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BIO-INFORMATICS
Abstract:
Bio-informatics is the field of science in which biology, computer science,
and information technology merge to form a single discipline. The ultimate goal of the
field is to enable the discovery of new biological insights as well as to create a global
perspective from which unifying principles in biology can be discerned. At the beginning
of the "genomic revolution," a bioinformatics concern was the creation and maintenance
of a database to store biological information, 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.
Ultimately, however, all of this information must be combined to form a
comprehensive picture of normal cellular activities so that researchers may study how
these activities are altered in different disease states. 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:
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 The development and implementation of tools that enable efficient access to, and
use and management of, various types of information; and
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
BIO-INFORMATICS
The collection, storage, and analysis of biochemical and biological
information using computers especially as applied in molecular genetics and
genomics.
In last the few decades, advances in molecular biology and the equipment
available for research in this field have allowed the increasingly rapid sequencing of large
portions of the genomes of several species. In fact, to date, several bacterial genomes, as
well as those of some simple eucalypts (e.g., Saccharomyces cerevisiae, or baker's yeast)
have been sequenced in full. The Human Genome Project, designed to sequence all 24 of
the human chromosomes, is also progressing. Popular sequence databases, such as
GenBank and EMBL, have been growing at exponential rates. This deluge of information
has necessitated the careful storage, organization and indexing of sequence information.
Information science has been applied to biology to produce the field called
Bioinformatics.
The simplest tasks used in bioinformatics concern the creation and maintenance of
databases of biological information. Nucleic acid sequences (and the protein sequences
derived from them) comprise the majority of such databases. While the storage and or
ganization of millions of nucleotides is far from trivial, designing a database and
developing an interface whereby researchers can both access existing information and
submit new entries is only the beginning.
The most pressing tasks in bioinformatics involve the analysis of sequence information.
Computational Biology is the name given to this process, and it involves the following:
 Finding the genes in the DNA sequences of various organisms
 Developing methods to predict the structure and/or function of newly
discovered proteins and structural RNA sequences.
 Clustering protein sequences into families of related sequences and the
development of protein models.
 Aligning similar proteins and generating phylogenetic trees to examine
evolutionary relationships.
The process of evolution has produced DNA sequences that encode proteins with very
specific functions. It is possible to predict the three-dimensional structure of a protein
using algorithms that have been derived from our knowledge of physics, chemistry and
most importantly, from the analysis of other proteins with similar amino acid sequences.
The diagram below summarizes the process by which DNA sequences are used to model
protein structure. The processes involved in this transformation are detailed in the pages
that follow.
Analysis of EST-driven gene annotation in human genomic
sequence
A systematic analysis of gene identification in genomic sequence is performed by
similarity search against expressed sequence tags (ESTs) to assess the suitability
of this method for automated annotation of the human genome. A BLAST-based
strategy was constructed to examine the potential of this approach, and was
applied to test sets containing all human genomic sequences longer than 5 kb in
public databases, plus 300 kb of exhaustively characterized benchmark sequence.
At high stringency, 70%-90% of all annotated genes are detected by near-identity
to EST sequence; >95% of ESTs aligning with well-annotated sequences overlap
a gene. These ESTs provide immediate access to the corresponding cDNA clones
for follow-up laboratory verification and subsequent biologic analysis. At lower
stringency, up to 97% of annotated genes were identified by similarity to ESTs.
The apparent false-positive rate rose to 55% of ESTs among all sequences and
20% among benchmark sequences at the lowest stringency, indicating that many
genes in public database entries are unannotated. Approximately half of the
alignments span multiple exons, and thus aid in the construction of gene
predictions and elucidation of alternative splicing. In addition, ESTs from
multiple cDNA libraries frequently cluster over genes, providing a starting point
for crude expression profiles. Clone IDs may be used to form EST pairs, and
particularly to extend models by associating alignments of lower stringency with
high-quality alignments. These results demonstrate that EST similarity search is a
practical general-purpose annotation technique.
A comparison of expressed sequence tags (ESTs) to human
genomic sequences.
The Expressed Sequence Tags (ESTs) are short, single pass cDNA
sequences generated from randomly selected library clones. The approximately
415 000 human ESTs represent a valuable, low priced, and easily accessible
biological reagent.
As many ESTs are derived from yet uncharacterized genes, dbEST is a prime
starting point for the identification of novel mRNAs. Conversely, other genes are
represented by hundreds of ESTs, a redundancy which may provide data about
rare mRNA isoforms. Here we present an analysis of >1000 ESTs generated by
the WashU-Merck EST project. These ESTs were collected by querying dbEST
with the genomic sequences of 15 human genes. When we aligned the matching
ESTs to the genomic sequences, we found that in one gene, 73% of the ESTs
which derive from spliced or partially spliced transcripts either contain intron
sequences or are spliced at previously unreported sites; other genes have lower
percentages of such ESTs, and some have none. This finding suggests that ESTs
could provide researchers with novel information about alternative splicing in
certain genes. In a related analysis of pairs of ESTs which are reported to derive
from a single gene, we found that as many as 26% of the pairs do not BOTH align
with the sequence of the same gene. We suspect that some of these unusual ESTs
result from artifacts in EST generation, and caution researchers that they may find
such clones while analyzing sequences in dbEST
