How Bioinformatics can change your life

Basic Concepts of Bioinformatics

M. Alroy Mascrenghe
MBCS, MIEEE, MIT mark_ai@yahoo.com A lecture given for the BCS Wolerhampton Branch at the University of Wolverhampton

http://www.geocities.com/mark_ai/

TOC
        

Introduction Basic concepts in Molecular biology Bioinformatics techniques Areas in bioinformatics Applications Related Computer Technology Conference in Glasgow Acknowledgements Reference
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Introduction

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2000
    

A Major event happened that was to change the course of human history It was a joint British and American effort nothing to do with IRAQ! It was a race who will complete first Race Test not whether they have taken drugs but whether they can produce them! Human genome was sequenced
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A Situsomewhere in the near future

  

 

A virus not I love you virus- creates an epidemic virusGeneticists and bioinformaticians role on their sleeves Genetic material of the virus is compared with the existing base of known genetic material of other viruses As the characteristics of the other viruses are known From genetic material computer programs will derive the proteins necessary for the survival of the virus When the protein (sequence and structure) is known then medicines can be designed

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What is


The marriage between computer science and molecular biology



The algorithm and techniques of computer science are being used to solve the problems faced by molecular biologists

Information technology applied to the management and analysis of biological data



Storage and Analysis are two of the important functions bioinformaticians build tools for each
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Biology

Chemistry

Computer Science

Statistics

Bioinformatics
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What is..


 

This is the age of the Information Technology However storing info is nothing new Information to the volume of Britannica Encyclopedia is stored in each of our cells Bioinformatics tries to determine what info is biologically important

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Basics of Molecular Biology.

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DNA & Genes

  

DNA is where the genetic information is stored Blonde hair and blue eyes are inherited by this Gene - The basic unit of heredity


There are genes for characteristics i.e. a gene for blond hair etc

 

Genes contain the information as a sequence of nucleotides Genes are abstract concepts like longitude and latitudes in the sense that you cannot see them separately Genes are made up of nucleotides
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Nucleotide (nt)


Each nt I made up of
  

Sugar Phospate group Base

    

The base it (nt) contains makes the only difference between one nt and the other There are 4 different bases


G(uanine),A(denine),T(hymine),C(ytosine)

The information is in the order of nucleotide and the order is the info Genes can be many thousands of nt long The complete set of genetic instructions is called genomes
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Chromosomes


DNA strings make chromosomes Analogy

Letters - nt  Sentences genes  Individual volumes of Britannica encyclopedia chromosomes  All voles together - Genome

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Double Helix
  

The DNA is a double helix Each strand has complementary information Each particular base in one strand is bonded with another particular base in the next strand  G-C  A-T For example  AATGC one strand  TTACG other strand

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Proteins


Proteins are very important biological feature

Amino Acids make up the proteins 20 different amino acids are there The function of a protein is dependant on the order of the amino acids

  

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Proteins
    

  

The information required to make aa is stored in DNA DNA sequence determines amino acid sequence Amino Acid sequence determines protein structure Protein structure determines protein function A Substance called RNA is used to carry the Info stored in the DNA that in turn is used to make proteins Storage - DNA Information Transfer RNA RNA is the message boy!
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Central dogma

DNA

transcription
RNA Polymerase

RNA

Translation
Ribosomes

Protein

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Proteins..


Since there are 20 amino acids to translate one nt cannot correspond to one aa, neither can it correspond as twos So in triplet codes codon protein information is carried The codons that do not correspond to a protein are stop codons UAA, UAG, UGA Some codons are used as start codons - AUG as well as to code methionine
(RNA has U instead of T)

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Protein Structure
 

 

 

Shows a wide variety as opposed to the DNA whose structure is uniform X-ray crystallography or Nuclear Magnetic Resonance (NMR) is used to figure out the structure Structure is related to the function or rather structure determines the function Although proteins are created as a linear structure of aa chain they fold into 3 d structure. If you stretch them and leave them they will go back to this structure this is the native structure of a protein Only in the native structure the proteins functions well Even after the translation is over protein 20 M.Alroy Mascrenghe goes through some changes to its structure

Gene Expression
   

 

Gene Expression the process of Transcripting a DNA and translating a RNA to make protein Where do the genes begin in a chromosome? How does the RNA identify the beginning of a gene to make a protein A single nt cannot be taken to point out the beginning of a gene as they occur frequently But a particular combination of a nucleotide can be Promoter sequences the order of nt which mark the beginning of a gene
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Bioinformatics Techniques..

