Basics of Bioinformatics Lecture Notes of the Graduate

Summer School on Bioinformatics of China

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Rui Jiang • Xuegong Zhang • Michael Q. Zhang
Editors

Basics of Bioinformatics
Lecture Notes of the Graduate Summer
School on Bioinformatics of China

123
Editors
Rui Jiang Michael Q. Zhang
Xuegong Zhang Department of Molecular and Cell Biology
Department of Automation The University of Texas at Dallas
Tsinghua University Richardson, TX, USA
Beijing
China, People’s Republic Tsinghua National Laboratory
for Information Science and Technology
Tsinghua University
Beijing, China, People’s Republic

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DOI 10.1007/978-3-642-38951-1
Springer Heidelberg New York Dordrecht London
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Foreword

This ambitious volume is the result of the successful 2007 Graduate Summer
School on Bioinformatics of China held at Tsinghua University. It is remarkable
for its range of topics as well as the depth of coverage. Bioinformatics draws on
many subjects for analysis of the data generated by the biological sciences and
biotechnology. This foreword will describe briefly each of the 12 chapters and close
with additional general comments about the field. Many of the chapters overlap and
include useful introductions to concepts such as gene or Bayesian methods. This is
a valuable aspect of the volume allowing a student various angles of approach to a
new topic.
Chapter 1, “Basics for Bioinformatics,” defines bioinformatics as “the storage,
manipulation and interpretation of biological data especially data of nucleic acids
and amino acids, and studies molecular rules and systems that govern or affect
the structure, function and evolution of various forms of life from computational
approaches.” Thus, the first subject they turn to is molecular biology, a subject that
has had an enormous development in the last decades and shows no signs of slowing
down. Without a basic knowledge of biology, the bioinformatics student is greatly
handicapped. From basic biology the authors turn to biotechnology, in particular,
methods for DNA sequencing, microarrays, and proteomics. DNA sequencing is
undergoing a revolution. The mass of data collected in a decade of the Human
Genome Project from 1990 to 2001 can be generated in 1 day in 2010. This is
changing the science of biology at the same time. A 1,000 genome project became
a 10,000 genome project 2 years later, and one expects another zero any time now.
Chromatin Immunoprecipitation or ChIP allows access to DNA bound by proteins
and thus to a large number of important biological processes. Another topic under
the umbrella of biological sciences is genetics, the study of heredity and inherited
characteristics (phenotypes). Heredity is encoded in DNA and thus is closely related
to the goals of bioinformatics. This whole area of genetics beginning with Mendel’s
laws deserves careful attention, and genetics is a key aspect of the so-called genetic
mapping and other techniques where the chromosomal locations of disease genes
are sought.

