ c- N ~ c
\ / O ··. f-N/ "" j }.
C -- C ... NH2 C"'- ../ )
/ I O cH 2
OH H 1
0
3'end I
o= p- o-
o-
/
5' end
c 5' AGTC
3' TCAG
FIG. 1-3 . Structure of DNA .

A. Close-up view of the bases and phosphate-sugar backbone . The two phosphate groups form the sides ofthe ladder. The positions of the
strands of DNA are joined together by base pairing where adenine atoms are exactly as they are in nature . C. The one-letter abbreviation s
associates with thymine and guanine associates with cytosine through used by bioinformaticists to write DNA sequences. Often thi s sequence
hydrogen bonds (signified by dots). B. This image shows more clearly is presented simply as AGTC because the lower strand is complemen-
the double helix structure of DNA. The base pairs appear as rungs, and tary and its sequence is inferred from the top strand .
TABLE 1-1. SINGLE-LETTER ABBREVIATIONSUSED FOR DNA NUCLEOTIDE SEQUENCES
ONE-LETTER
ABBREVIATION NUCLEOTIDE NAME BASE NAME CATEGORY
A Adenosine monophosphate Adenine Purine
C Cytidine monophosphate Cytosine Pyrimidine
G Guanosine monophosphate Guanine Purine
T Thymidine monophosphate Thymine Pyrimidine
N Any nucleotide Any base NA

R AorG AorG Purine
y CorT C orT Pyrimidine
-or* Gap
genome The DNAfound in the of DNA where two complementary strands associate with each other through hy-
organism. For some cells a separate drogen bonding. Note that the ends of each strand are labeled with numbers (5' or
genome exists in some organelles. In 3'). These numbers originate from the naming conventions of the sugars found in
such cases, we distinguish the two DNA. Figure l-3B shows the chemical structure of a longer stretch of DNA, reveal-
genomes by saying there is a nuclear
ing its double helical structure. Figure l-3C shows the single-letter abbreviations of
genome and an organelle genome
the bases of the DNA that correspond to the DNA depicted in Figure l-3A. By
(mitochondrial genome, chloroplast
genome, etc.). In rare instances the convention, nucleotides are written as a sequence ofletters from left to right with
genome can be composed of RNA,but the left nucleotide being the 5' nucleotide and the right nucleotide being the 3' nu-
this is limited to RNAviruses. cleotide. The complementary strand is listed below the first strand in the opposite
orientation. Because the two strands of DNA are always complementary , the lower
gene A segment of the genome that strand is often not explicitly included when writing a sequence. Thus, the sequence
produces a protein or a functional RNA, can be written as AGTC. In this book we will adopt the convention of writing the
such as transfer RNA,small nuclear RNA, sequence of one strand of DNA with the 5' nucleotide on the far left to represent the
ribosomal RNA,and so on. double strand DNA.
Table 1-1 lists the single-letter abbreviations used for each nucleotide. The two
nucleotide A molecule composed of a larger bases (see Figure 1-2) as a group are called purines, and the two smaller
nitrogenous base, a sugar, and a bases are called pyrimidines. In rare instances, when the DNA nucleotide cannot
minimum of one phosphate.
be identified experimentally , a placeholder, N, is used to represent any nucleotide
when writing the sequence. In bioinformatics, it is common to try to find regions of
complementary strand The DNA
similarity in DNA sequences that may reveal structural, functional , or evolution-
strand that binds to the written strand
through hydrogen bonds formed by ary relationships. To find such regions one typically lines up the sequences to find
pairs of nucleotide bases. sections that are identical. This process is called sequence alignment. If two DNA
sequences are compared by aligning them, one may need to place a gap in one se-
sequence alignment Optimized quence to achieve an optimal match, or alignment (see Chapter 5 for an in-depth
pairwise matching of nucleotide or discussion of gaps). A gap is denoted as a single dash or an asterisk. Figure 1-4
amino acid sequences . shows the alignment of two nucleotide sequences where gaps are introduced to
create an optimal alignment.
1.3 RNA:THE INTERMEDIARY

We are now able to broach the subject of RNA (ribonucleic acid), which, as the
name suggests , is similar to DNA. RNA is the molecule that is intermediary be-
tween DNA and protein. RNA is transcribed from DNA and looks very similar to
DNA, with three exceptions. First , RNA is usually a single strand ; second , it uses
the uracil (U) base instead of the thymine (T) base; and finally, it has a hydroxyl
AMINOACIDSTHEBUILDING
BLOCKS
OF PROTEINS 5
Human------CTGCCATGGAGGAGCCGCAGTCAGA A B
(N
;H
Frog--------. CTGCCATG- - -GAACCTTCTTCTGA
FIG. 1-4. Segments oftwo gene sequences that are optimally

