Bioinformatics

Tina Elizabeth Varghese

S1 MBA IB,
Roll No. 30,
School of Management Studies,
CUSAT, Kochi- 22.
E-mail: [email protected]

Abstract: Bioinformatics is the application of computer technology to the

management of biological information. Computers are used to gather,
store, analyze and integrate biological and genetic information which
can then be applied to gene-based drug discovery and development.
The need for Bioinformatics capabilities has been precipitated by the
explosion of publicly available genomic information resulting from the
Human Genome Project. The goal of this project - determination of the
sequence of the entire human genome (approximately three billion base
pairs) - will be reached by the year 2002. 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 for drug
discovery.

Keywords: DNA, mRNA, HT, MS, annotation, BLAST, NCBI, EBI,

BSA, MSA.

1.0 INTRODUCTION

1.1 General Information

Bioinformatics is the application of information technology to the field of molecular

biology. The term bioinformatics was coined by Paulien Hogeweg in 1979 for the
study of informatic processes in biotic systems. Bioinformatics now entails the

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creation and advancement of databases, algorithms, computational and statistical
techniques, and theory to solve formal and ractical problems arising from the
management and analysis of biological data. Over the past few decades rapid
developments in genomic and other molecular research technologies and
developments in information technologies have combined to produce a tremendous
amount of information related to molecular biology. It is the name given to these
mathematical and computing approaches used to glean understanding of biological
processes. Common activities in bioinformatics include mapping and analyzing DNA
and protein sequences, aligning different DNA and protein sequences to compare
them and creating and viewing 3-D models of protein structures.

The primary goal of bioinformatics is to increase our understanding of biological

processes. What sets it apart from other approaches, however, is its focus on
developing and applying computationally intensive techniques (e.g., pattern
recognition, data mining, machine learning algorithms, and visualization) to achieve
this goal. Major research efforts in the field include sequence alignment, gene finding,
genome assembly, protein structure alignment, protein structure prediction, prediction
of gene expression and protein-protein interactions, genome-wide association studies
and the modeling of evolution.

Bioinformatics was applied in the creation and maintenance of a database to store

biological information at the beginning of the "genomic revolution", such as nucleotide
and amino acid sequences. Development of this type of database involved not only
design issues but the development of complex interfaces whereby researchers could
both access existing data as well as submit new or revised data.

In order to study how normal cellular activities are altered in different disease states,
the biological data must be combined to form a comprehensive picture of these
activities. Therefore, the field of bioinformatics has evolved such that the most
pressing task now involves the analysis and interpretation of various types of data,
including nucleotide and amino acid sequences, protein domains, and protein
structures. The actual process of analyzing and interpreting data is referred to as
computational biology. Important sub-disciplines within bioinformatics and
computational biology include:

a) The development and implementation of tools that enable efficient access to, and
use and management of, various types of information.

b) The development of new algorithms (mathematical formulas) and statistics with

which to assess relationships among members of large data sets, such as
methods to locate a gene within a sequence, predict protein structure and/or
function, and cluster protein sequences into families of related sequences.

2.0 SEQUENCE ANALYSIS

Since the Phage Φ-X174 was sequenced in 1977, the DNA sequences of hundreds of
organisms have been decoded and stored in databases. The information is analyzed
to determine genes that encode polypeptides, as well as regulatory sequences. A
comparison of genes within a species or between different species can show
similarities between protein functions, or relations between species (the use of
molecular systematics to construct phylogenetic trees). With the growing amount of

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data, it long ago became impractical to analyze DNA sequences manually. Today,
computer programs are used to search the genome of thousands of organisms,
containing billions of nucleotides. These programs would compensate for mutations
(exchanged, deleted or inserted bases) in the DNA sequence, in order to identify
sequences that are related, but not identical. A variant of this sequence alignment is
used in the sequencing process itself. The so-called shotgun sequencing technique
(which was used, for example, by The Institute for Genomic Research to sequence
the first bacterial genome, Haemophilus influenzae) does not give a sequential list of
nucleotides, but instead the sequences of thousands of small DNA fragments (each
about 600-800 nucleotides long). The ends of these fragments overlap and, when
aligned in the right way, make up the complete genome. Shotgun sequencing yields
sequence data quickly, but the task of assembling the fragments can be quite
complicated for larger genomes. In the case of the Human Genome Project, it took
several days of CPU time (on one hundred Pentium III desktop machines clustered
specifically for the purpose) to assemble the fragments. Shotgun sequencing is the
method of choice for virtually all genomes sequenced today, and genome assembly
algorithms are a critical area of bioinformatics research.

