BIOINFORMATICS

A SEMINAR REPORT

Submitted by

NITHYA K. PILLAI

in partial fulfillment for the award of the degree

of

BACHELOR OF TECHNOLOGY

IN

COMPUTER SCIENCE AND ENGINEERING

SCHOOL OF ENGINEERING

COCHIN UNIVERSITY OF SCIENCE &TECHNOLOGY,

KOCHI-682022

AUGUST 2008
DIVISION OF COMPUTER SCIENCE AND ENGINEERING
SCHOOL OF ENGINEERING
COCHIN UNIVERSITY OF SCIENCE & TECHNOLOGY,
COCHIN-682 022

Certificate

Certified that this is a bonafide record of the Seminar Entitled

“BIOINFORMATICS”
Done by the following Student
Nithya K Pillai
Of the VIIth semester, Computer Science and Engineering in the year 2008
in partial fulfillment of the requirements to the award of Degree Of Bachelor
Of Technology in Computer Science and Engineering of Cochin University
of Science and Technology.

Mrs.Rahna P. Muhammed Dr. David Peter

Seminar Guide Head of the Department

Date:
 ACKNOWLEDGEMENT

At the outset, I thank the Lord Almighty for the grace, strength and
hope to make my endeavor a success.

I also express my gratitude to Dr. David Peter, Head of the

Department and my Seminar Guide for providing me with adequate
facilities, ways and means by which I was able to complete this seminar. I
express my sincere gratitude to him for his constant support and valuable
suggestions without which the successful completion of this seminar would
not have been possible.

I thank Mrs.Rahna P. Muhammed, my seminar guide for her

boundless cooperation and helps extended for this seminar. I express my
immense pleasure and thankfulness to all the teachers and staff of the
Department of Computer Science and Engineering, CUSAT for their
cooperation and support.

Last but not the least, I thank all others, and especially my classmates
and my family members who in one way or another helped me in the
successful completion of this work.

NITHYA K.PILLAI
 ABSTRACT

Rapid advances in bioinformatics are providing new hopes to patients

of life threatening diseases. Gene chips will be able to screen heart attack

and diabetics years before patients develop symptoms. In near future,

patients will go to a doctor’s clinic with lab- on- a- chip devices. The device

will inform the doctor in real time if the patient’s ailment will respond to a

drug based on his DNA. These will help doctors diagnose life-threatening

illness faster, eliminating expensive, time-consuming ordeals like biopsies

and sigmoidoscopies. Gene chips reclassify diseases based on their

underlying molecular signals, rather than misleading surface symptoms. The

chip would also confirm the patient’s identity and even establish paternity.
 TABLE OF CONTENTS

CHAPTER NO TITLE PAGE NO

ABSTRACT
LIST OF FIGURES
LIST OF TABLES

1. INTRODUCTION 1
2. EVOLUTION OF BIOINFORMATICS 2
3. HUMAN ELECTRONICS 4
4. GENE EXPRESSION 8
5. CHIP ELECTRONICS 11
5.1 Biochips
5.2 Clinical chips
6. PRESENT GOALS OF BIOINFORMATICS 13
7. ALGORITHMS USED 14
7.1 Comparing sequence
7.2 Constructing evolutionary trees
7.3 Detection patterns
7.4 Determining 3d structure
8. APPLICATIONS 23
8.1 Applications of internal chips
8.2 Applications of external chips
9. FUTURE DEVELOPMENTS 30
10. CONCLUSION 32
11. REFERENCES 33
 LIST OF FIGURES

FIG.NO NAME PAGE NO

1. DNA 4
2. INVOLVEMENT OF COMPUTERS 6
3. GENE EXPRESSION 8
4. MICROARRAY 10
5. ACTIVA IMPLANT 25
6. COCHLEAR IMPLANT 26
7. CHIP IMPLANTED IN EYE 27
8. GENE CHIP 29
 LIST OF TABLES

NO NAME PAGE NO

1. SOURCE OF DATA 7
BIOINFORMATICS

1.INTRODUCTION

Bioinformatics is an inter disciplinary research area. It is a fusion of

computing, biotechnology and biological sciences. Bioinformatics is poised to one of the
most prodigious growth areas in the next to decades. Being the interface between the
most rapidly advancing fields of biological and computational sciences, it is immense in
scope and vast in applications.

Bioinformatics is the study of biological information as it passes from its

storage site in the genome to the various gene products in the cell. Bioinformatics
involves the creation and computational technologies for problems in molecular biology.
As such, it deals with methods for storing, retrieving and analyzing biological data, such
as nuclei acid (DNA/RNA) and protein sequence, structures, functions, path ways and
interactions. The science of Bioinformatics, which is the melding of molecular biology
with computer science, is essential to the use of genomic information in understanding
human diseases and in the identification of new molecular targets of drug discovery. New
discoveries are being made in the field of genomics, an area of study which looks at the
DNA sequence of an organism in order to determine which genes code for beneficial
traits and which genes are involved in inherited diseases.
If you are not tall enough, the stature could be altered accordingly. If you are
weak and not strong enough, your physique could be improved. If you think this is the
script for a science fiction movie, you are mistaken. It is the future reality.