aligned. The top gene sequence is from human, and the bottom is
from Xenopus silurana (frog).The dashes in the frog sequence were
inserted by the computer software program ClustalWto achieve
optimal alignment between the two sequences.
NAO
I
H
Uracil (U)
group (-OH) on the 2' carbon atom of the sugar. Figure 1-5
shows the structure of the RNA nucleotide and the uracil
base. RNA nucleotides are linked to each other into a
Sugar (ribose)
single strand not unlike a single strand of DNA. However ,
due to these small chemical deviations from DNA, RNA FIG. 1-5. Structure of a nucleotide within RNA.
adopts a variety of configurations. One important func- A. The green atoms form the phosphate, the black atoms form the
sugar (ribose),and the base (in blue) can be any one of four types:
tion of RNA is to transform the gene information within
uracil,cytosine, adenine, and guanine. B. The structure of uracil.
DNA into protein.
Now might be a good time to introduce the central
dogma of molecular biology (Figure 1-6). Developed in
the 1960s, the central dogma explains how information encoded in DNA relates to RNA (ribonucleic acid) A chain of
information encoded in RNA and proteins. According to the central dogma, DNA nucleotides where each nucleotide is
replicates itself, RNA is transcribed from DNA, and protein is translated from one of four bases, adenine, guanine,
RNA . In rare instances, RNA can be reverse transcribed into DNA. cytosine, uracil, and a ribose sugar and a
It should be mentioned that RNA molecules are not always mere intermediaries single phosphate within each
nucleotide . RNAis transcribed from
that convey information from DNA in order to create proteins. RNA molecules can
DNAand performs many functions
also be found in important structures of the cell , especially in the translation machin-
including the coding of proteins.
ery, and can carry out a few chemical reactions. The structures of RNA are diverse
and are often found in tight complexes with proteins. More recently, RNA was dis-
central dogma A term that explains
covered to control the process of transcription and translation through RNA inter- the relationship between DNA,RNA,
ference, often abbreviated RNAi. and proteins. Briefly,DNAreplicates and
serves as the template for its
transcription into RNA. RNAserves as
1.4 AMINO ACIDS: THE BUILDING BLOCKS OF PROTEINS the template for its translation into
protein. RNAcan also be reverse
By far the most abundant biological molecules on earth are proteins. Whenever you transcribed into DNA.
look at someone's face, you are actually looking at proteins. Proteins are made up of
20 amino acids. The amino acids are linked together in a linear fashion, and each transcription The process of
amino acid has a unique side chain. Figure 1-7A shows a picture of two amino acids polymerizing nucleotides to produce
combining together to form a dipeptide (a peptide with two amino acids bound to RNAfrom DNA.
translation The process of
r. __
~
(•R•e•v-er•s•e-tr•a•n-sc•r-ip•t-io_n_J.,.
( T,amc,ipfoo )
RNA
[ Translation ]
Protein
polymerizing amino acids in an order
dictated by messenger RNA.
amino acid A molecule composed

of an alpha carbon, a carboxyl group,
an amino group, and a side chain.
Amino acids can be polymerized to
form proteins with distinct molecular
functions. Each side chain gives a
[ Replication) unique chemical property to its
amino acid.
FIG. 1-6. Central dogma of molecular life science. The curved arrow surrounding the DNAsigni-
fies that DNAis capable of replicating itself.
A Glycine (a:nino acid) Alanine (a,mino acid) Glycylalanine (dipeptide)
1
IHI --····-I I ~ IHI
~/
r Side ?roup r ] [ Pep:ide bond ]
Amino group Carb7xyl group rn H H

