BIOINFORMATICS INTRODUCTION

Bioinformatics is the application of computer science and information technology to the field
of biology.

The primary goal of bioinformatics is to increase the 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, drug design, drug discovery, protein structure alignment, protein structure prediction,
prediction of gene expression and protein–protein interactions, genome-wide association
studies and the modeling of evolution.

The term bioinformatics was coined by Paulien Hogeweg and Ben Hesper in 1978 for the study
of informatics processes in biotic systems. Its primary use since at least the late 1980s has been
in genomics and genetics, particularly in those areas of genomics involving large-scale DNA
sequencing.

Bioinformatics now entails the creation and advancement of databases, algorithms,

computational and statistical techniques and theory to solve formal and practical 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.
Introduction

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:

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

There are two fundamental ways of modelling a Biological system (e.g. living cell) both coming
under Bioinformatic approaches.

Static
Sequences – Proteins, Nucleic acids and Peptides
Structures – Proteins, Nucleic acids, Ligands (including metabolites and drugs) and
Peptides
Interaction data among the above entities including microarray data and Networks of
proteins, metabolites
 Dynamic
Systems Biology comes under this category including reaction fluxes and variable
concentrations of metabolites
Multi-Agent Based modelling approaches capturing cellular events such as signalling,
transcription and reaction dynamics

A broad sub-category under bioinformatics is structural bioinformatics.

Major research areas

Sequence analysis

Since the Phage -X174 was sequenced in 1977, the DNA sequences of thousands of organisms
have been decoded and stored in databases. This sequence information is analyzed to determine
genes that encode polypeptides (proteins), RNA genes, regulatory sequences, structural motifs,
and repetitive 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 data, it
long ago became impractical to analyze DNA sequences manually.

Today, computer programs such as BLAST are used daily to search sequences from more than
260 000 organisms, containing over 190 billion nucleotides. These programs can compensate for
mutations (exchanged, deleted or inserted bases) in the DNA sequence, 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 produce entire chromosomes, but instead generates the sequences of many
thousands of small DNA fragments (ranging from 35 to 900 nucleotides long, depending on the
sequencing technology).

The ends of these fragments overlap and, when aligned properly by a genome assembly program,
can be used to reconstruct the complete genome. Shotgun sequencing yields sequence data
quickly, but the task of assembling the fragments can be quite complicated for larger genomes.
For a genome as large as the human genome, it may take many days of CPU time on large-
memory, multiprocessor computers to assemble the fragments, and the resulting assembly will
usually contain numerous gaps that have to be filled in later. 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 annotation, which involves

computational gene finding to search for protein-coding genes, RNA genes, and other functional
sequences within a genome. Not all of the nucleotides within a genome are part of 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.

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 at The Institute for Genomic Research 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.

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,
 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 not necessarily related.

Literature analysis

The growth in the number of published literature makes it virtually impossible to read every
paper, resulting in disjointed subfields of research. Literature analysis aims to employ
computational and statistical linguistics to mine this growing library of text resources. For
example:

abbreviation recognition - identify the long-form and abbreviation of biological terms,

named entity recognition - recognizing biological terms such as gene names
protein-protein interaction - identify which proteins interact with which proteins from text

The area of research uses statistics and computational linguistics, and is substantially influenced
by them.

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), RNA-Seq, also known as "Whole Transcriptome Shotgun Sequencing"
(WTSS), 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.
Analysis of regulation

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 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.

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.

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 technologies 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.

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 family’s computation.

Modeling biological systems

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.
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 bothdiagnostics and
research. Some examples are:

high-throughput and high-fidelity quantification and sub-cellular localization (high-content

screening, cytohistopathology, Bioimage informatics)
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
Structural Bioinformatic Approaches

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 – a.k.a. 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 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.

Molecular Interaction

Efficient software is available today for studying interactions among proteins, ligands and
peptides. Types of interactions most often encountered in the field include – Protein–ligand
(including drug), protein–protein and protein–peptide.

Molecular dynamic simulation of movement of atoms about rotatable bonds is the fundamental
principle behind computational algorithms, termed docking algorithms for studying molecular
interactions.

Docking algorithms

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
doingprotein–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.
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.

Open source bioinformatics software

Many free and open source software tools have existed and continued to grow since the
1980s.[6] The combination of a continued need for new algorithms for the analysis of emerging
types of biological readouts, the potential for innovative in silico experiments, and freely
available open code bases have helped to create opportunities for all research groups to
contribute to both bioinformatics and the range of open source software available, regardless of
their funding arrangements. The open source tools often act as incubators of ideas, or
community-supported plug-ins in commercial applications. They may also provide de
facto standards and shared object models for assisting with the challenge of bioinformation
integration. The range of open source software packages includes titles such
as Bioconductor, BioPerl, BioJava, Bioclipse, EMBOSS, Taverna workbench, and UGENE. In
order to maintain this tradition and create further opportunities, the non-profit Open
Bioinformatics Foundation has supported the annual Bioinformatics Open Source Conference
(BOSC) since 2000.[7]

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 parts of the world. The main
advantages derive from the fact that end users do not have 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.