Another aspect of bioinformatics in sequence analysis is the automatic search for

genes and regulatory sequences within a genome. Not all of the nucleotides within a
genome are genes. Within the genome of higher organisms, large parts of the DNA
do not serve any obvious purpose. This so-called junk DNA may, however, contain
unrecognized functional elements. Bioinformatics helps to bridge the gap between
genome and proteome projects--for example, in the use of DNA sequences for protein
identification.

3.0 GENOME ANNOTATION

In the context of genomics, annotation is the process of marking the genes and other
biological features in a DNA sequence. The first genome annotation software system
was designed in 1995 by Dr. Owen White, who was part of the team that sequenced
and analyzed the first genome of a free-living organism to be decoded, the bacterium
Haemophilus influenzae. Dr. White built a software system to find the genes (places in
the DNA sequence that encode a protein), the transfer RNA, and other features, and
to make initial assignments of function to those genes. Most current genome
annotation systems work similarly, but the programs available for analysis of genomic
DNA are constantly changing and improving.

3.0 COMPUTATIONAL EVOLUTIONARY BIOLOGY

Evolutionary biology is the study of the origin and descent of species, as well as their
change over time. Informatics has assisted evolutionary biologists in several key
ways; it has enabled researchers to:

• trace the evolution of a large number of organisms by measuring changes in their

DNA, rather than through physical taxonomy or physiological observations alone,

• more recently, compare entire genomes, which permits the study of more
complex evolutionary events, such as gene duplication, horizontal gene transfer, and
the prediction of factors important in bacterial speciation,

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• build complex computational models of populations to predict the outcome of the
system over time

• track and share information on an increasingly large number of species and

organisms

Future work endeavours to reconstruct the now more complex tree of life.
The area of research within computer science that uses genetic algorithms is
sometimes confused with computational evolutionary biology, but the two areas are
unrelated.

4.0 BIODIVERSITY

Biodiversity of an ecosystem might be defined as the total genomic complement of a

particular environment, from all of the species present, whether it is a biofilm in an
abandoned mine, a drop of sea water, a scoop of soil, or the entire biosphere of the
planet Earth. Databases are used to collect the species names, descriptions,
distributions, genetic information, status and size of populations, habitat needs, and
how each organism interacts with other species. Specialized software programs are
used to find, visualize, and analyze the information, and most importantly,
communicate it to other people. Computer simulations model such things as
population dynamics, or calculate the cumulative genetic health of a breeding pool (in
agriculture) or endangered population (in conservation). One very exciting potential of
this field is that entire DNA sequences, or genomes of endangered species can be
preserved, allowing the results of Nature's genetic experiment to be remembered in
silico, and possibly reused in the future, even if that species is eventually lost

5.0 ANALYSIS OF GENE EXPRESSION

The expression of many genes can be determined by measuring mRNA levels with
multiple techniques including microarrays, expressed cDNA sequence tag (EST)
sequencing, serial analysis of gene expression (SAGE) tag sequencing, massively
parallel signature sequencing (MPSS), or various applications of multiplexed in-situ
hybridization. All of these techniques are extremely noise-prone and/or subject to bias
in the biological measurement, and a major research area in computational biology
involves developing statistical tools to separate signal from noise in high-throughput
gene expression studies. Such studies are often used to determine the genes
implicated in a disorder: one might compare microarray data from cancerous epithelial
cells to data from non-cancerous cells to determine the transcripts that are up-
regulated and down-regulated in a particular population of cancer cells