v
vi Foreword

Chapter 2, “Basic Statistics for Bioinformatics,” presents important material

for the understanding and analysis of data. Probability and statistics are basic
to bioinformatics, and this chapter begins with the fundamentals including many
classical distributions (including the binomial, Poisson, and normal). Usually the
observation of complete populations such as “all people in China over 35 years
old” is not practical to obtain. Instead random samples of the population of interest
are obtained and then inferences about parameters of the population are made.
Statistics guides us in making those inferences and gaining information about
the quality of the estimates. The chapter describes techniques such as method of
moments, maximum likelihood, and Bayesian methods. Bayesian methods have
become indispensable in the era of powerful computing machines. The chapter treats
hypothesis testing which is less used than parameter estimation, but hypothesis
testing provides understanding of p-values which are ubiquitous in bioinformatics
and data analysis. Classical testing situations reveal useful statistics such as the
t-statistic. Analysis of variance and regression analysis are crucial for testing and
fitting large data sets. All of these methods and many more are included in the free
open-source package called R.
Chapter 3, “Topics in Computational Genomics,” takes us on a tour of important
topics that arise when complete genome information is available. The subject did
not begin until nearly 2000 when complete genome sequences became a possibility.
The authors present us with a list of questions, some of which are listed next.
What are the genes of an organism? How are they turned off and on? How do they
interact with each other? How are introns and exons organized and expressed in
RNA transcripts? What are the gene products, both structure and function? How has
a genome evolved? This last question has to be asked with other genomes and with
members of the population comprising the species. Then the authors treat some of
the questions in detail. They describe “finding protein coding genes,” “identifying
promoters,” “genomic arrays and a CGH/CNP analysis,” “modeling regulatory
elements,” “predicting transcription factor binding sites,” and motif enrichment and
analysis. Within this last topic, for example, various word counting methods are
employed including the Bayesian methods of expectation maximization and Gibbs
sampling.
An alert reader will have noticed the prominence of Bayesian methods in the
preceding paragraphs. Chapter 4, “Statistical Methods in Bioinformatics,” in this
collection focuses on this subject. There is a nice discussion of statistical modeling
and then Bayesian inference. Dynamic programming, a recursive method of opti-
mization, is introduced and then employed in the development of Hidden Markov
Models (HMMs). Of course the basics of Markov chains must also be covered. The
Metropolis-Hastings algorithm, Monte Carlo Markov chains (MCMC), and Gibbs
sampling are carefully presented. Then these ideas find application in the analysis
of microarray data. Here the challenging aspects of multiple hypothesis testing
appear, and false discovery rate analysis is described. Hierarchical clustering and
bi-clustering appear naturally in the context of microarray analysis. Then the issues
of sequence analysis (especially multiple sequence analysis) are approached using
these HHM and Bayesian methods along with pattern discovery in the sequences.
Foreword vii

Discovering regulatory sequence patterns is an especially important topic in this

section. The topics of this chapter appear in computer science as “machine learning”
or under “data mining”; here the subject is called statistical or Bayesian methods.
Whatever it is named, this is an essential area for bioinformatics.
The next chapter (Chap. 5), “Algorithms in Computational Biology,” takes up
the formal computational approach to our biological problems. It should be pointed
out that the previous chapters contained algorithmic content, but there it was less
acknowledged. It is my belief that the statistical and algorithmic approaches go
hand in hand. Even with the Euclid’s algorithm example of the present chapter,
there are statistical issues nearby. For example, the three descriptions of Euclid’s
algorithm are analyzed for time complexity. It is easy to ask how efficient the
algorithms are on randomly chosen pairs of integers. What is the expected running
time of the algorithms? What is the variance? Amazingly these questions have
answers which are rather deep. The authors soon turn to dynamic programming
(DP), and once again they present clear illustrative examples, in this case Fibonacci
numbers. Designing DP algorithms for sequence alignment is covered. Then a more
recently developed area of genome rearrangements is described along with some
of the impressive (and deep) results from the area. This topic is relevant to whole
genome analysis as chromosomes evolve on a larger scale than just alterations of
individual letters as covered by sequence alignment.
In Chap. 6, “Multivariate Statistical Methods in Bioinformatics Research,”
we have a thorough excursion into multivariate statistics. This can be viewed as
the third statistical chapter in this volume. Here the multivariate normal distribution
is studied in its many rich incarnations. This is justified by the ubiquitous nature
of the normal distribution. Just as with the bell-shaped curve which appears in one
dimension due to the central limit theorem (add up enough independent random
variables and suitably normalized, one gets the normal under quite general condi-
tions), there is also a multivariate central limit theorem. Here detailed properties
are described as well as related distributions such as the Wishart distribution (the
analog of the chi-square). Estimation is relevant as is a multivariate t-test. Principal
component analysis, factor analysis, and linear discriminant analysis are all covered
with some nice examples to illustrate the power of approaches. Then classification
problems and variable selection both give platforms to further illustrate and develop
the methods on important bioinformatics application areas.
Chapter 7, “Association Analysis for Human Diseases: Methods and Examples,”
gives us the opportunity to look more deeply into aspects of genetics. While this
chapter emphasizes statistics, be aware that computational issues also drive much
of the research and cannot be ignored. Population genetics is introduced and then
the important subjects of genetic linkage analysis and association studies. Genomic
information such as single-nucleotide polymorphisms (SNPs) provide voluminous
data for many of these studies, where multiple hypothesis testing is a critical issue.
Chapter 8, “Data Mining and Knowledge Discovery Methods with Case Exam-
ples,” deals with the area of knowledge discovery and data mining. To quote the
authors, this area “has emerged as an important research direction for extracting
useful information from vast repositories of data of various types. The basic
viii Foreword