b Y~
~ rt @~ H
~l @k ~ - ~ r c-r@k
~ I II
~
I ~
+ @
B Polypeptide
'
IEa-cI g_N
0 d c-k c ~-N d c-k c g_N d c-k / ~ I
~ H~ Gp ~ H~ Gp ~ H~ 0
1~ 11 I 1 ~ 11 I 1 ~ 11 I~
H H ~ O H H ~ O H H ~ O H
FIG. 1-7. Amino acids, the building blocks of proteins . A. Two amino acids combined together to form a di peptide . B. Seven amino acids combined
together to form a peptide.
each other). 4 When the two amino acids such as glycine and alanine combine, water
is removed and the resulting bond between the amino acids is called a peptide bond .
Once peptides are more than 50 amino acids long , they are called polypeptides,
which are also known as proteins. Polypeptides (or proteins) can contain up to sev-
eral hundred amino acids. Figure l-7B shows seven amino acids combined together
to form a peptide . By convention , the sequence of amino acids within a protein or
peptide is written starting on the left with the first amino acid that contains a free
amino group (sometimes called the amino terminus or N-terminus). The last amino
acid in the protein contains the free acid group (sometimes called the carboxyl
terminus or C-terminus).
It is incredible that the diversity of life that one sees can be attributed to just
20 amino acids. The proteins composed of these amino acids, in different arrange-
ments and with different lengths , facilitate the multitude of chemical reactions that
constitutes life. The side chains of the amino acids give proteins their particular char-
acteristics or structures. Just as the bases are what distinguish nucleotides from one
another, the side chains are what distinguish amino acids from one another. Scientists
have divided the amino acids into different classes based on their relative ability to
dissolve in aqueous (water) solutions. Figure 1-8 shows three classes of amino acids .
In the hydrophobic class are those that are least able to dissolve in water. In the hydro-
philic class are those that readily dissolve in water. The third class contains those
amino acids that dissolve in water only slightly . Importantly, each amino acid has both
a three-letter abbreviation and a single-letter abbreviation. The single-letter abbrevia-
tions (often called single-letter codes) are used extensively by bioinformaticians.
Hydrophobicity is a simple way of classifying amino acids, and there are other,
more detailed classification schemes. Hydrophobic amino acids can be divided into
those with aromatic and aliphatic side chains , both of which are composed of only
carbon and hydrogen. Aromatic side chains are planar, and aliphatic side chains have
kinks in them . Hydrophilic amino acids can be divided further into those with side
chains that are , at physiological pH , electrically charged and uncharged. The amino
4
When amino acids are chemically bonded to each other in proteins they are named "amino acid
residues," or simply "residues."
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for the guests from town to appear mammas and maids were busy in
the bedrooms, dressing their young ladies for the occasion.
Meanwhile the plantation musicians were assembling, two violins, a
flute, a triangle, and a tambourine. A platform had been erected at
one end of the rooms, with kitchen chairs and cuspidors, for their
accommodation. Our own negroes furnished the dance music, but
we borrowed Col. Hicky’s Washington for the tambourine. He was
more expert than any “end man” you ever saw. He kicked it and
butted it and struck it with elbow and heel, and rattled it in perfect
unison with the other instruments, making more noise, and being
himself a more inspiring sight, than all the rest of the band put
together. Col. Hicky always said it was the only thing Washington
was fit for, and he kept the worthless negro simply because he was
the image (in bronze) of Gen. Lafayette. Col. Hicky was an
octogenarian, and had seen Gen. Lafayette, so he could not have
been mistaken. When Washington flagged, a few drops of whisky
was all he needed to refresh his energies.
The whirl of the dance waxed as the night waned. The tired
paterfamiliases sat around the rooms, too true to their mission to
retire for a little snooze. They were restored to consciousness at
intervals by liberal cups of strong coffee. Black William, our first
violin, called out the figures, “Ladies to the right!” “Set to your
partners!”—and the young people whirled and swung around in the
giddy reel as though they would never have such another
opportunity to dance—as, indeed, many of them never did. From the
porch and lawn windows black faces gazed at the inspiring scene.
They never saw the like again, either.
Laughing, wide-awake girls and tired fathers and mothers started
homeward at the first blush of dawn, when they could plainly see
their way over the roads. I started too early from a party the year
before, and the buggy I was in ran over a dust-colored cow lying
asleep in the road. The nodding maid again perilously perched on
top the champagne basket, and skiffs with similar freight plied across
the broad river as soon as there was sufficient light to enable them to
dodge a passing steamboat.
The last ball was a noble success. We danced on and on, never
thinking this was to be our last dance in the big house. Clouds were
hovering all about us the following Christmas. No one had the heart
to dance then. The negroes had already become restless and
discontented. After that the Deluge! The big house long ago slid into
the voracious Mississippi. The quarters where the wedding feast was
spread are fallen into ruins, the negroes scattered or dead. The
children, so happy and so busy then, are now old people—the only
ones left to look on this imperfectly drawn picture with any personal
interest. We lived, indeed, a life never to be lived again.
XXXIII
A WEDDING IN WAR TIME
“Marse Green says cum right away; he’s gwine to marry Miss
Fanny to de Captain.”
“When?”
“Soon’s I kin git de preacher. I can’t wait for you; I ain’t got no
preacher yit.”
That was a summons I had one hot day in early summer, in war
times. Yankees in New Orleans; gunboats almost hourly reported
“jist ’round de p’int”; and we people distractedly hanging on the
ragged edge of alarm and anxiety, did not pause to think how
impossible it was for us to know what was happening “jist ’round de
p’int,” for all information about things beyond our physical eyesight
was questionable. In the rush of uncertain and unlooked-for events,
we could not plan any future, even one day ahead, so overwhelmed
were we in mind and estate (not to mention body) with the
strenuousness of the pitiful present.
I hastily changed my dress and was ready when my carriage was
brought to the door. “Marse Green” (I will not give the full name;
everybody in his old district knows who I mean), was a lawyer, a
politician, a man of family, while not a family man, and his little
cottage home in town was presided over, the best they knew how, by
his three daughters, the eldest of whom was scarcely out of her
teens. The disturbed state of the country had compelled me to stay
quietly as I could at my plantation home, and in the absorbing and
frequent rumor of Yankees coming, no real town news and gossip
sifted in. Thus I had not heard that Miss Fanny’s fiancé, a wounded
soldier, was at Marse Green’s.
I was driven at a rapid pace up the road and through the restless,
crowded street throngs to the home of these motherless girls, whose
New England governess had returned North. I had long been their
mother’s dearest friend, and a refuge for her daughters in all their
troubles and perplexities. We were completely cut off from any
reliable information of the doings of the world, almost at our doors.
Everybody knew New Orleans had fallen and Butler was treading the
prostrate people with hoofs of iron, and also it was only a matter of
time when his rule would reach our town only 130 miles off. As a
matter of course, under such circumstances, we were alive to any
startling rumor.