6.0 ANALYSIS OF REGULATION ANALYSIS OF EXPRESSION

Regulation is the complex orchestration of events starting with an extracellular signal

such as a hormone and leading to an increase or decrease in the activity of one or
more proteins. Bioinformatics techniques have been applied to explore various steps
in this process. For example, promoter analysis involves the identification and study of
sequence motifs in the DNA surrounding the coding region of a gene. These motifs
influence the extent to which that region is transcribed into mRNA. Expression data

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can be used to infer gene regulation: one might compare microarray data from a wide
variety of states of an organism to form hypotheses about the genes involved in each
state. In a single-cell organism, one might compare stages of the cell cycle, along with
various stress conditions (heat shock, starvation, etc.). One can then apply clustering
algorithms to that expression data to determine which genes are co-expressed. For
example, the upstream regions (promoters) of co-expressed genes can be searched
for over-represented regulatory elements.

7.0 ANALYSIS OF PROTEIN EXPRESSION

Protein microarrays and high throughput (HT) mass spectrometry (MS) can provide a
snapshot of the proteins present in a biological sample. Bioinformatics is very much
involved in making sense of protein microarray and HT MS data; the former approach
faces similar problems as with microarrays targeted at mRNA, the latter involves the
problem of matching large amounts of mass data against predicted masses from
protein sequence databases, and the complicated statistical analysis of samples
where multiple, but incomplete peptides from each protein are detected.

8.0 ANALYSIS OF MUTATIONS IN CANCER

In cancer, the genomes of affected cells are rearranged in complex or even

unpredictable ways. Massive sequencing efforts are used to identify previously
unknown point mutations in a variety of genes in cancer. Bioinformaticians continue to
produce specialized automated systems to manage the sheer volume of sequence
data produced, and they create new algorithms and software to compare the
sequencing results to the growing collection of human genome sequences and
germline polymorphisms. New physical detection technology are employed, such as
oligonucleotide microarrays to identify chromosomal gains and losses (called
comparative genomic hybridization), and single nucleotide polymorphism arrays to
detect known point mutations. These detection methods simultaneously measure
several hundred thousand sites throughout the genome, and when used in high-
throughput to measure thousands of samples, generate terabytes of data per
experiment. Again the massive amounts and new types of data generate new
opportunities for bioinformaticians. The data is often found to contain considerable
variability, or noise, and thus Hidden Markov model and change-point analysis
methods are being developed to infer real copy number changes.
Another type of data that requires novel informatics development is the analysis of
lesions found to be recurrent among many tumors.

9.0 PREDICTION OF PROTEIN STRUCTURE

Protein structure prediction is another important application of bioinformatics. The

amino acid sequence of a protein, the so-called primary structure, can be easily
determined from the sequence on the gene that codes for it. In the vast majority of
cases, this primary structure uniquely determines a structure in its native environment.
(Of course, there are exceptions, such as the bovine spongiform encephalopathy -
aka Mad Cow Disease - prion.) Knowledge of this structure is vital in understanding
the function of the protein. For lack of better terms, structural information is usually
classified as one of secondary, tertiary and quaternary structure. A viable general

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solution to such predictions remains an open problem. As of now, most efforts have
been directed towards heuristics that work most of the time.
One of the key ideas in bioinformatics is the notion of homology. In the genomic
branch of bioinformatics, homology is used to predict the function of a gene: if the
sequence of gene A, whose function is known, is homologous to the sequence of
gene B, whose function is unknown, one could infer that B may share A's function. In
the structural branch of bioinformatics, homology is used to determine which parts of
a protein are important in structure formation and interaction with other proteins. In a
technique called homology modeling, this information is used to predict the structure
of a protein once the structure of a homologous protein is known. This currently
remains the only way to predict protein structures reliably.

One example of this is the similar protein homology between hemoglobin in humans
and the hemoglobin in legumes (leghemoglobin). Both serve the same purpose of
transporting oxygen in the organism. Though both of these proteins have completely
different amino acid sequences, their protein structures are virtually identical, which
reflects their near identical purposes.

Other techniques for predicting protein structure include protein threading and de
novo (from scratch) physics-based modeling.