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Prediction and Pattern Recognition



The two main areas of bioinformatics are Pattern recognition



A particular sequence or structure has been seen before and that a particular characteristic can be associated with it From a sequence (what we know) we can predict the structure and function (what we dont know)
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Prediction


Dot plots.


Simple way of evaluating similarity between two sequences In a graph one sequence is on one side the next on the other side Where there are matches between the two sequences the graph is marked
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Alignments
 

A match for similarity between the characters of two or more sequences Eg.
 

TTACTATA TAGATA

There are so many ways to align the above two sequences



1.
 

TTACTATA TAGATA TTACTATA TAGATA TTACTATA TAGATA

2.
 

3.
 

 

So which one do we choose and on what basis? Solution is to Provide a match score and mismatch score
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Gaps


Introduce gaps and a penalty score for gaps

TTACTATA  T_A_GATA

In gap scores a single indel which is two characters long is preferred to two indels which are each one character long

However not all gaps are bad

     

TTGCAATCT CAA How do we align? ---CAA-----CAA--These gaps are not biologically significant Semi Global Alignments
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Scoring Matrix
   

For DNA/protein sequence alignment we create a matrix If A and A score is 1 If A and T score is -5 If A and C score is -1

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Dynamic Programming


 

As the length of the query sequences increase and the difference of length between the two sequence also increases more gaps has to be inserted in various places We cannot perform an exhaustive search Combinatorial explosion occurs too much combinations to search for Dynamic programming is a way of using heuristics to search in the most promising path
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Databases


Sequence info is stored in databases So that they can be manipulated easily The db (next slide) are located at diff places They exchange info on a daily basis so that they are up-to-date up-toand are in sync Primary db sequence data
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Major Primary DB
Nucleic Acid EMBL (Europe) Protein PIR Protein Information Resource MIPS SWISS-PROT SWISSUniversity of Geneva, now with EBI TrEMBL A supplement to SWISSSWISSPROT NRLNRL-3D

GenBank (USA) DDBJ (Japan)

Composite DB


As there are many db which one to search? Some are good in some aspects and weak in others? Composite db is the answer which has several db for its base data Search on these db is indexed and streamlined so that the same stored sequence is not searched twice in different db
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Composite DB


OWL has these as their primary db

SWISS PROT (top priority)  PIR  GenBank  NRL-3D NRL

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Secondary db


Store secondary structure info or results of searches of the primary db Compo Primary DB Source PROSITE SWISS-PROT SWISSPRINTS OWL
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Database Searches
  

We have sequenced and identified genes. So we know what they do The sequences are stored in databases So if we find a new gene in the human genome we compare it with the already found genes which are stored in the databases. Since there are large number of databases we cannot do sequence alignment for each and every sequence So heuristics must be used again.
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Areas in Bioinformatics

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Genomics


Because of the multicellular structure, each cell type does gene expression in a different way although each cell has the same content as far as the genetic i.e. All the information for a liver cell to be a liver cell is also present on nose cell, so gene expression is the only thing that differentiates

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Genomics - Finding Genes

 

  

Gene in sequence data needle in a haystack However as the needle is different from the haystack genes are not diff from the rest of the sequence data Is whole array of nt we try to find and border mark a set o nt as a gene This is one of the challenges of bioinformatics Neural networks and dynamic programming are being employed
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Organism

Genome Gene Size Number (Mb)

bp * 1,000,000

Web Site

Yeast

13.5

6,241

Fruit Flies Homo Sapiens

180 3,000

13,601 45,000

http://genomehttp://genomewww.stanford.ed u/Saccharomyce s http://flybase.bio. indiana.edu http://www.ncbi.n lm.nih.gov/geno me/guide

Proteomics
 

Proteome is the sum total of an organisms proteins More difficult than genomics
  

4 Simple chemical makeup Can duplicate

20 complex cant

 

We are entering into the post genome era Meaning much has been done with the Genes not that its a over
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Proteomics..
 

