Algorithms in Bioinformatics

1
Algorithms in Bioinformatics
Instructor Yao-Ting Huang
Bioinformatics Laboratory, Department of Computer
Science Information Engineering, National Chung
Cheng University.
2
Introduction

• The need of bioinformatics
• The rapid growth of data produced by biologists
  requires efficient programs to analyze.
• Replace wet-lab experiments with dry-lab program
  to save time and cost.
• Prediction and mining knowledge from the data.
• Introduction to classical problems and algorithms
  in bioinformaitcs.
• We will mainly focus on problems at DNA and RNA
  levels.

3
Reference Book

• An Introduction to Bioinformatics Algorithms, by
  Neil C. Jones and Pavel A. Pevzner, MIT Press,
  2004.

4
Reference Book

• Molecular Biology An Algorithmic Approach, by
  Pavel A. Pevzner, MIT Press, 2000.

5
Grading Policy

• Homework assignments and Class participation
  (15)
• Two midterm exams (30 each)
• November 14, 2007.
• December 19, 2007 (tentatively)
• Mostly from the lectures.
• Presentation of selected papers (25).

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Selection of papers

• Possible sources (to be announced later)
• Journals
• Bioinformatics, Journal of Computational Biology,
  BMC Bioinformatics, Genome Research, Genome
  Research, Nature, Nature Genetics
• Conferences
• RECOMB, ISMB, PSB, ECCB, WABI, ,

7
Teaching Information

• Instructor
• Yao-Ting Huang ythuang_at_cs.ccu.edu.tw
• Office 511
• Office hours 10AM12AM, Thursday.

8
Prerequisites

• Basic knowledge on biology is welcome but not
  required.
• Basic concepts in algorithms
• Basic data structures
• Big-O notations

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Syllabus

• Alignment Algorithms
• Genome Annotation
• Single Nucleotide Polymorphisms
• Copy Number Polymorphisms
• Linkage Disequilibrium and recombination
  hotspots
• Evolutionary Analysis
• Statistical tests and simulation
• Other Selected Topics

10
A Brief History of Genetics
11
The Origin of Species

• At the age of 51, Charles Darwin published the
  book On the Origin of Species (1859).
• Populations evolve over the course of generations
  through a process of natural selection.

12
Double Helix

• Discovered by Watson and Crick, Nature, 1953.
• 900 words, 2 pages

13
Human Genome Project

• 1977
• Maxam and Gilbert and Frederick Sanger
  independently develop methods for sequencing DNA.
• 1990
• The Human Genome Project (HGP) began and was
  expected to take 15 years.
• The HGP consortium included geneticists in China,
  France, Germany, Japan, and the United Kingdom.
• 1998
• A company Celera claims to sequence the human
  genome within 3 years for 300 million.
• In response, the Wellcome Trust doubles its
  support for the HGP to 330 million.

14
Human Genome Project

• 2000
• At a White House ceremony, HGP and Celera jointly
  announce working drafts of the human genome
  sequence, declare their feud at an end.
• 2001
• The HGP consortium publishes its draft genome in
  Nature (15 February), and Celera publishes its
  genome in Science (16 February).
• 2003
• The completely human genome is released (2 years
  earlier).

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Genome Assembly

• The HGP human genome is assembled hours ahead of
  Celera.
• Jim Kent wrote the program that assembled the HGP
  genome and run it on a grid of PCs with Linux.
• His efforts ensured that the human genome were
  not patented by Celera.

16
Other Sequencing Projects

• 2002 Mouse genome
• 2002 Rice genome
• 2004 Rat genome
• 2005 Chimpanzee genome
• http//www.ensembl.org/index.html

17
The Primate Family Tree
Source Nature
18
Comparison of Genomes of Different Species

• The comparison of genomes of distinct species can
  reveal the evolutionary history.
• E.g., which gene is newly derived or presented
  long time ago?
• The chimpanzee genome differs with human genome
  with only 1.