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2. EVOLUTION OF BIOINFORMATICS

DNA is the genetic material of organism. It contains all the information needed
for the development and existence of an organism. The DNA molecule is formed of two
long polynucleotide chains which are spirally coiled on each other forming a double
helix. Thus it has the form of spirally twisted ladder. DNA is a molecule made from
sugar, phosphate and bases. The bases are guanine(G), cytosine(C), adenine(A) and
thiamine(T).Adenine pairs only with Thiamine and Guanine pairs only with Cytosine.
The various combinations of these bases make up with DNA. That is; AAGCT, CCAGT,
TACGGT etc. An infinite number of combinations of these bases is possible. And then
the gene is a sequence of DNA that represents a fundamental unit of heredity. Human
genome consists of approximately 30,000 genes, containing approximately 3 billion base
pairs.
Currently, scientists are trying to determine the entire DNA sequence of various
living organisms. DNA sequence analysis could identify genes, regulatory sequences and
other functions. Molecular biology, algorithms, and computing have helped in
sequencing larger portions of genomics of several species. Sequence is the determination
of the order of nucleotides in a DNA as also the order of amino acids in a protein.
Sequence analysis, which is at the core of bioinformatics, enables function identification
of genes.

The human found in every cell of a human being consists of 23pairs of

chromosomes. These chromosomes constitute the 3 billion letters of chemical code that
specify the blue print for a human being. Human Genome Project, one of the best known
projects in the world. The world Human Genome Project, a vast endeavor aimed at
reading this entire DNA code will completely transform biology, medicine and
biotechnology. Using this entire code all 30,000 human genes will be identified; all 5000
inherited diseases will become diagnosable and potentially curable; and drug design will
be completely transformed. The Genome Project focuses on two main objective:

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mapping-pinpointing the genomic location of all genes and markers; and DNA
sequencing-reading the chemical "text" of all the genes and their intervening sequences.
DNA sequences are entered in to large data bases, where they can be compared with the
known genes, including inter-species comparisons. The explosion of publicly available
genomic information resulting from the Human Genome Project has precipitated the need
for bioinformatics capabilities.
Determination of genome organization and gene
regulation will promote the understanding of how humans develop from single cells to
adults, why this process some times goes wrong, and the changes that take place as
people age. Bioinformatics finds applications in medicine for recommending individually
tailored drugs based on an individual's profile. It helps to identify a specific genetic
sequence that is responsible for a particular disease, its associated protein, and protein
function. For curing the disease a new drugs can be developed.

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3. HUMAN ELECTRONICS

The nucleus is the most obvious organelle in the human cell. Within the nucleus
is the DNA responsible for providing the cell with its unique characteristics. The DNA is
similar in every cell of the body, but depending on the specific cell type; some genes may
be turned on or off-that is why a liver cell is different from a muscle cell, and a muscle
cell is different from a fat cell. About 99.9% of the sequence is identical between any two
people. But because the small percentage of DNA that differs can relate to an individual’s
disease. Scientists are comparing sequence using DNA chips from healthy people and
those from patients with a specific disease to help identify genetic targets for drug
discovery information about genetic variation can help to predict which patients are likely
to benefit from specific drugs
The most significant and the biggest application of DNA
chips is the use of DNA micro arrays for expression profiling. In expressions profiling
the chip controls how different parts of the genes turned on or off to create certain types
of cells. If the gene is expressed in one way, it may result in normal muscle, for instance.
If it is expressed in another way, it may result in a tumor. By comparing these different
expressions, researchers hope to discover ways to predict and perhaps to prevent diseases.

Fig 1.DNA

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Electronic circuit can be incorporated in the chip to detect various states of DNA.
DNA carries an electric charge. That charge can be read on the chip, just like cells on a
memory array. This DNA chip would like to diagnose life-threatening bacterial
infections.

In DNA the medium is a chain of two units (phosphate & ribose), and the most
easily recognizable message is provided by a sequence of letters (bases) attached to the
chain. The DNA has two sequences of letters wrapped in the form of a double helix. The
DNA has two sequences of letters wrapped around each other in the form of a double
helix. One is the complement of other, so that the sequence of one string (strand) can be
inferred from the sequence of other. The DNA sequence of bases encodes 20 amino
acids. Under instructions received from DNA, amino acids join together in the same
order as they are encoded in DNA to form proteins. Chains of amino acids, which fold in
complicated ways, play a major role in determining how we interact with the
environment.
Genomic information is revolutionizing life sciences. The quest for under
standing how genetic factors contribute to human disease is gathering speed. The 46
human chromosomes house almost three billion base pairs of DNA that contain 30,000 to
40,000 protein-coding genes. Using bioinformatics find out how genes contribute to
diseases that have a complex pattern of inheritance, such as diabetics, asthma, and mental
illness. No one gene can tell whether a person has a disease or not. A number of genes
may make a subtle contribution to a person's susceptibility to a disease. Gene may also
affect how a person reacts to the environment. As the entire human genome is too big a
sequence on its own, sequencing and reading a genome demand heavy computational
resources.
Bioinformatics is largely, although not exclusively, a computer-based discipline.
Computers are important in bioinformatics for two reasons:
First, many bioinformatics problems require the same task to be repeated millions
of times. For example, comparing a new sequence to every other sequence stored in a
database or comparing a group of sequences systematically to determine evolutionary