Protein sequence similarity searches using patterns as seeds.
Protein families often are characterized by conserved sequence patterns or
motifs. A researcher frequently wishes to evaluate the significance of a specific pattern
within a protein, or to exploit knowledge of known motifs to aid the recognition of
greatly diverged but homologous family members. To assist in these efforts, the pattern-
hit initiated BLAST (PHI-BLAST) program described here takes as input both a protein
sequence and a pattern of interest that it contains. PHI-BLAST searches a protein
database for other instances of the input pattern, and uses those found as seeds for the
construction of local alignments to the query sequence. The random distribution of PHI-
BLAST alignment scores is studied analytically and empirically. In many instances, the
program is able to detect statistically significant similarity between homologous proteins
that are not recognizably related using traditional single-pass database search methods.
PHI-BLAST is applied to the analysis of CED4-like cell death regulators, HS90-type
ATPase domains, archaeal tRNA nucleotidyltransferases and archaeal homologs of
DnaG-type DNA primases.
A New Algorithm for RNA Secondary Structure Design
The function of many RNAs depends crucially on their structure. Therefore, the design of
RNA molecules with specific structural properties has many potential applications, e.g. in
the context of investigating the function of biological RNAs, of creating new ribozymes,
or of designing artificial RNA nanostructures. Here, we present a new algorithm for
solving the following RNA secondary structure design problem: given a secondary
structure, find an RNA sequence (if any) that is predicted to fold to that structure. Unlike
the (pseudoknot-free) secondary structure prediction problem, this problem appears to be
hard computationally. Our new algorithm, "RNA Secondary Structure Designer (RNA-
SSD)", is based on stochastic local search, a prominent general approach for solving hard
combinatorial problems. A thorough empirical evaluation on computationally predicted
structures of biological sequences and artificially generated RNA structures as well as on
empirically modelled structures from the biological literature shows that RNA-SSD
substantially outperforms the best known algorithm for this problem, RNAinverse from
the Vienna RNA Package. In particular, the new algorithm is able to solve structures,
consistently, for which RNAinverse is unable to find solutions.
Searching for Genes
The collecting, organizing and indexing of sequence information into a database, a
challenging task in itself, provides the scientist with a wealth of information, albeit of
limited use. The power of a database comes not from the collection of information, but in
its analysis. A sequence of DNA does not necessarily constitute a gene. It may constitute
only a fragment of a gene or alternatively, it may contain several genes.
Luckily, in agreement with evolutionary principles, scientific research to date has shown
that all genes share common elements. For many genetic elements, it has been possible to
construct consensus sequences, those sequences best representing the norm for a given
class of organisms (e.g, bacteria, eukaroytes). Common genetic elements include
promoters, enhancers, polyadenylation signal sequences and protein binding sites. These
elements have also been further characterized into further subelements.
Genetic elements share common sequences, and it is this fact that allows mathematical
algorithms to be applied to the analysis of sequence data. A computer program for
finding genes will contain at least the following elements.
The Challenge of Protein Modelling
There are a myriad of steps following the location of a gene locus to the realization of a
three-dimensional model of the protein that it encodes.
1.,Location of Transcription Start/Stop
A proper analysis to locate a genetic locus will usually have already pinpointed at least
the approximate sites of the transcriptional start and stop. Such an analysis is usually
sufficient in determining protein structure. It is the start and end codons for translation
that must be determined with accuracy.
2.Location of Translation Start/Stop
The first codon in a messenger RNA sequence is almost always AUG. While this reduces
the number of candidate codons, the reading frame of the sequence must also be taken
into consideration.
There are six reading frames possible for a given DNA sequence, three on each strand,
that must be considered, unless further information is available. Since genes are usually
transcribed away from their promoters, the definitive location of this element can reduce
the number of possible frames to three. There is not a strong concensus between different
species surrounding translation start codons. Therefore, location of the appropriate start
codon will include a frame in which they are not apparent abrupt stop codons.
Knowledge of a proteinÕs predicted molecular mass can assist this analysis. Incorrect
reading frames usually predict relatively short peptide sequences. Therefore, it might
seem deceptively simple to ascertain the correct frame. In bacteria, such is frequently the
case. However, eukaryotes add a new obstacle to this process: INTRONS!
3.Detection of Intron/Exon Splice Sites
In eukaryotes, the reading frame is discontinuous at the level of the DNA because of the
presence of introns. Unless one is working with a cDNA sequence in analysis, these
introns must be spliced out and the exons joined to give the sequence that actually codes
for the protein.
Intron/exon splice sites can be predicted on the basis of their common features. Most
introns begin with the nucleotides GT and end with the nucleotides AG. There is a branch
sequence near the downstream end of each intron involved in the splicing event. There is
a moderate concensus around this branch site.
4.3-D Structure modelling
With the completed primary amino acid sequence in hand, the challenge of modelling the
three-dimensional structure of the protein awaits. This process uses a wide range of data
and CPU-intensive computer analysis. Most often, one is only able to obtain a rough
model of the protein, and several conformations of the protein may exist that are equally
probable.
Importance of bio-informatics
The rationale for applying computational approaches to facilitate the understanding of
various biological processes includes:
 a more global perspective in experimental design; and
 the ability to capitalize on the emerging technology of database-mining--the
process by which testable hypotheses are generated regarding the function or
structure of a gene or protein of interest by identifying similar sequences in better
characterized organisms.