  

The relationship between the RNA and the protein it codes are usually very different After translation proteins do change  So aa sequence do not tell anything about the post translation changes Proteins are not active until they are combined into a larger complex or moved to a relevant location inside or outside the cell So aa only hint in these things Also proteins must be handled more carefully in labs as they tend to change when in touch with an inappropriate material

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Protein Structure Prediction



Is one of the biggest challenges of bioinformatics and esp. biochemistry No algorithm is there now to consistently predict the structure of proteins

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Structure Prediction methods



Comparative Modeling
Target proteins structure is compared with related proteins  Proteins with similar sequences are searched for structures


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Phylogenetics
 

  

The taxonomical system reflects evolutionary relationships Phylogenetics trees are things which reflect the evolutionary relationship thru a picture/graph Rooted trees where there is only one ancestor Un rooted trees just showing the relationship Phylogenetic tree reconstruction algorithms are also an area of research

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Applications.

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Medical Implications


Pharmacogenomics  Not all drugs work on all patients, some good drugs cause death in some patients  So by doing a gene analysis before the treatment the offensive drugs can be avoided  Also drugs which cause death to most can be used on a minority to whose genes that drug is well suited volunteers wanted!  Customized treatment Gene Therapy  Replace or supply the defective or missing gene  E.g: Insulin and Factor VIII or Haemophilia

BioWeapons (??)
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Diagnosis of Disease


   

Diagnosis of disease  Identification of genes which cause the disease will help detect disease at early stage e.g. Huntington disease Symptoms uncontrollable dance like movements, mental disturbance, personality changes and intellectual impairment Death in 10-15 years 10The gene responsible for the disease has been identified Contains excessively repeated sections of CAG So once analyzed the couple can be counseled
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Drug Design
 

Can go up to 15yrs and $700million One of the goals of bioinformatics is to reduce the time and cost involved with it. The process


Discovery


Computational methods can improves this

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Testing

Discovery
Target identification
   

Identifying the molecule on which the germs relies for its survival Then we develop another molecule i.e. drug which will bind to the target So the germ will not be able to interact with the target. Proteins are the most common targets

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Discovery


For example HIV produces HIV protease which is a protein and which in turn eat other proteins This HIV protease has an active site where it binds to other molecules So HIV drug will go and bind with that active site


Easily said than done!

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Discovery


Lead compounds are the molecules that go and bind to the target proteins active site Traditionally this has been a trial and error method Now this is being moved into the realm of computers

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Related Computer Technology.

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PERL


 

 

Perl is commonly used for bioinformatics calculations as its ability to manipulate character symbols The default CGI language It started out as a scripting language but has become a fully fledged language IT has everything now, even web service support http://bio.perl.org
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The place of XML & Web Services



    

Various markup languages are being created Gene Markup language etc to represent sequence/gene data Web Services program to program interaction, making the web application centric as opposed to human centric So this has to platform language independent Protocols like SOAP help in this regard In bioinformatics various databases are being used, different platforms, languages etc So web services helps achieve platform independence and program interaction Since sequence data bases are in various formats, platforms SOAP also helps in this regards
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The place of GRID

  

 

GRID - new kid on the block Using many computers to fulfill a single computational tasks Bioinformatics is the ideal platform as it has to deal with a large amount of data in alignment and searches E-science initiative in the UK ORACLE 10g the worlds first GRID database
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Data bases and Mining



Lot of the sequence databases are available publicly As there is a DB involved various data mining techniques are used to pull the data out As there is a lot of literature articles etc on this area a data mining on the literature not on the sequence data has also become a PhD topic for many
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European Molecular Biology Network (EMBnet)

   

A central system for sharing, training and centralizing up to date bio info Some of the EMBnet sites are: SQENET


http://www.seqnet.dl.ac.uk http://www.biochem.ucl.ac.uk/bsm/dbbro wser/embnet/

UCL


EBI European Bioinformatics Institute



www.ebi.ac.uk
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References


Dan E. Krane and Michael L. Raymer  Basic Concepts of Bioinformatics Arthur M Lesk  Intro to Bioinformatics T.K. Attwood & D. J. Parry-Smith Parry Intro to Bioinformatics The genetic Revolution  Dr Patrick Dixon

Prof David Gilberts Site  http://www.brc.dcs.gla.ac.uk/~drg/

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Thank You!

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