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relationships. In such cases, the ability of computers to process information and test
alternative solutions rapidly is indispensable.
Second, computers are required for their problem-solving power.
Typical problems that might be addressed using bioinformatics could include solving the
folding pathways of protein given its amino acid sequence, or deducing a biochemical
pathway given a collection of RNA expression profiles. Computers can help with such
problems, but it is important to note that expert input and robust original data are also
required.

Fig 2. Involvement of computers

We start with an overview of the sources of information: these may be divided into raw
DNA sequences, protein sequences, macromolecular structures, genome sequences, and
other whole genome data. Raw DNA sequences are strings of the four baseletters
comprising genes, each typically 1,000 bases long. The GenBank repository of nucleic

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acid sequences currently holds a total of 9.5 billion bases in 8.2 million entries (all
database figures as of August 2000). At the next level are protein sequences comprising
strings of 20 amino acid-letters. At present there are about 300,000 known protein
sequences.

Data source Data size Bioinformatics topics

Raw DNA sequence 8.2 million sequences Separating coding and non-
(9.5 billion bases) coding regions
Identification of introns and
exons Gene product prediction
Forensic analysis
Protein sequence 300,000 sequences Sequence comparison
(~300 amino acids algorithms Multiple sequence
each) alignments algorithms
Identification of conserved
sequence motifs
13,000 structures Secondary, tertiary structure
Macromolecular (~1,000 atomic prediction
structure coordinates each) 3D structural alignment
algorithms Protein geometry
measurements
Surface and volume shape
calculationsIntermolecular
interactions
Genomes 40 complete genomes Characterisation of repeats
(1.6 million – Structural assignments to
3 billion bases each) genes
Phylogenetic analysis
Genomic-scale censuses
(characterisation of protein
content, metabolic pathways)
Linkage analysis relating
specific genes to diseases
Gene expression largest: ~20 time Correlating expression
point measurements patterns
for ~6,000 genes Mapping expression data to
sequence, structural and
biochemical data

Table 1. Sources of data used in bioinformatics, the quantity of each type of data that is
currently available, and bioinformatics subject areas that utilise this data.

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4.GENE EXPRESSION

Fig.3 Gene Expression

mRNA encodes the genetic information as copied from the DNA molecules.
Transcription is the process in which DNA is copied into an RNA molecule. The
resulting linear molecule is an mRNA transcript. tRNA molecules develop a well-defined
three-dimensional structure which is critical in the creation of proteins. Translation is the
process in which the nucleotide base sequence of the processed mRNA is used to order
and join the amino acids into a protein with the help of ribosomes and tRNA.

The 3D structure of proteins is mainly determined by X-ray crystallography and

by nuclear magnetic resonance (NMR). It is time consuming and costly.

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A powerful new tool available in biology is microarrays. They allow determining

simultaneously the amount of mRNA production of thousands of genes. Microarray
experiments require threephases. In the first phase one places thousands of different one-
stranded chunks of RNA in minuscule wells on the surface of a small glass chip. (This
task is not unlike that done by a jet printer using thousands of different colors and placing
each of them in different spots of a surface.) The chunks correspond to the RNA known
to have been generated by a given gene. The 2D coordinates of each of the wells are of
course known.
The second phase consists of spreading—on the surface of the glass— genetic
material (again one-stranded RNA) obtained by a cell experiment one wishes to perform.
Those could be the RNAs produced by a diseased cell, or by a cell being subjected to
starvation, high temperature, etc. The RNA already in the glass chip combines with the
RNA produced by the cell one wishes to study. The degree of combined material
obtained by complementing nucleotides is an indicator of how much RNA is being
expressed by each one of the genes of the cell being studied.
The third phase consists of using a laser scanner connected to a computer. The
apparatus measures the amount of combined material in each chip well and determines
the degree of gene expression—a real number—for each of the genes originally placed on
the chip. Microarray data is becoming available in huge amounts. A problem with this
data is that it is noisy and its interpretation is difficult. Microarrays are becoming
invaluable for biologists studying how genes interact with each other. This is crucial in
understanding disease mechanisms.

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FIG.4 MICROARRAY

The most significant and the biggest application of DNA chips is the use of DNA
micro arrays for expression profiling. In expressions profiling the chip controls how
different parts of the genes turned on or off to create certain types of cells. If the gene is
expressed in one way, it may result in normal muscle, for instance. If it is expressed in
another way, it may result in a tumor. By comparing these different expressions,
researchers hope to discover ways to predict and perhaps to prevent diseases.