19
Functions of the Human Genome

• The ENCyclopedia Of DNA Elements (ENCODE) Project
  aims to identify all functional elements in the
  human genome sequence (Nature, 2007).

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Discovery of Genetic Variants in Human Populations

• The HapMap project collect 269 samples from
  African, European, and Asian descendants to
  identify genetic variants among individuals.
• 90 Yoruba of African, 90 European descendants, 45
  Chinese and 44 Japanese.

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Discovery of Genetic Variants

• The DNA of two individuals differs in less than
  0.1.
• Hinds et al. identified 1,586,383 Single
  Nucleotide Polymorphisms across three human
  populations (Science, 2005).

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Perspective of Computer Scientists

• Formulate biological problems into combinatorial
  problems
• Develop efficient algorithms to solve them
  exactly or approximately.
• Design simulation methods to validate the
  experimental results.

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Introduction to Some Biology Background
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DNA The Code of Life

• Four codes Adenine, Guanine, Thymine, and
  Cytosine.
• They pair A-T and C-G on complimentary strands.

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Structure of DNA

• DNA has four bases
• Adenine (A), Guanine (G), Cytosine (C), Thymine
  (T)
• A and G are purines, where C and T are
  pyrimidines.
• Purines are double ring bases
• Pyrimidines are single ring bases.

N
O
N
O
N
C
C
N
N
C
N
C
O
O
C
C
C
C
N
C
C
C
C
N
N
C
N
C
N
C
C
N
C
N
C
N
N
Cytosine
Thymine
Adenine
Guanine
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DNA A Huge Amount of Information

• The human genome is 3 biilion length.
• Which portion is functional?

AGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATTTAAAGCGTA
AGAGCTATGCCATTTATATAAAATTTAAAGGCGCGGGGGGTTAAGAGGCG
CGGGGGGTTAAGAGCTATGCCATTTATATAAAATTTAAAGCGTAAGAAGC
TATGCCATTTATATAAAATTTAAAGCGTAAGAGCTATGCCATTTATATAA
AATTTAAAGAGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATTT
AAAGCGTAAGAGCTATGCCATTTATATACAATCTAAAGTTAAAGCGTAAG
AGCTATGCAGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATTTA
AAGCGTAAGAGCTATGCCATTTATATAAAATTTAAAGAGGCGCGGGGGGT
TAAGAGCTATGCCATTTATATAAAATTTAAAGCGTAAGAGCTATGCCATT
TATATAAAATTTAAAGAAAGCGTAAGAGCTATGCCATTTATATAAAATTT
AAAGGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATTTAAAGCG
TAAGAGCTATGCCATTTATATAAAATTTAAAGGGCGCGGGGGGTTAAGAG
CTATGCCATTAGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATT
TAAAGCGTAAGAGCTATGCCATTTATATAAAATTTAAAGTATAAAATTTA
AAGAGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATTTAAAGCG
TAAGAGCTATGCCATTTATATAAAATTTAAAGAAAGCGTAAGAGCTATGC
CATTTATATAAAATTTAAAGGGCGCGGGGGGTTAAGAGCTATGCCATTTA
TATAAAATTTAAAGCGTAAGAGCTATGCCATTTATATAAAATTTAAAGGG
CGCGGGGGGTTAAGAGCTATGCCATTTAAAATTTAAAGGCGCGGGGGGTT
AAGAGGCGCGGGGGGTTAAGAGCTATGCCATTTATATAAAATTTAAAGCG
TAAGAAGCTATGCCATTTATATAAAATTTAAAGCGTAAGAGCTATGCCAT
TTATATAAAATTTAAAGAGGCGCGGGGGGTTAAGAGCTATGCCATTTATA
TAAAATTTAAAGCGTAAGAGCTATGCCATTTATATAAAATTTAAAGTTAA
AGCGTAAGAGCTATGCAGGCGCGGGGAGCTGGGTTTATATAAAATTTA
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Genes in the Human Genome

• A gene is a set of segments of DNA necessary to
  produce a functional RNA product.
• Genes are only portion of the human genome.
• The gene density of the human genome is roughly
  1215 genes/Mb.
• It is estimated that the human genome contains
  about 20,00025,000 genes.