Marse Green, who did things by fits and starts, and did them very
thoroughly, too, when he started, had announced to his daughters on
the morning of my visit that they must be ready by early dawn the
following day to move themselves and everything else they might
need to his plantation on the Amite. Then the man of family shook
the dust of further assistance from his feet and proceeded to his
office for the day’s enlightenments. Of course, all business of a legal
nature was suspended. The few able-bodied men lingering outside
the rank of fighters, who were facetiously called “Druthers,” because
they’d druther not fight, or in other words, would druther stay at
home, had dropped in Marse Green’s office to while pleasantly away
their idle time. The old gentleman hobbled on his crutches to his
favorite chair and was telling his lounging visitors that gunboats
being “jist ’round de p’int,” he was sending his family out of harm’s
way, when some one casually remarked, “What you going to do with
the Captain? He can’t stay here, a paroled soldier, and he can’t go
with those young girls that way.” “By gracious!” Marse Green had not
thought of that. The Captain must marry Fanny right away, or run the
risk of being captured, for he had no place to go. In pursuance of
that sudden plan, an emissary was dispatched to summon me, and
to get the Methodist preacher. Messengers were also sent with flying
feet among the few near neighbors, asking their presence that
afternoon, while Marse Green himself rushed back home to
announce the decision to his family.
I arrived in a scene of confusion beyond words to express. Already
some kindly neighbors were there helping the distracted girls to
pack. Trunks, boxes, bags, barrels, baskets, were in every room with
piles and piles of household and personal articles to be stowed.
Everybody was busy and everybody stumbling and tearing about in
every other body’s way. Marse Green had already descended upon
them with his ultimatum, and worse became the confusion with this
new and unexpected element injected into it. Dear Fanny must be
married in white, so every one declared. Then ensued a ransacking
of trunks and drawers for a pretty white lawn she had—somewhere!
At length it was brought to light in a very crumpled condition, not
having been worn since the winter (the last Buchanan winter) Fanny
spent in Washington with her father. There was no time or
opportunity or place, apparently, to press the wrinkles out and make
the really handsome gown presentable. Then there arose a clamor
and frantic search for white stockings. Nobody had the temerity to
mention white kid gloves. They were of the past, as completely as a
thousand other necessities we had learned to do without. The black
dress was laid aside. Fanny looked very lovely in her white gown,
the most calm and composed of any of us.
The dazed, bewildered and half-sick Captain meandered around in
his dingy Confederate gray, the only suit he had. His skull had been
fractured in battle (I think at Shiloh), the hair had been shaved off
one side of his head and a silver plate covered and protected the
wound. Time was passing swifter than the motions of the little party,
fast as they were. All the packing and loading of wagons had to be
completed for the early morning start. The rest of us could stay in our
homes and run our chances—which we did, woe is me!—but Marse
Green’s girls must be off, in accordance with his dictum, and, of
course, a Confederate officer had to get out of the enemy’s reach.
Meanwhile the other invited neighbors were arriving, and also an
Episcopal minister. Mr. Crenshaw, the Methodist preacher, could not
be found. He had spent hours haranguing the few peace-loving
Jews, superannuated cripples and handful of “Druthers” remaining in
town, telling those incapables or insufficients they were not patriotic
to stand aside and let the enemy’s gunboats land at our wharf, but it
appears when the latter really were “just behind de p’int,” the voluble
gentleman’s discretion got the better of his valor, and he had
ingloriously fled.
One kindly neighbor, a late arrival, whispered to another, who had
been there all day helping, “Any refreshments?” Not a soul had
thought of refreshments; we isolated housekeepers had not even
heard the name for so long that it had not occurred to us to talk of
furnishing what we could not procure. The late comer rushed home
and quickly returned with the half of a cornmeal pound-cake and a
pitcher of brown sugar lemonade. Then the minister required some
one to give the bride away. That was not in Marse Green’s Methodist
service, and besides Marse Green was getting mortally tired and
fractious, so, without my knowing it, Mr. McHatton volunteered to
perform that function. We guests who had been behind the scenes,
and were getting to be mortally tired and fractious, too, assembled in
the hastily-cleared parlor to witness the ceremony.
I was struck with amazement to see my husband, who had been
the busiest man there all day, march into the room with dear, pretty
Fanny on his arm! I never did know where the necessary ring came
from, but somebody produced a plain gold ring, which, no doubt, was
afterwards returned with appropriate thanks. The Captain was a
strikingly handsome man, even with a bandaged head and those ill-
fitting clothes, not even store-made, and we all agreed Fanny looked
very placid and happy. Their healths were drunk in tepid lemonade
(did you ever drink brown sugar lemonade? If your grandmother is a
Southern woman I’ll be bound she has). There was a hurried “God
bless you!” and a kiss, and I had to rush home to two wounded
brothers needing my care.
Some near neighbors stayed to assist in the further preparations
for an early flight. I afterwards heard the entire family, groom and all,
were at work all night, and at early dawn Marse Green was able to
start the loaded wagons to the piny, sandy country. The bride and
groom and two young sisters piled into the ramshackle old family
carriage, and were driven off, a ten hours’ trip to Amite. I trust they
made it before night, but it was many years thereafter before I knew
anything further of them.
I asked my husband, afterwards, when we talked the wedding
over, who paid the minister? We had not seen yet a Confederate
soldier with as much money as a wedding fee in his pocket. “I don’t
think the Captain had a dollar,” he replied, “so I whispered him to be
easy; we would attend to the minister.” No hat was passed around,
but someone produced a fifty-dollar Confederate bill—unless it was
parted with very promptly it was not worth fifty cents to the preacher.
The gunboats the frantic negroes had so long heralded, got “round
de p’int” at last, and a battle ensued in the very streets of our town.
Marse Green’s house happened to be in the thick of it, and
consequently was so riddled that it was put permanently out of
commission. The family never returned to it, even to view the ruins.
At the time of the exposition I accidentally met the Captain and his
wife on a street car in New Orleans. At Napoleon avenue the car
stopped and the passengers were leaving. I asked in a general way,
knowing no one, “Do we change cars here?” A voice, whose owner
was out of sight, promptly replied, “Yes, madam, you wait for me.” I
was thus the last passenger to descend, and to my unspeakable
amazement I was received by the Captain and Fanny! She said,
though she did not see me, she had recognized my voice, and she
reminded me that it was almost twenty-one years since we parted. It
was sweet to know that the marriage in haste had not the proverbial
sequel of repentance at leisure. They were a happy couple.
The whole wedding affair was a painful and pitiful episode, and for
years I had thought of it with a tinge of sadness; but a few years ago,
on a later visit to New Orleans, I had the happiness to meet a dear
old friend who was one of the busiest helpers on the occasion, and