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5. CHIP ELECTRONICS

Chip electronics can be divided into two.

5.1. Biochips
5.2. Clinical chip

5.1.BIOCHIP

Biochip is an IC who’s electrical and logical functions are performed by protein

molecules appropriately manipulated. Advances in molecular biology and
semiconductor fabrication have resulted in new formats for hybridization arrays. Instead
of these being based on a membrane or a glass slide platforms these arrays several
electrodes covered by a thin layer of agarose coupled with affinity moiety. Each micro
electrode is capable of generating a controllable electric current that can be used to draw
biological samples, reagents and probes to specify locations on the chip surface. The
number of genes covered by these arrays depends on the number of electrodes made
within the area of that array.
5.2. CLINICAL CHIPS

A decade ago, an eight-year old kid jumped from his swing set and landed flat,
shattering a leg bone where most kids would have sprained an ankle. An X-ray revealed
this problem. Where there should have been hard bone, a soft tumour was present. The
kid needed a precise diagnosis. If the cancer was aggressive, it needed immediate
treatment with the powerful but toxic drug 'adriamycin'. If the tumour was growing
slowly, doctors had the time to try out weaker but safer drugs.
A biopsy was inconclusive. Like many paediatric bone tumours, the kid’s tumour
was a small, round blue- cell tumour. The doctor had a problem treating the kid. As
“adriamycin” could cause serious heart damage, doctors weren't willing to give it to the
kid. Of all blue cell tumours spreads aggressively enough to require this potentially
deadly medicine. Doctors hoped that a less toxic medicine will do and gave the same to

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the kid, resulting in the death of the kid just after six months. Today, rapid advances in
bioinformatics are providing new hopes to such patients. The new technology enables
doctors to proceed straight to genetic codes that instruct tumours to grow, finding
invisible molecular signals that differentiate cancers as well as a host of other deadly
diseases.
The key to this life saving, cost effective diagnostic power is a tiny glass chip
peppered with DNA strips, called the gene chip. Today, 60% of gene chips are used for
are research purposes, where these are speeding up drug design and helping researchers
to mine genomic data bases.

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6. PRESENT GOALS OF BIOINFORMATICS

The present role of bioinformatics is to aid biologists in gathering and processing

genomic data to study protein function. Another important role is to aid researchers at
pharmaceutical companies in making detailed studies of protein structures to facilitate
drug design. Typical tasks done in bioinformatics include:
—Inferring a protein’s shape and function from a given a sequence of amino acids.
—Finding all the genes and proteins in a given genome.
—Determining sites in the protein structure where drug molecules can be attached.

To perform these tasks, one usually has to investigate homologous sequences or proteins
for which genes have been determined and structures are available. Homology between
two sequences (or structures) suggests that they have a common ancestor. Since those
ancestors may well be extinct, one hopes that similarity at the sequence or structural level
is a good indicator of homology.

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7. ALGORITHMS FREQUENTLY USED

IN BIOINFORMATICS

Based on the availability of the data now present the various algorithms that lead to a
better understanding of gene function. They can be summarized as follows:

(1) COMPARING SEQUENCES.

Given the huge number of sequences available, there is an urgent need to develop
algorithms capable of comparing large numbers of long sequences. These algorithms
should allow the deletion, insertion, and replacements of symbols representing
nucleotidesor amino acids, for such transmutations
occur in nature.
(2) CONSRUCTING EVOLUTIONARY TREES
These trees are often constructed after comparing sequences belonging to different
organisms. Trees group the sequences according to their degree of similarity. They serve
as a guide to reasoning about how these sequences have been transformed through
evolution. For example, they infer homology from similarity, and may rule out erroneous
assumptions that contradict known evolutionary
processes.
(3) DETECTING PATTERNS IN SEQUENCE
There are certain parts of DNA and amino acid sequences that need to be detected. Two
prime examples are the search for genes in DNA and the determining of subcomponents
of a sequence of amino acids
(secondary structure). There are several ways to perform these tasks. Many of them are
based on machine learning and include probabilistic grammars, or neural networks.
(4) DETERMINING 3D STRUCTURES FROM PATTERNS
The problems in bioinformatics that relate sequences to 3D structures are
computationally difficult. The determination of RNA shape from sequences requires

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algorithms of cubic complexity. The inference of shapes of proteins from amino acid
sequences remains an unsolved problem.