10.0 COMPARATIVE GENOMICS

The core of comparative genome analysis is the establishment of the correspondence

between genes (orthology analysis) or other genomic features in different organisms.
It is these intergenomic maps that make it possible to trace the evolutionary
processes responsible for the divergence of two genomes. A multitude of evolutionary
events acting at various organizational levels shape genome evolution. At the lowest
level, point mutations affect individual nucleotides. At a higher level, large
chromosomal segments undergo duplication, lateral transfer, inversion, transposition,
deletion and insertion. Ultimately, whole genomes are involved in processes of
hybridization, polyploidization and endosymbiosis, often leading to rapid speciation.
The complexity of genome evolution poses many exciting challenges to developers of
mathematical models and algorithms, who have recourse to a spectra of algorithmic,
statistical and mathematical techniques, ranging from exact, heuristics, fixed
parameter and approximation algorithms for problems based on parsimony models to
Markov Chain Monte Carlo algorithms for Bayesian analysis of problems based on
probabilistic models.

Many of these studies are based on the homology detection and protein families
computation.

11.0 MODELING BIOLOGICAL SYSTEM

Systems biology involves the use of computer simulations of cellular subsystems

(such as the networks of metabolites and enzymes which comprise metabolism,
signal transduction pathways and gene regulatory networks) to both analyze and
visualize the complex connections of these cellular processes. Artificial life or virtual
evolution attempts to understand evolutionary processes via the computer simulation
of simple (artificial) life forms.

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12.0 HIGH-THROUGHPUT IMAGE ANALYSIS

Computational technologies are used to accelerate or fully automate the processing,

quantification and analysis of large amounts of high-information-content biomedical
imagery. Modern image analysis systems augment an observer's ability to make
measurements from a large or complex set of images, by improving accuracy,
objectivity, or speed. A fully developed analysis system may completely replace the
observer. Although these systems are not unique to biomedical imagery, biomedical
imaging is becoming more important for both diagnostics and research. Some
examples are:
• high-throughput and high-fidelity quantification and sub-cellular localization (high-
content screening, cytohistopathology)
• morphometrics
• clinical image analysis and visualization
• determining the real-time air-flow patterns in breathing lungs of living animals
• quantifying occlusion size in real-time imagery from the development of and
recovery during arterial injury
• making behavioral observations from extended video recordings of laboratory
animals
• infrared measurements for metabolic activity determination
• inferring clone overlaps in DNA mapping, e.g. the Sulston score

12.0 PROTEIN-PROTEIN DOCKING

In the last two decades, tens of thousands of protein three-dimensional structures

have been determined by X-ray crystallography and Protein nuclear magnetic
resonance spectroscopy (protein NMR). One central question for the biological
scientist is whether it is practical to predict possible protein-protein interactions only
based on these 3D shapes, without doing protein-protein interaction experiments. A
variety of methods have been developed to tackle the Protein-protein docking
problem, though it seems that there is still much work to be done in this field.

13.0 SOFTWARE AND TOOLS

Software tools for bioinformatics range from simple command-line tools, to more
complex graphical programs and standalone web-services available from various
bioinformatics companies or public institutions. The computational biology tool best-
known among biologists is probably BLAST, an algorithm for determining the similarity
of arbitrary sequences against other sequences, possibly from curated databases of
protein or DNA sequences. BLAST is one of a number of generally available
programs for doing sequence alignment. The NCBI provides a popular web-based
implementation that searches their databases.

14.0 WEB SERVICES IN BIOINFORMATICS

SOAP and REST-based interfaces have been developed for a wide variety of
bioinformatics applications allowing an application running on one computer in one
part of the world to use algorithms, data and computing resources on servers in other

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parts of the world. The main advantages lay in the end user not having to deal with
software and database maintenance overheads. Basic bioinformatics services are
classified by the EBI into three categories: SSS (Sequence Search Services), MSA
(Multiple Sequence Alignment) and BSA (Biological Sequence Analysis). The
availability of these service-oriented bioinformatics resources demonstrate the
applicability of web based bioinformatics solutions, and range from a collection of
standalone tools with a common data format under a single, standalone or web-based
interface, to integrative, distributed and extensible bioinformatics workflow
management systems.

15.0 REFERENCES

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