we merrily laughed over the recalled incidents that at the time were
so pathetic. The handsome Captain may be living; I have since lost
track of him, but every other soul that was at that wedding has gone
where there’s no marrying or giving in marriage—I, only, am left to
chronicle this wedding in war-time.
XXXIV
SUBSTITUTES
Mrs. Walker sent me a pan of flour! It was the first time in months
and almost the last time in years that I saw flour. These, you must
know, were war times, and flour was not the only necessary we
lacked. Dear Dr. Stone had a bluff, hearty way of arriving at things.
When the Federals were in New Orleans he was often called for a
surgical consultation, or to administer to an officer, with headache or
backache, for they were mortally afraid of yellow fever, and it was
just the season for it; and their regimental surgeons were not familiar
with the scourge. Dr. Stone frequently “made a bargain” before he
would act, and so I do not doubt in that way he obtained permission
to ship a barrel of flour—for which all of us were famishing—to Mrs.
Stone’s sister on the coast. Mrs. Walker most generously shared it
with her neighbors.
Indians had lived on cornmeal and prospered therewith. Negroes
had lived on cornmeal and prospered also. We were living on
cornmeal and not prospering, for we had been brought up on
(metaphorically speaking) nectar and ambrosia. Our cakes even,
everybody had to have cakes! were made of cornmeal and
molasses.... But I want to tell more about our Dr. Stone. When one
Northern officer sent for him to consult about amputating a leg the
doctor told him, in his blunt, positive way, he would not even
examine the wounded member until he had in his pocket a permit for
Mrs. Stone and the ladies associated with her to visit the Parish
Prison and minister to the Confederates confined there. It was the
only time any of us ever heard of a body asking the privilege of
entering that dirty old calaboose down by Congo Square.
Many such stories were wafted to us about Dr. Stone. Some may
not have been authentic, but we loved to hear and to repeat them.
However, after the war, I did hear him tell of a Union officer offering
him the present of a fine horse in recognition of some professional
obligation. “I needed that horse,” he said, “for I had none, and so I
was going my rounds a-foot, but it was branded U. S. and I returned
it.” Years after I met that Federal officer in St. Paul, and, speaking of
the doctor, whom he admired greatly, he told of the horse he had
tendered him, which was promptly returned, accompanied with a
most amusing note, ending with “So US don’t want that horse.”
Every blessed one of us was a coffee drinker, and even before the
secession of Louisiana we were weighing and measuring what
coffee we had on hand, not knowing where we could replenish our
diminishing stock. Gov. Manning, of South Carolina, and his wife
were our guests at this crisis, and Mrs. Manning showed me how to
prepare a substitute for coffee. Gracious me! that was the first, but
we had substitutes for almost every article, both to eat and to wear,
before we were whipped like naughty children and dragged back into
the Union, and made to take our nauseous medicine, labeled
“Reconstruction.” And now we are all cured! and will never be
naughty again.
That first substitute, which was followed by a score of others, was
sweet potatoes, cut, dried, toasted, ground and boiled. The
concoction did not taste so very bad, but it had no aroma, and, of
course, no exhilarating quality; it was simply a sweety, hot drink. We
had lots of Confederate money, but it quickly lost any purchasing
power it ever had. There was nothing for sale, and we could not
have bought anything even if shops had been stocked with goods
and supplies. A pin! Why to this day I always stoop to pick up a pin, I
learned so to value that insignificant necessary in the days we could
not buy a pin. A hairpin! Many women in country towns used thorns
to secure their “waterfalls.” We wore waterfalls; chignons they were
called later. I saw many of them made of silk strings, plaited or
twisted. Women had to be in the fashion, as Dr. Talmage once said,
“though the heavens fell.” If we had had anything to sew we would
have missed the usual needle supply.
I was visiting one day when one large and one small needle were
all there were in the house; if they had been made entirely of gold,
instead of “gold-eyed” only, they could not have been more
cherished. I can hear the wailing voice now, inquiring, “Where is the
needle?”
You may smile now at the idea of a substitute for a toothbrush,
but, my dear, that oft-quoted mother of invention taught us an althea
switch made a fairly good toothbrush; of course, it was both scratchy
and stiff, but we never found a better substitute for the necessary
article. As for tea, we Southerners have never been addicted to the
tea habit; however, we soon became disgusted with the various
coffee substitutes. We tried to vary our beverages with draughts of
catnip tea, that the darkies always give their babies for colic; and
orange leaf tea, that old ladies administered to induce perspiration in
cases of chills; and sassafras tea we had drunk years gone by in the
spring season to thin the blood. We did not fancy posing as babies
or ague cases—the taste of each variety was highly suggestive. I
wonder if any lady of to-day ever saw a saucer of home-made soft
soap on her washstand? After using it one had to grease (no use
saying oil, for it was generally mutton tallow) the hands to prevent
the skin cracking. I never used that soap, but traveling in out-of-the-
way roads I saw it on many a stand. Clothes, too, wore out, as is
their nature, and the kind we were used to wearing were not of the
lasting variety like osnaburgs and linseys.
Quite early in the war Cuthbert Slocomb and De Choiseul stopped
over a night with us on their way to the front. With them was another
young man whose name escapes me now, who was suffering from
chills, so he remained a few days as our guest. We dosed him with
orange-leaf tea, which was about the best we could do, having no
quinine on hand. In his kit he had a lot of chamois skins, which he
laid out before me with the modest request I make a pair of
pantaloons out of them. We talked the project over and decided
overalls were the only thing in that line that could be made of
chamois skins, that, of course, had to be pieced lengthways,
crossways and sideways. The result was satisfactory, and the young
man proudly carried off his overalls. I hoped, but did not expect, that
he would escape a rain or two on his expedition clad in chamois
skins! However, I was amply repaid for my ingenuity and skill, for I
had scraps enough of the skins left me to supply tobacco pouches
and gloves to lots of soldier friends thereafter.
At one time, in dire need, I paid one dollar a yard for thin coarse
muslin, white with black dots, which looked distressingly bad after a
wetting or two, but my crowning extravagance was paying thirty
dollars a yard for common blue denim; that was in Houston. Thus
went the last of my Confederate money. After that for a while we did
without things.
Mr. James Phelps of New Orleans—scores of us must remember
genial Jim Phelps—made a call on me in Texas, introducing himself
with the whimsical remark that I must look at him from shoulder up
and not down, for he had on a brand new paper collar, and had
borrowed the use of a razor, and was now out making ceremonious
calls! Oh, dear me! we lived through all of these privations, and the
few remaining survivors are not afflicted with nervous prostration, or
any of the fashionable ills of the day. Their nerves were
strengthened, their spirits brightened. They bravely bore the fires of
trouble and privation that make them placidly content with the
comforts and solaces of their declining years.
XXXV
AN UNRECORDED BIT OF NEW ORLEANS
HISTORY
Since there are still living descendants of the persons concerned