concepts, problems and challenges deals with the area of knowledge discovery and
data mining that has emerged as an important research direction for extracting useful
information from vast repositories of data of various types. The basic concepts,
problems and challenges are first briefly discussed. Some of the major data mining
tasks like classification, clustering and association rule mining are then described in
some detail. This is followed by a description of some tools that are frequently used
for data mining. Two case examples of supervised and unsupervised classification
for satellite image analysis are presented. Finally an extensive bibliography is
provided.”
The valuable chapter on Applied Bioinformatics Tools (Chap. 9) provides a step-
by-step description of the application tools used in the course and data sources as
well as a list of the problems. It should be strongly emphasized that no one learns
this material without actually having hands-on experience with the derivations and
the applications. This is not a subject for contemplation only!
Protein structure and function is a vast and critically important topic. In this
collection it is covered by Chap. 10, “Foundations for the Study of Structure and
Function of Proteins.” There the detailed structure of amino acids is presented
with their role in the various levels of protein structure (including amino acid
sequence, secondary structure, tertiary structure, and spatial arrangements of the
subunits). The geometry of the polypeptide chain is key to these studies as are the
forces causing the three-dimensional structures (including electrostatic and van der
Waals forces). Secondary structural units are classified into ’-helix, “-sheets, and
“-turns. Structural motifs and folds are described. Protein structure prediction is an
active field, and various approaches are described including homology modeling
and machine learning.
Systems biology is a recently described approach to combining system-wide data
of biology in order to gain a global understanding of a biological system, such as
a bacterial cell. The science is far from succeeding in this endeavor in general,
let alone having powerful techniques to understand the biology of multicellular
organisms. It is a grand challenge goal at this time. The fascinating chapter on
Computational Systems Biology Approaches for Deciphering Traditional Chinese
Medicine (Chap. 11) seeks to apply the computational systems biology (CSB)
approach to traditional Chinese medicine (TCM). The chapter sets up parallel
concepts between CSB and CTM. In Sect. 11.3.2 the main focus is “on a CSB-based
case study for TCM ZHENG—a systems biology approach with the combination
of computational analysis and animal experiment to investigate Cold ZHENG and
Hot ZHENG in the context of the neuro-endocrine-immune (NEI) system.” With
increasing emphasis on the so-called nontraditional medicine, these studies have
great potential to unlock new understandings for both CSB and TCM.
Finally I close with a few remarks about this general area. Biology is a major
science for our new century; perhaps it will be the major science of the twenty-
first century. However, if someone is not excited by biology, then they should find a
subject that does excite them. I have almost continuously found the new discoveries
such as introns or microRNA absolutely amazing. It is such a young science when
such profound wonders keep showing up. Clearly no one analysis subject can
Foreword ix

solve all the problems arising in modern computational molecular biology. Statistics
alone, computer science alone, experimental molecular biology alone, none of these
are sufficient in isolation. Protein structure studies require an entire additional set
of tools such as classical mechanics. And as systems biology comes into play,
systems of differential equations and scientific computing will surely be important.
None of us can learn everything, but everyone working in this area needs a set of
well-understood tools. We all learn new techniques as we proceed, learning things
required to solve the problems. This requires people who evolve with the subject.
This is exciting, but I admit it is hard work too. Bioinformatics will evolve as it
confronts new data created by the latest biotechnology and biological sciences.