AGCCTACGAATAACCCCTACGAATACATATG
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Annotation of Human Genes

• People were developing software to annotate the
  human genome.
• Align protein or RNA sequences to the genome.
• GC-content is positively correlated with gene
  length and gene density.
• e.g., identification of rich GC-islands is a
  computational problem.

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Central Dogma of Molecular Biology
Translation
Transcription

• Transcription
• The DNA codes for the production of messenger RNA
  (mRNA).
• Translation
• The mRNA is used for protein synthesis.

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Gene
UTR
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Gene
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Alternative Splicing

• The diversity of proteins is due to alternative
  splicing.

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Research Issues

• The major research topics years ago mainly focus
  on annotation of human genes.
• Comparative methods often rely on alignment
  algorithms (e.g., BLAST).
• The RNA or protein sequences are aligned to the
  human genome.
• Recently the target has been shifted to discover
  events of alternative splicing.

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Translation

• The mRNA is translated into amino acids to form a
  protein.

AGCCUACGAAUAACCCCUACGAAUACAUAUGCUACGAAUAACCCCUACG
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Translation

• The amino acids are created based on the codons.

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RNAi

• Nobel Prize 2006, "for their discovery of RNA
  interference - gene silencing by double-stranded
  RNA"

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Central Dogma of Molecular Biology
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Remarks

• In 2007, the ENCODE project declares that the
  human genome is pervasively transcribed (Nature,
  2007).
• The majority of nucleotides can be found in
  primary transcripts, including non-protein-coding
  transcripts.
• Some other factors might still affect the
  expression of genes or protein synthesis.
• Post translation modification.
• Epigenomic factors.

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Genetic Variants in the Population
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Genetic Variants

• The genetic variants differ among members in the
  human population.

Black eye Brown eye Black eye Blue eye Brown
eye Brown eye
GATATTCGTACGGA-T GATGTTCGTACTGAAT GATATTCGTACGGA-T
GATATTCGTACGGAAT GATGTTCGTACTGAAT GATGTTCGTACTGAA
T
DNASequences of 6 individuals
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Genetic Variants Over Time
Variants observed in a population
Mutations over time
Common Ancestor
time
present
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Point Mutation

• Mutation is caused by chemicals or malfunction of
  DNA replication and exchange a single nucleotide
  for another.
• Transition exchanges a purine for a purine or a
  pyrimidine for a pyrimidine.
• e.g., C -gt T or A -gt G.
• Transversion exchanges a purine for a pyrimidine
  or a pyrimidine for a purine.
• e.g., A -gt C or T -gt G

T
A
G
C
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Other Genetic Variants

• Insertion/deletion.
• A portion of DNA is inserted or deleted compared
  with the reference genome.
• Inversion.
• A portion of DNA is inversed with respect to the
  reference genome.
• Copy number polymorphisms.
• Duplication and deletion of a segment of DNA.

44
Microarray Technology

• Thanks to the advance of array technology, tens
  of thousands of genetic variants can be
  identified within affordable cost.
• Affymetrix 500k SNP array.
• Tiling array.

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Association Study

• The study of genetic variants using cases and
  controls can find out the cause of disease.

S1 S2 S3 S4 S5 S6 S7 S8
1 0 1 1 0 x 0 0
Cases
1 1 0 1 1 2 x 0
0 2 1 1 0 0 1 0
0 1 1 0 0 1 0 0
0 0 x 0 1 0 1 1
Controls
0 2 1 0 0 x 0 1
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Recombination

• The chromosome recombination breaks up and
  reorganizes the DNA.

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NCBI

• National Center for Biotechnology Information
• http//www.ncbi.nlm.nih.gov/

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Public Database

• UCSC Genome Browser
• http//genome.ucsc.edu/

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Public Database

• Ensembl
• http//www.ensembl.org/