in this incident, I have omitted names. The story is entirely true and
well known to many old residents of New Orleans.
More than sixty-five years ago, a man I shall not name, was tried
and convicted of fraud against the State Land office. He was in the
prime of life, educated, a West Point graduate, of good parentage,
splendid physique, gracious though a trifle pompous and self-
asserting in manner and of presumed wealth. Of course, his case,
when it came to trial, was bravely contested inch by inch. Rich
relatives, influential friends, and the best legal talent were enlisted,
but it was too plain a case of fraud. So, after tedious trial, conviction
and sentence to the Penitentiary at Baton Rouge resulted. There
were the usual delays, a stay of sentence, a wrangle as to final
commitment, a question of length of sentence. His sureties were
caught in the net, and tremendous efforts they made to dodge
liability for the amount of the bond. Two of the sureties did escape,
but the third made good. In steamboat parlance, he “went to the
clerk’s office and settled.”
The Calaboose.
Meanwhile the convicted man—he was called “Colonel,” not by

courtesy only, for, unlike most Southern Colonels of that date, he had
had military training and might have been even more if he had
waited till Generals were in dire demand in Dixie—the Colonel was
behind bars in the Parish Prison. The horrid old calaboose down by
Congo Square, where more than one Confederate languished two
decades later, when the prison was twenty years older and forty
years dirtier. The Colonel’s devoted wife, who had worn out the
energies of a dozen wives, and was still alert and active in behalf of
her unfortunate mate, never relaxed her vigilance. When the coils of
the law wrapped tighter and tighter around the doomed man, she
rose to every emergency. No personal appeals, nothing her fertile
mind had suggested, had availed to stay the process of the law. Now
that worse had come to the worst, and the Colonel was under lock
and key, awaiting the final decision as to length of sentence, Madam
and the Colonel’s oldest daughter (her step-daughter, by the way)
went daily to the calaboose to visit the prisoner. Their visits were
made always in the afternoon. The two cloaked and heavily veiled
ladies remained till the closing of the gates.
It was in the fall of the year, and election times, when politics were
rife. Madam was not only bright and intelligent, but endowed with
remarkable tact, and brim full of schemes and resources. At every
visit she stopped at the gate and had converse with the warden or
turnkey, or whoever was on duty, and related to him the latest news
and political gossip and bantered him on his political bias, no matter
what that bias was. This course she pursued daily and vigorously.
The daughter, still in her teens, was a mere figurehead, always
heavily veiled and enveloped in a voluminous long coat. With the
slightest nod of recognition to “the powers that be,” she proceeded
rapidly to her father’s cell, leaving her mother, so bursting with talk
and information that she could neither enter nor depart without first
unburdening herself of the latest political news.
One evening, when matters at court were nearing the crisis, the
two ladies rushed into prison, almost breathless, they had hurried so!
They had had all sorts of detentions. They realized they were late,
and would only have a minute, but they could not let the day pass
without the customary visit to the Colonel, etc., etc. While madam
was endeavoring to explain to the warden the cause of the delay,
and tell also some anecdote anent the election which was too good
to keep, the quiet young girl proceeded at once to the cell of her
father. The turnkey came in sight, significantly rattling his keys, which
roused madam to the consciousness that she had not been in to kiss
the Colonel good-night, after all. She had been so interested in Mr.
Warden, he was so entertaining, and had such queer views and
opinions of the candidates, etc., etc. So, to the Colonel she rushed,
returning immediately to the gate, where her friend was impatiently
waiting to lock up, signal to do so having been given. The dim lamps
about Congo Square had been lighted and a darkening November
day was fast closing around them. “Lavinia, come, the jailor is
waiting to lock up.” “Yes, ma,” was the reply from the cell. A moment
later: “Lavinia, it is getting too dark for us to be out; come at once.”
“Yes, ma, I’m coming right now.” “That girl can’t bear to leave her
father.” As the madam said this, out rushed Lavinia. Her mother
caught her arm and both parties darted through the closing gate,
with a wave from madam’s hand and a “Good-bye, we will be early
to-morrow and never keep you waiting again.”
The lock-up took his rounds at the usual time to close the cells for
the night. The Colonel seemed to be quietly sleeping in his narrow
cot, trousers and stockings carelessly thrown upon the chair. The
door was securely fastened by the officer.
Next morning, when it was opened, a gruff voice called to the
sleeper, who seemed to be stupidly half awake. Miss Lavinia rose
from the bed, showing her face to the attendant for the first time in all
these weeks. The Colonel, disguised in his daughter’s cloak and veil,
had flown!
There were no telegraphs, or wireless, nothing, in fact, but nimble
legs and more nimble horses to facilitate the frantic search. The bird
had flown afar.
Long before the cage door was opened the prisoner was beyond
the reach of the long arm of the law. Madam had for weeks been
skillfully planning escape, how skillfully, the result proved. She had
engaged the services of the captain of a fruit schooner to take a lady
passenger on his next trip to Havana. To insure results, she had
privately conveyed provisions and necessary articles for the
passenger’s comfort to the vessel, bribed the captain to secrecy, and
it was planned he would give her timely notice when the tides and
winds were favorable to raise sail, and put rapidly and silently to sea
from Lake Pontchartrain.
He fulfilled his promises so to do.
When the two (supposed) women rushed into the hack awaiting
them round the corner from the jail, the driver whipped up his horses
and trotted rather faster than usual down the old shell road he had
conveyed these ladies more times than he could remember, right
from that old corner to the schooner landing.
Years after these events had ceased to be talked of, or even
remembered, and the ladies who bore the colonel’s name had
vanished from Louisiana, from the deck of an incoming steamer in
the harbor of Havana my husband was frantically hailed by a stout
old gentleman standing in a lighter. The gray-haired man, who did
not dare venture into an American vessel, recognized my husband,
whom he had slightly known in the days of his prosperity. He was
now an exile, a runner for a Cuban hotel. How eagerly and gladly he
took possession of us and our belongings; how he piloted us through
the narrow streets; how he domiciled us in the best rooms, and how
assiduous he was in attention to our comfort, I cannot tell.
A few years thereafter the poor old man, who had one daughter
with him to solace his declining years, passed sadly away, and I was
summoned from my plantation home to the stricken girl. She tearfully
told me the story of his flight, which had never been revealed before,
and, together, we turned the leaves of the worn and faded diary he
had kept during that exciting voyage to the Spanish Dominion, where
there was no extradition treaty to compel his deliverance to his
country. In the early days, when there were no telegraphs, no cables,
he managed to support his wife and daughters in New York by acting
as commercial correspondent for several newspapers, both in New
York and New Orleans, and Charleston also, I think; but that
business died out, and he gradually became too infirm for any active
or sustained occupation.
His death was a blessed release.
XXXVI
CUBAN DAYS IN WAR TIMES
Not a Confederate who was stranded in Havana in the ’60’s but