7.1. Comparing Sequences

From the biological point of view sequence comparison is motivated by the fact that
all living organisms are related by evolution. That implies that the genes of species that
are closer to each other should exhibits similarities at the DNA level; one hopes that
those similarities also extend to gene function.
The following definitions are useful in understanding what is meant by the
comparison of two or more sequences. An alignment is the process of lining up sequences
to achieve a maximal level of identity. That level expresses the degree of similarity
between sequences. Two sequences are homologous if they share a common ancestor,
which is not always easy to determine. The degree of similarity obtained by alignment can
be useful in determining the possibility of homology between two sequences.
In biology, the sequences to be compared are either nucleotides (DNA, RNA) or amino
acids (proteins). In the case of nucleotides, one usually aligns identical nucleotide
symbols. When dealing with amino acids the alignment of two amino acids occurs if they
are identical or if one can be derived from the other by substitutions that are likely to
occur in nature. An alignment can be either local or global. In the former, only portions
of the sequences are aligned, whereas in the latter one aligns over the entire length of the
sequences. Usually, one uses gaps, represented by the symbol “-”, to indicate that it is
preferable not to align two symbols because in so doing, many other pairs can be aligned.
In local alignments there are
larger regions of gaps. In global alignments, gaps are scattered throughout the alignment.
A measure of likeness between two sequences is percent identity: once an alignment is
performed we count the number of columns containing identical symbols. The percent
identity is the ratio between that number and the number of symbols in the (longest)
sequence. A possible measure or score of an alignment is calculated by summing up the
matches of identical (or similar) symbols and counting gaps as negative.

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With these preliminary definitions in mind, we are ready to describe the algorithms that
are often used in sequence comparison.
7.1.1. Pairwise Alignment. Many of the methods of pattern matching used in computer
science assume that matches contain no gaps. Thus there is no match for the pattern bd in
the text abcd. In biological sequences, gaps are allowed and an alignment abcd with bd
yields the representation:
abcd
− b − d.
Similarly, an alignment of abcd with buc yields:
ab−cd
− b u c −.
The above implies that gaps can appear both in the text and in the pattern. Therefore there
is no point in distinguishing texts from patterns. Both are called sequences. Notice that, in
the above examples, the alignments maximize matches of identical symbols in both
sequences. Therefore, sequence alignment is an optimization problem. A similar problem
exists when we attempt to automatically correct typing errors like character replacements,
insertions, and deletions. Google and Word, for example, are able to handle some typing
errors and display suggestions for possible corrections. That implies searching a
dictionary for best matches.
7.1.2. Aligning Amino Acids Sequences. The DP algorithm is applicable to any
sequence provided the weights for comparisons and gaps are properly chosen. When
aligning nucleotide sequences the previously mentioned weights yield good results. A
more careful assessment of the weights has to be done when aligning sequences of amino
acids. This is because the comparison between any two amino acids should take evolution
into consideration. Biologists have developed 20×20 triangular matrices that provide the
weights for comparing identical and different amino acids as well as the weight that
should be attributed to gaps. The two more frequently used matrices are known as PAM
(Percent Accepted Mutation) and BLOSUM (Blocks Substitution Matrix). These matrices
reflect the weights obtained by comparing the amino acids substitutions that have
occurred through evolution. They are often called substitution
matrices.

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7.1.3. Complexity Considerations and BLAST. The quadratic complexity of the Dpbased
algorithms renders their usage prohibitive for very large sequences. Recall that the
present genomic database contains about 30 billion base pairs (nucleotides) and
thousands of users accessing that database simultaneously would like to determine if a
sequence being studied and made up of thousands of symbols can be aligned with
existing data. That is a formidable problem! The program called BLAST (Basic Local
Alignment Search Tool) developed by the National Center for Biotechnology Information
(NCBI) has been designed to meet that challenge. The best way to explain the workings
of BLAST is to recall the approach using dot matrices. In BLAST the sequence, whose
presence one wishes to investigate in a huge database, is split into smaller subsequences.
The presence of those subsequences in the database can be determined efficiently (say by
hashing and indexing).

7.2. Phylogenetic Trees

Since evolution plays a key role in biology, it is natural to attempt to depict it

using trees. These are referred to as phylogenetic trees: their leaves represent various
organisms, species, or genomic sequences; an internal node Pstands for an abstract
organism (species, sequence) whose existence is presumed and whose evolution led to
the organisms whose direct descendants are the branches emanating from P. A
motivation for depicting trees is to express—in graphical form—the outcome of multiple
alignments by the relationships that exist between pairs or groups of sequences. These
trees may reveal evolutionary inconsistencies that have to be resolved. In that sense the
construction of phylogenetic validates or invalidates conjectures made about possible
ancestors of a group of organisms.
There are several types of trees used in bioinformatics. Among them, we mention the
following:
(1) Unrooted trees are those that specify distances (differences) between species. The
length of a path between any two leaves represents the accumulated differences.
(2) Cladograms are rooted trees in which the branches’ lengths have no meaning; the
initial example in this section is a cladogram.

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(3) Phylograms are extended cladograms in which the length of a branch quantifies the
number of genetic transformations that occurred between a given node and its immediate
ancestor.
(4) Ultrametric trees are phylograms in which the accumulated distances from the
root to each of the leaves is quantified by the same number; ultrametric trees are therefore
the ones that provide most information about evolutionary changes. They are also the
most difficult to construct. The above definitions suggest establishing some sort of
molecular clock in which mutations occur at some predictable rate and that there exists a
linear relationship between time and number of changes.