University of Southern California Michael S. Waterman

Los Angeles, USA
March 2, 2013
Contents

1 Basics for Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Xuegong Zhang, Xueya Zhou, and Xiaowo Wang
1.1 What Is Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Some Basic Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2.1 Scale and Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.2 Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.3 DNA and Chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.4 The Central Dogma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.2.5 Genes and the Genome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.2.6 Measurements Along the Central Dogma . . . . . . . . . . . . . . . . 10
1.2.7 DNA Sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.2.8 Transcriptomics and DNA Microarrays . . . . . . . . . . . . . . . . . . 13
1.2.9 Proteomics and Mass Spectrometry . . . . . . . . . . . . . . . . . . . . . . 16
1.2.10 ChIP-Chip and ChIP-Seq . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.3 Example Topics of Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.1 Examples of Algorithmatic Topics . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.2 Examples of Statistical Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.3.3 Machine Learning and Pattern
Recognition Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3.4 Basic Principles of Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2 Basic Statistics for Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Yuanlie Lin and Rui Jiang
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2 Foundations of Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2.1 Probabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2.2 Random Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.3 Multiple Random Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.2.4 Distributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

xi
xii Contents

2.2.5 Random Sampling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

2.2.6 Sufficient Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.3 Point Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.3.1 Method of Moments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2.3.2 Maximum Likelihood Estimators . . . . . . . . . . . . . . . . . . . . . . . . 41
2.3.3 Bayes Estimators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2.3.4 Mean Squared Error . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4 Hypothesis Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4.1 Likelihood Ratio Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.4.2 Error Probabilities and the Power Function . . . . . . . . . . . . . . 46
2.4.3 p-Values. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2.4.4 Some Widely Used Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.5 Interval Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.6 Analysis of Variance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
2.6.1 One-Way Analysis of Variance . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
2.6.2 Two-Way Analysis of Variance . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2.7 Regression Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
2.7.1 Simple Linear Regression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2.7.2 Logistic Regression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
2.8 Statistical Computing Environments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.8.1 Downloading and Installation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.8.2 Storage, Input, and Output of Data . . . . . . . . . . . . . . . . . . . . . . . 67
2.8.3 Distributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
2.8.4 Hypothesis Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.8.5 ANOVA and Linear Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
3 Topics in Computational Genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Michael Q. Zhang and Andrew D. Smith
3.1 Overview: Genome Informatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.2 Finding Protein-Coding Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
3.2.1 How to Identify a Coding Exon? . . . . . . . . . . . . . . . . . . . . . . . . . 72
3.2.2 How to Identify a Gene with Multiple Exons? . . . . . . . . . . 72
3.3 Identifying Promoters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.4 Genomic Arrays and aCGH/CNP Analysis. . . . . . . . . . . . . . . . . . . . . . . . 75
3.5 Introduction on Computational Analysis
of Transcriptional Genomics Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.6 Modeling Regulatory Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.6.1 Word-Based Representations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.6.2 The Matrix-Based Representation . . . . . . . . . . . . . . . . . . . . . . . . 78
3.6.3 Other Representations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.7 Predicting Transcription Factor Binding Sites . . . . . . . . . . . . . . . . . . . . . 79
3.7.1 The Multinomial Model for Describing Sequences . . . . . 80
3.7.2 Scoring Matrices and Searching Sequences . . . . . . . . . . . . . 81
Contents xiii