can recall with grateful feelings the only hotel there kept by an
American woman and kept on American lines. Every Confederate
drifted under that roof-tree. If he possessed the wherewithal he paid
a round sum for the privilege. If he was out of pocket, and I could
name a score who were not only penniless but baggageless, he was
quite welcome, well cared for and in several instances clothed!
Some, notwithstanding her “positive orders,” exposed themselves to
night air, when mosquitoes were most in evidence, and came in with
headache and yellow fever. They were cared for and nursed back to
health. No one knew better than Mrs. Brewer how to manage such
cases. I could call the roll of the guests who came—and went, some
to Canada, some to Mexico: Gen. and Mrs. Toombs of Georgia, Gen.
Magruder, Gen. Fry and his beautiful wife, who was a Micou of
Alabama; Commodore Moffitt and Ex-Gov. Moore of Louisiana;
Major Bloomfield and his wife—some of us still remember
Bloomfield. He had for years a blank-book and stationery shop in
New Orleans. I have one of his books now, a leather-bound ledger.
He was in service on somebody’s staff. There were some not of the
army, but on business bent, blockade running and so on.
My gracious! I can’t begin to tell of the crowd that promenaded the
galleries and azotea of Hotel Cubano toward the end of the war.
They all talked and talked fight, the ex-army men declaring they
would not return to their homes with sheathed swords. Alas! They
did, though. Before their talks came to an end the Confederacy did.
J. P. Benjamin arrived on a sailboat with Gen. Breckinridge. They
were wise as owls and had nothing to say. I remember the news
came of the assassination of President Lincoln while a large party of
the braves were dining at our house—on the cerro of Havana. Some
of them were jubilant, but a quiet word from Gen. Breckinridge:
“Gentlemen, the South has lost its best friend,” and a quieter word
from Mr. Benjamin: “We will let the painful subject drop,” acted as a
quietus for our boisterous guests....
But I must not wander from our hostess of Hotel Cubano. A
strange mixture was she of parsimony and prodigality, vindictiveness
and gratitude, a grand woman withal, capable of doing heroic things.
She knew intimately and had entertained the family of Pierre Soulé,
who tarried at the Cubano en route to Spain, when Soulé was
minister. The Slidells also were her friends, Jeff Davis’ family and
scores of other prominent people. She made the first donation of
$500 to the Jefferson Davis Monument Association. With vigorous,
watchful management she accumulated a large fortune in Havana,
though she maintained a host of parasites, poor relatives from the
States. She had four girls at one time belonging to her kindred who
were too poor to educate them. But her business methods were too
queer and unconventional for words. She had leased the large hotel
long before the war in the United States, for what was, even in those
dull days in Havana, considered a low sum, for the chance of making
it pay was a trifle against her. She kept it American style—had batter
cakes and mince pies—so that, though her prices were, as we say
now, “the limit,” every refugee and newspaper correspondent who
was sick of garlic and crude oil diet, felt he had to live at the
American hotel. Havana was then the refuge of defaulters and others
of lax business methods, there being no extradition treaty between
the United States and Spain.
In Cuba when you rent a house, you pay by the month, and so
long as you meet the payments, you cannot be dispossessed. (I do
not know what the law may be now; I write of forty years ago.) Not
long after Mrs. Brewer’s venture proved a success, the owner tried
every possible way to make her throw up the lease. Anyone knowing
Mrs. Brewer as I did, could well understand there was no coercing
her. She maintained her rights, paying rent with utmost promptness,
and when paper currency made its unwelcome advent and was
legally declared of equal value with gold, the payments were made in
paper. That currency depreciated steadily and so greatly, too, that
Mrs. Brewer told me the rent of her basement to the German
consulate for storage purposes, which rent she exacted in gold, was,
when exchanged for paper currency, sufficient to pay the rent of her
entire building. When I remonstrated with her as being unjust, she
explained that all the years she had occupied the building the owner
refused to make necessary repairs and alterations. She had been
compelled to put in modern plumbing, repairs, painting—in fact,
everything—at her own expense, and now she was simply
reimbursing herself. When she amassed a fortune, tired of the life,
she threw up the lease, returned to the United States and a few
years ago died at an advanced age. Her previous history is like a
“story told by night.”
She was the wife of a United States army officer, stationed at
Charleston, who eloped with his wife’s seamstress. She did not know
nor did she take steps to inform herself, where they fled. He had
cashed his bank account and gone. In her shameful abandonment
she took passage on the first vessel leaving port for foreign lands.
She arrived, a young, deserted wife, in Havana, years before I knew
her, homeless and friendless, and was removed from the schooner
on which she made the voyage from Charleston ill of yellow fever.
When she was ready to leave the hospital, it was found not only the
small amount of money in her purse, but her jewelry as well, was
barely sufficient to pay her expenses. When she recovered, she
speedily found work in Havana, sewing in the house of a Spanish
marquesa, who became deeply interested in the case of the forlorn
woman, eventually assisting her in getting an independent start at
keeping a boarding house for foreigners in the city who chafed at
Cuban cooking.
A proposition had been made to Mrs. Brewer by two or three
American refugees to keep house for them, they to furnish
everything, but the generous marquesa vetoed the plan and offered
to finance a better scheme. So Mrs. Brewer rented and furnished a
small house, and the men came to her as boarders, thereby placing
herself in a more independent position. From that small beginning
sprung the largest, best equipped and most expensive—for her
charges were exorbitant—hostelry in the island. Meanwhile the
kindly marquesa went her way gaily in the fashionable wealthy
society of Havana, Mrs. Brewer working and managing, toiling and
accumulating in her own domain. They rarely met.
When my family went to Cuba it was to escape from war troubles
at home. We sought for rest and peace, but it was not long before
we felt we may have “jumped from the frying pan into the fire.”
Rebellion soon became rife on the island. We, being neutrals, had
occasional visits from both parties of the guerilla type. The captains-
general sent at frequent intervals from the mother country ruled with
severity.
One morning while I was visiting Mrs. Brewer, the marquesa
called, in a terrible state of mind. Her young son, an only child, had
been arrested, imprisoned and sentenced to be executed as a rebel
sympathizer. She declared to Mrs. Brewer that she and her friends
were powerless to do anything in the case, and she implored Mrs.
Brewer’s assistance. It was grand to see how the American woman
responded. “Go to your home, possess your soul in peace, if you
can. I will intercede with the Captain-general.” She did, too. As I
remember, Mr. Henry Hall was the American consul. A messenger
was sent with flying feet to summon him. By the time she had
dressed herself in her finest finery and decked her person with all the
jewels she could muster and had her carriage and liveried coachman
ready, Mr. Hall had put on his official dress, both knowing how
important it was to create an impression on the wily Spaniard. They
looked as if they might be more than count and countess, marquis
and marquesa themselves.
Arriving at the palace, our consul obtained immediate access to
the potentate. Mrs. Brewer was introduced with a flourish, and she at
once proceeded to tell her story. She told of the extreme youth of the
prisoner, too immature to be a volunteer on either side, too
inexperienced to have any opinion, and so on, imploring him to spare
the life of “an only son, and his mother a widow.” The stern old man
only shook his head and repeated that his orders were absolute and
unchangeable. Mrs. Brewer fell upon her knees before him,
declaring she would not rise until he at least commuted the sentence
to banishment to Spain. She told him her own story; how she, a