7.3. Finding Patterns in Sequences

It is frequently the case in bioinformatics that one wishes to delimit parts of

sequences that have a biological meaning. Typical examples are determining the
locations of promoters, exons, and introns in RNA, that is, gene finding, or detecting the
boundaries of α-helices, β-sheets, and coils in sequences of amino acids. There are
several approaches for performing those tasks. They include neural nets, machine
learning, and grammars, especially variants of grammars called probabilistic In this
subsection, we will deal with two of such approaches. One is using grammars and
parsing. The other, called Hidden Markov Models or HMMs, is a probabilistic variant of
parsing using finite-state grammars. It should be remarked that the recent capabilities of
aligning entire genomes also provides means for gene finding in new genomes: assuming
that all the genes of a genome G1 have been determined, then a comparison with
the genome G2 should reveal likely positions for the genes in G2.
7.3.1. Grammars and Parsing. Chomsky’s language theory is based on grammar rules
used to generate sentences. In that theory, a nonterminal is an identifier naming groups of
contiguous words that may have subgroups identified by other nonterminals. In the
Chomsky hierarchy of grammars and languages, the finite-state (FS) model is the lowest.
In that case, a nonterminal corresponds to a state in a finite-state automaton. In context-
free grammars one can specify a potentially infinite number of states. Context-free
grammars (CFG) allow the description of palindromes or matching parentheses, which

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cannot be described or generated by finite-state models. Higher than the context-free

languages are the so-called contex sensitive ones (CSL). Those can specify repetitions of
sequence of words like ww, where w is any sequence using a vocabulary. These
repetitions cannot be described by CFGs. Parsing is the technique of retracing the
generation of a sentence using the given grammar rules. The complexity of parsing
depends on the language or grammar being considered. Deterministic finite-state models
can be parsed in linear time. The worst case parsing complexity of CF languages is cubic.
Little is known about the complexity of general CS languages but parsing of its strings
can be done in finite time. The parse of sentences in a finite-state language can be
represented by the sequence of states taken by the corresponding finite-state automaton
when it scans the input string. A tree conveniently represents the parse of a sentence in a
context-free language. Finally, one can represent the parse of sentence in a CSL by a
graph. Essentially, an edge of the graph denotes the symbols (or nonterminals) that are
grouped together.
In what follows, we briefly describe the types of patterns that are necessary to detect
genes in DNA.nonterminal G, defined by the rules below, can roughly describe the
syntax of genes:
G → PR
P→N
R → EIR|E
E→N
I → gtNag,
where N denotes a sequence of nucleotides a , c , g , t ; E is an exon, I an intron, R a
sequence of alternating exons and introns and P is a promoter region, that is, a heading
announcing the presence of the gene. In this simplified grammar, the markers gt and ag
are delimiters for introns. Notice that it is possible to transform the above CFG into an
equivalent FSG since there is a regular expression that defines the above language. But
the important remark is that the grammar is highly ambiguous since the markers gt or ag
could appear anywhere within an exon an intron or in a promoter region. Therefore, the
grammar is descriptive but not usable in constructing a parser. The alternation exons-

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introns can be interpreted in many different ways, thus accounting for the fact that a
given gene may generate alternate proteins depending on contexts.
7.3.2. Hidden Markov Models (HMMs). HMMs are widely used in biological sequence
analysis. HMMs can be viewed as variants of probabilistic or stochastic finite-state
transducers (FSTs). In an FST, the automaton changes states according to the input
symbols being examined. On a given state, the automaton also outputs a symbol.
Therefore, FSTs are defined by sets of states, transitions, and input and output
vocabularies. There is as usual an initial state and one or more final states. The automata
that we are dealing with can be and usually are nondeterministic. Therefore, upon
examining a given input symbol, the transition depends on the specified probabilities. An
HMMis a probabilistic FST in which there is also a set of pairs [p, s] associated to each
state; p is a probability and s is a symbol of the output vocabulary. The sum of the p’s in
each set of pairs within a given state also has to equal 1. One can assume that the input
vocabulary for an
HMM consists of a unique dummy symbol (say, the equivalent of an empty
symbol). Actually, in the HMM paradigm, we are solely interested in state transitions and
output symbols. As in the case of finitestate automata, there is an initial state and a final
state. Upon reaching a given state, the HMM automaton produces the output symbol s
with a probability p. The p’s are called emission probabilities. As we described so far, the
HMM behaves as a string generator.

The main usage of HMMs is in the reverse problem: recognition or parsing. Given a
sequence of H’s and T’s, attempt to determine the most likely corresponding state
sequence of F’s and L’s.