3.7.3 Algorithmic Techniques for Identifying

High-Scoring Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
3.7.4 Measuring Statistical Significance of Matches . . . . . . . . . . 83
3.8 Modeling Motif Enrichment in Sequences . . . . . . . . . . . . . . . . . . . . . . . . 84
3.8.1 Motif Enrichment Based on Likelihood Models. . . . . . . . . 84
3.8.2 Relative Enrichment Between Two Sequence Sets . . . . . . 86
3.9 Phylogenetic Conservation of Regulatory Elements . . . . . . . . . . . . . . 88
3.9.1 Three Strategies for Identifying Conserved
Binding Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
3.9.2 Considerations When Using Phylogenetic Footprinting 90
3.10 Motif Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
3.10.1 Word-Based and Enumerative Methods . . . . . . . . . . . . . . . . . . 92
3.10.2 General Statistical Algorithms Applied
to Motif Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
3.10.3 Expectation Maximization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.10.4 Gibbs Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
4 Statistical Methods in Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Jun S. Liu and Bo Jiang
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
4.2 Basics of Statistical Modeling and Bayesian Inference . . . . . . . . . . . 102
4.2.1 Bayesian Method with Examples. . . . . . . . . . . . . . . . . . . . . . . . . 102
4.2.2 Dynamic Programming and Hidden Markov Model . . . . 104
4.2.3 Metropolis–Hastings Algorithm and Gibbs Sampling . . 107
4.3 Gene Expression and Microarray Analysis . . . . . . . . . . . . . . . . . . . . . . . . 109
4.3.1 Low-Level Processing and Differential
Expression Identification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.3.2 Unsupervised Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
4.3.3 Dimension Reduction Techniques . . . . . . . . . . . . . . . . . . . . . . . . 117
4.3.4 Supervised Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.4 Sequence Alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4.4.1 Pair-Wise Sequence Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4.4.2 Multiple Sequence Alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.5 Sequence Pattern Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
4.5.1 Basic Models and Approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
4.5.2 Gibbs Motif Sampler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
4.5.3 Phylogenetic Footprinting Method
and the Identification of Cis-Regulatory Modules . . . . . . . 138
4.6 Combining Sequence and Expression Information
for Analyzing Transcription Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
4.6.1 Motif Discovery in ChIP-Array Experiment . . . . . . . . . . . . . 140
4.6.2 Regression Analysis of Transcription Regulation . . . . . . . 141
4.6.3 Regulatory Role of Histone Modification . . . . . . . . . . . . . . . . 143
xiv Contents

4.7 Protein Structure and Proteomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

4.7.1 Protein Structure Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
4.7.2 Protein Chip Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
5 Algorithms in Computational Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Tao Jiang and Jianxing Feng
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
5.2 Dynamic Programming and Sequence Alignment . . . . . . . . . . . . . . . . 153
5.2.1 The Paradigm of Dynamic Programming . . . . . . . . . . . . . . . . 153
5.2.2 Sequence Alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
5.3 Greedy Algorithms for Genome Rearrangement . . . . . . . . . . . . . . . . . . 157
5.3.1 Genome Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5.3.2 Breakpoint Graph, Greedy Algorithm and
Approximation Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
6 Multivariate Statistical Methods in Bioinformatics Research . . . . . . . . . 163
Lingsong Zhang and Xihong Lin
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.2 Multivariate Normal Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.2.1 Definition and Notation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.2.2 Properties of the Multivariate Normal
Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
6.2.3 Bivariate Normal Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
6.2.4 Wishart Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.2.5 Sample Mean and Covariance . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.3 One-Sample and Two-Sample Multivariate Hypothesis Tests . . . . 168
6.3.1 One-Sample t Test for a Univariate Outcome . . . . . . . . . . . 168
6.3.2 Hotelling’s T 2 Test for the Multivariate
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
6.3.3 Properties of Hotelling’s T 2 Test . . . . . . . . . . . . . . . . . . . . . . . . . 170
6.3.4 Paired Multivariate Hotelling’s T 2 Test . . . . . . . . . . . . . . . . . . 171
6.3.5 Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
6.3.6 Two-Sample Hotelling’s T 2 Test . . . . . . . . . . . . . . . . . . . . . . . . . 174
6.4 Principal Component Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
6.4.1 Definition of Principal Components . . . . . . . . . . . . . . . . . . . . . . 178
6.4.2 Computing Principal Components . . . . . . . . . . . . . . . . . . . . . . . 179
6.4.3 Variance Decomposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
6.4.4 PCA with a Correlation Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
6.4.5 Geometric Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
6.4.6 Choosing the Number of Principal Components . . . . . . . . 183
6.4.7 Diabetes Microarray Data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
6.5 Factor Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
6.5.1 Orthogonal Factor Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
6.5.2 Estimating the Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
6.5.3 An Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190