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Concepts in Bioinformatics and

Genomics Jamil Momand: Alison

Concepts in Bioinformatics and Genomics Jamil Momand

The War for Kindness Building Empathy in a Fractured

Computational Modeling in Bioengineering and

Fundamentals of Heat Engines 1st Edition Jamil Ghojel

Pronouns in Literature: Positions and Perspectives in

Coulson and Richardson’s Chemical Engineering, Fourth

Bioinformatics in Aquaculture: Principles and Methods

Bioinformatics Algorithms Design and Implementation in

New York Oxford

Oxford University Press is a department of the University of Oxford.

Oxford New York

Copyright © 2017 by Oxford University Press

For titles covered by Section 112 of the US Higher Education

Published by Oxford University Press

Oxford is a registered trademark of Oxford University Press

All rights reserved. No part of this publication may be reproduced ,

Library of Congress Cataloging-in-Publication Data

Names: Momand,Jamil, author. I McCurdy, Alison , author.

Printed in the United States of America

To our colleague Ray Garcia,

About the Authors xix

CHAPTER 1 • REVIEWOF MOLECULAR BIOLOGY

CHAPTER 2 • INFORMATION ORGANIZATION AND SEQUENCEDATABASES 21

CHAPTER 3 • MOLECULAR EVOLUTION 38

CHAPTER 6 • BASIC LOCAL ALIGNMENT SEARCHTOOL (BLAST) AND MULTIPLE

CHAPTER 7 • PROTEINSTRUCTUREPREDICTION 129

CHAPTER 8 • PHYLOGENETICS 168

CHAPTER 9 • GENOMICS 210

CHAPTER 10 • TRANSCRIPTAND PROTEINEXPRESSIONANALYSIS 253

CHAPTER 11 • BASIC PROBABILITY 284

CHAPTER 12 • ADVANCED PROBABILITYFOR BIOINFORMATICSAPPLICATIONS 320

CHAPTER 13 • PROGRAMMING BASICSAND APPLICATIONSTO

CHAPTER 14 • DEVELOPINGA BIOINFORMATICSTOOL 407

Preface xiii The Gene Feature Key and FASTAFormat 29

Acknowledgments xvii Thought Question 2.1 30

About the Authors xix 2.5 LIMITATIONS OF GENBANK 31

Introduction xxi 2.6 REFERENCE SEQUENCE (REFSEQ) 31

UniProt Knowledge Base 34

1.8 DNA ALTERATIONS 13

1.9 A CASE STUDY: SICKLE CELL ANEMIA 15

Sickle Cell Anemia Is the First Disease Linked LEARNING OUTCOMES 38

viii TABLE OF CONTENTS

CHAPTER 4 • SUBSTITUTIONMATRICES 66 5.3 THE NEEDLEMAN-WUNSCH GLOBAL

4.8 CONVERSION OF THE PAM1 MUTATIONAL EXERCISES 104

REFERENCES 88 Thought Question 6-1 113

Low Complexity Regions and Masking 114

Usefulness of BLAST 114

LEARNING OUTCOMES 89 6.3 MULTIPLE SEQUENCE ALIGNMENT 118

5.1 INTRODUCTION 89 ClustalW 120

5.2 SLIDING WINDOW 90 SUMMARY 126

Dot Plots 92 EXERCISES 126

The Dotter Program 93 ANSWERS TO THOUGHT QUESTIONS 127

REFERENCES 127 8.2 PHYLOGENY AND PHYLOGENETICS 170

How to Tell if Sequences in Two Lineages Are

LEARNING OUTCOMES 129 DNA, RNA, and Protein-Based Trees 182

7.1 INTRODUCTION 129 8.3 TWO CLASSES OF TREE-GENERATION

7.4 MOLECULAR VIEWERS 141 Thought Question 8-4 196

Thought Question 7-1 142 Bootstrap Analysis 196

7.5 PROTEIN FOLDING 143 Other Substitution Rate Models: Kimura

BOX 7-1. A CLOSER LOOK: p53 Co-crystallized with

Step-by-Step Procedure of DNA Sequencing 213