7.4. Determining Structure

From the beginning of this article, we reminded the reader of the importance of structure
in biology and its relation to function. In this section, we review some of the approaches
that have been used to determine 3D structure from linear sequences. A particular case of
structure determination is that of RNA, whose structure can be approximated in two
dimensions. Nevertheless, it is known that 3D knot-like structures exist in RNA. This

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section has two subsections. In the first, we cover some approaches available to infer 2D
representations from RNA sequences. In the second, we describe one of the most
challenging problems in biology: the determination of the 3D structure of proteins from
sequences of amino acids. Both problems deal with minimizing energy functions.
7.4.1. RNA Structure. It is very convenient to describe the RNA structure problem in
terms of parsing strings generated by context-free-grammars (CFG). As in the case of
finite-state automata used in HMMs we have to deal with highly ambiguous grammars.
The generated strings can be parsed in multiple ways and one has to choose an optimal
parse based on energy considerations. RNA structure is determined by the attractions
among its nucleotides: A (adenine) attracts U (uracil) and C (cytosine) attracts G
(guanine). These nucleotides will be represented using small case letters. The CFG rules:
S → aSu/uSa/ε
generate palindrome-like sequences of u’s and a’s of even length. One could map this
palindrome to a 2D representation in which each a in the left of the generated string
matches the corresponding u in the right part of the string and viceversa. In this
particular case, the number of matches is maximal. This grammar is nondeterministic
since a parser would not normally know where lies the middle of the string to be parsed.
The grammar becomes highly ambiguous if we introduce a new nonterminal N generating
any sequence of a’s and u’s. S → aSu/uSa/N N→aN/uN/ε. Now the problem becomes
much harder since any string admits a very a large number of parses and we have to
chose among all those parses the one that matches most a’s with u’s and vice versa. The
corresponding 2D representation of that parse is what is called a hairpin loop. An actual
grammar describing RNA should also include the rules specifying the attractions among
c’s and g’s:
S → cSg/gSc/.
7.4.2. Protein Structure. The largest repository of 3D protein structures is the PDB
(Protein Data Base): it records the actual x, y, z coordinates of each atom making up each
of its proteins. That information has been gathered mostly by X-ray crystallography and
NMR techniques. There are very valuable graphical packages (e.g., Rasmol) that can
present the dense information in the PDB in a visually attractive and useful form
allowing the user to observe a protein by rotating it to inspect its details viewed from

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different angles. The outer surface of a protein consists of the amino acids that are
hydrophilic (tolerate well the water media that surrounds the protein). In contrast, the
hydrophobic amino acids usually occupy the protein’s core. The configuration taken by
the protein is one that minimizes the energy of the various attractions and repulsions
among the constituent atoms.

A domain is a portion of the protein that has its own function. Domains are capable of
independently folding into a stable structure. The combination of domains determines the
protein’s function. Protein folding, the determination of protein structure from a given
sequence of amino acids, is one of the most difficult problems in present-day science.
The approaches that have been used to solve it can only handle short sequences and
require the capabilities of the fastest parallel computers available.

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8.APPLICATIONS

Biochips can be mainly classified into two based on the applications:

1. Internal biochips

2. External biochips

Applications of internal biochips are

1. Glucose measurement
2. Brain surgery for Parkinson’s disease
3. Cochlear implant
4. Eye implant
5. Personal identification

Applications of external biochips are

1. lab on a chip
2. mass spectrometry

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8.1 APPLICATION OF INTERNAL BIOCHIPS

1. GLUCOSE MEASUREMENT

Nowadays diabetics measure the level of sugar glucose in their blood by using a
skin prick and a hand held blood test and medicate them with insulin. The disadvantage
of this simple system is that the need to draw blood makes the diabetics not to test the
sugar levels themselves as often as they could.

By using Biochips the measurement can be done in a much simpler way. The
chips are of size less than an uncooked grain of rice can be injected under the skin. It
sense the glucose level and send the result back out by radio frequency communication.

2. BRAIN SURGERY FOR PARKINSON’S DISEASE

Parkinson’s disease is caused by a brain messenger dopamine, which is a product

of dying brain cells. This disease causes uncontrolled movements or tremors on body
parts.
Drug therapy for Parkinson’s disease aims to replace dopamine but the drugs
effect wear off after some time. This causes the erratic movements coming back to the
patients.

Activa implant is a biochip which uses high frequency electrical pulses to

reversibly shut off the thalamus. These chips turn off brain signals that cause the
uncontrolled movements or tremors. The implantation surgery is far simpler. Electrodes
will be entered in to the thalamus region whose extension is connected to the pulse
generator placed near the chest. The pulse generator generates pulses according to the
heart beat of the patient.

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If there are any post operative problems the simulator (pulse generator) can be
simply turned off.

FIG.2. ACTIVA IMPLANT

3. COCHLEAR IMPLANT

Hearing aids used in present days are glorified amplifiers, but the cochlear
implant is for patients who have lost the hair cells that detect sound waves. For these
individuals no amount of amplification is enough.

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Fig.3. cochlear implant

The cochlear implant delivers electrical pulses directly to the nerve cells in the
cochlea, the spiral shaped structure that translates sound into nerve pulses. In normal
hearing individuals, sound wave set up vibrations in the walls of the cochlea, and hair
cells detect these vibrations.