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Bio-informatics is the field of science in which biology, computer science,

of a database to store biological information, such as nucleotide and amino acid

as well as submit new or revised data.

Ultimately, however, all of this information must be combined to form a

interpreting data is referred to as computational biology. Important sub-disciplines within

bioinformatics and computational biology include:

use and management of, various types of information; and

The development of new algorithms (mathematical formulas) and

information using computers especially as applied in molecular genetics and

the human chromosomes, is also progressing. Popular sequence databases, such as

ganization of millions of nucleotides is far from trivial, designing a database and

submit new entries is only the beginning.

 Finding the genes in the DNA sequences of various organisms

 Developing methods to predict the structure and/or function of newly

discovered proteins and structural RNA sequences.

 Clustering protein sequences into families of related sequences and the

development of protein models.

 Aligning similar proteins and generating phylogenetic trees to examine

specific functions. It is possible to predict the three-dimensional structure of a protein

Analysis of EST-driven gene annotation in human genomic

A systematic analysis of gene identification in genomic sequence is performed by

of this method for automated annotation of the human genome. A BLAST-based

public databases, plus 300 kb of exhaustively characterized benchmark sequence.

At high stringency, 70%-90% of all annotated genes are detected by near-identity

to EST sequence; >95% of ESTs aligning with well-annotated sequences overlap

for follow-up laboratory verification and subsequent biologic analysis. At lower

stringency, up to 97% of annotated genes were identified by similarity to ESTs.

genes in public database entries are unannotated. Approximately half of the

predictions and elucidation of alternative splicing. In addition, ESTs from

particularly to extend models by associating alignments of lower stringency with

high-quality alignments. These results demonstrate that EST similarity search is a

practical general-purpose annotation technique.

A comparison of expressed sequence tags (ESTs) to human

sequences generated from randomly selected library clones. The approximately

represented by hundreds of ESTs, a redundancy which may provide data about

rare mRNA isoforms. Here we present an analysis of >1000 ESTs generated by

could provide researchers with novel information about alternative splicing in

such clones while analyzing sequences in dbEST

Protein sequence similarity searches using patterns as seeds.

Protein families often are characterized by conserved sequence patterns or

motifs. A researcher frequently wishes to evaluate the significance of a specific pattern

within a protein, or to exploit knowledge of known motifs to aid the recognition of

sequence and a pattern of interest that it contains. PHI-BLAST searches a protein

program is able to detect statistically significant similarity between homologous proteins

PHI-BLAST is applied to the analysis of CED4-like cell death regulators, HS90-type

ATPase domains, archaeal tRNA nucleotidyltransferases and archaeal homologs of

DnaG-type DNA primases.

A New Algorithm for RNA Secondary Structure Design

or of designing artificial RNA nanostructures. Here, we present a new algorithm for

the (pseudoknot-free) secondary structure prediction problem, this problem appears to be

combinatorial problems. A thorough empirical evaluation on computationally predicted

structures of biological sequences and artificially generated RNA structures as well as on

consistently, for which RNAinverse is unable to find solutions.

Searching for Genes

The collecting, organizing and indexing of sequence information into a database, a

only a fragment of a gene or alternatively, it may contain several genes.

class of organisms (e.g, bacteria, eukaroytes). Common genetic elements include

elements have also been further characterized into further subelements.

algorithms to be applied to the analysis of sequence data. A computer program for

finding genes will contain at least the following elements.

The Challenge of Protein Modelling