High frequency noises vibrate the base of the cochlea, while low frequency notes
vibrate near the top of the spiral.
The cochlear implant does the job of the hair cells. It splits the frequencies of
incoming noises into a number of channels and then stimulates the appropriate part of
cochlea.
Increasing the number of channels will improve sound perception. But speech is
perceived in an area of the cochlea only 14 mm long and spacing the electrodes to close
to each other causes signals to bleed from one channel to another. This causes a broad
version of hearing.

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4. EYE IMPLANT
Vision occurs as the light reflected from a body is received by photoreceptors, the
light sensing cells at the back of the eye. Blindness occurs if the photoreceptors are lost
in retinitis pigmentosa, a genetic disease and in related macular degeneration.
The chip used in eye implant does the function of photoreceptors. The chip will
be at least ten times smaller than the thickness of the human hair with an area of 1mm2.
There will be a camera mounted on a pair of glasses. The camera will detect and encode
the scene and then send it into the eye as a laser pulse. The laser will also provide the
energy to drive the chip. The energy required for stimulating a nerve cell in the eye is
almost 100 times lower than that required in stimulating a nerve cell in an ear.

Fig.4. size of a chip implanted in eye (compared with a penny)

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5. PERSON IDENTIFICATION

Biochips when implanted into human body can have an identification number,
and all the details about that person. This can help agencies to locate lost children,
soldiers and Alzheimer’s patient. Biochips are widely used in identification of criminals
and terrorists in America.

8.2 APPLICATIONS OF EXTERNAL CHIPS

1. LAB ON A CHIP
Biochips scan, process biological data very rapidly. The technology is commonly
known as ‘lab on a chip’. The idea of a cheap and reliable computer chip look alike that
performs thousands of biological reactions is very attractive to drug developers. Because
these chips automate highly repetitive laboratory tasks by replacing cumbersome
equipment with miniaturized micro fluidic assay chemistries. Biochips are able to
provide ultrasonic detection methodologies at significantly lower costs per assay than
traditional and also amount of space.

Applications of lab on a chip are basically two

 For the detection of mutations in specific genes as diagnostic “markers” on the
onset of a particular disease. E.g.: HIV gene chip
 To detect the differences in gene expression levels in cells those are diseased
versus those that are healthy.
E.g.: cancer studies

2. MASS SPECTROMETRY
Mass spectrometry determines molecular structures from ionized samples of
materials. Biochips can be used to perform mass spectrometry and researches are going in
that area. This can help in saving much space and time in laboratories

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Gene chip will be able to screen diseases like heart attack and diabetics years
before patients develop symptoms. These will help doctors diagnose life-threatening
illness faster, eliminating expensive, time-consuming ordeals like biopsies and
sigmoidoscopies, or simple blood, saliva, stool, or urine tests. Gene chips reclassify
diseases based on their underlying molecular signals, rather than misleading surface
symptoms.

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9. FUTURE DEVELOPMENT

Researchers are working on Bioinformatics that will perform fundamental body

changes apart from customizing looks of the people. If you aren’t born perfect, any
disease and deformity, you need not despair. Because rapid advances in bioinformatics
are providing new hopes to such patients. Researchers are going on in the field of`
biological computers’ hybrid machine like science fiction cyborg which would blend
organics and electronics in a single machine. The information processing and storage
capabilities of organic molecules are far more superior than the devices that human have
been able to create out of silicon.

A few specific areas that fall within the scope of bioinformatics are as follows:

1.Sequence assembly –

The genome of an organisation is assembled from thousands of fragments, which

must be correctly 'switched' together. this process requires sophisticated computer- based
methods and is carred out by bioinformatics specialists.

2.Sequence (gene) analysis –

Once the DNA sequence of a fragment of the genome is determined, the next step
is the understanding of the function of the gene. This involves various analyses, which
are carried out by high- powered computing and specialised software. Many would
concider this activity as the most important area of focus within bioinformatics.

3.Proteomics –

A relatively new area, proteomics studies not the entire genome, but the portion of
the genome that is expressed in particular cells. This involves the collections between

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patterns of expression of the genes and a particular disease state to determine likely
targets for drug and/or gene therapy. Bioinformatics specialists work closely with
scientists to accomplish the same.
4.Pharmacogenomics –

Alterations in the genome at specific positions can be associated with particular

disease states, reduced or increased sensitivity to particular drugs, or with side effects to
those medications. Such databases are rapidly evolving, and are likely to play an
important role in the future drug development efforts and in the design of clinical trails.
Bioinformatics experts are at the forefront to collect, analyse and apply this crucial data.

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10. CONCLUSION

Days aren't far off when beauty saloons will perform fundamental body changes
apart from customizing looks of the people. If you aren't born perfect, free from any
diseases and deformity, you need not despair. Rapid advances in bioinformatics are
providing new hopes to such patients. At the first sign of physical defect or deformity,
people will shop around for a better and stronger organically grown heart, brain, or
kidney, as the case may be. With bioinformatics man kind will be able to prolong its life
or , even live forever.

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11.REFERENCES

Websites

www.electronicsforu.com

www.inbios.org

www.bioinformatics.org

www.biochip.org

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