Bioinformatics

Bioinformatics
Bioinformatics is the application of statistics and computer science to the field of molecular biology. The term bioinformatics was coined by Paulien Hogeweg and Ben Hesper in 1978 for the study of informatic processes in biotic systems[1] . 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. 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.

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

Bioinformatics 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[2] , 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 of organisms, containing over 190 billion nucleotides[3] . These programs can 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[4] ) 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.

Bioinformatics

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.

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.

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.

Bioinformatics

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 families 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 both diagnostics and research. Some examples are: high-throughput and high-fidelity quantification and sub-cellular localization (high-content screening, cytohistopathology, Bioimage informatics) morphometrics

Bioinformatics 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 - 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 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. See also: structural motif and structural domain. 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. See also: protein-protein interaction prediction.

Bioinformatics 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 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.

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.

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.

References
[1] Hogeweg, P. (1978). Simulating the growth of cellular forms. Simulation 31, 90-96; Hogeweg, P. and Hesper, B. (1978) Interactive instruction on population interactions. Comput Biol Med 8:319-27. [2] Sanger F, Air GM, Barrell BG, Brown NL, Coulson AR, Fiddes CA, Hutchison CA, Slocombe PM, Smith M (February 1977). "Nucleotide sequence of bacteriophage phi X174 DNA". Nature 265 (5596): 68795. PMID870828. [3] Benson DA, Karsch-Mizrachi I, Lipman DJ, Ostell J, Wheeler DL (January 2008). "GenBank" (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez& artid=2238942). Nucleic Acids Res. 36 (Database issue): D2530. doi:10.1093/nar/gkm929. PMID18073190. PMC2238942. [4] Fleischmann RD, Adams MD, White O, Clayton RA, Kirkness EF, Kerlavage AR, Bult CJ, Tomb JF, Dougherty BA, Merrick JM (July 1995). "Whole-genome random sequencing and assembly of Haemophilus influenzae Rd". Science 269 (5223): 496512. PMID7542800.

Achuthsankar S Nair Computational Biology & Bioinformatics - A gentle Overview (http://print.achuth. googlepages.com/BINFTutorialV5.0CSI07.pdf), Communications of Computer Society of India, January 2007 Aluru, Srinivas, ed. Handbook of Computational Molecular Biology. Chapman & Hall/Crc, 2006. ISBN 1584884061 (Chapman & Hall/Crc Computer and Information Science Series) Baldi, P and Brunak, S, Bioinformatics: The Machine Learning Approach, 2nd edition. MIT Press, 2001. ISBN 0-262-02506-X Barnes, M.R. and Gray, I.C., eds., Bioinformatics for Geneticists, first edition. Wiley, 2003. ISBN 0-470-84394-2 Baxevanis, A.D. and Ouellette, B.F.F., eds., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, third edition. Wiley, 2005. ISBN 0-471-47878-4 Baxevanis, A.D., Petsko, G.A., Stein, L.D., and Stormo, G.D., eds., Current Protocols in Bioinformatics. Wiley, 2007. ISBN 0-471-25093-7 Claverie, J.M. and C. Notredame, Bioinformatics for Dummies. Wiley, 2003. ISBN 0-7645-1696-5 Cristianini, N. and Hahn, M. Introduction to Computational Genomics (http://www.computational-genomics. net/), Cambridge University Press, 2006. (ISBN 9780521671910 | ISBN 0521671914)

Bioinformatics Durbin, R., S. Eddy, A. Krogh and G. Mitchison, Biological sequence analysis. Cambridge University Press, 1998. ISBN 0-521-62971-3 Gilbert, D. Bioinformatics software resources (http://bib.oxfordjournals.org/cgi/content/abstract/5/3/300). Briefings in Bioinformatics, Briefings in Bioinformatics, 2004 5(3):300-304. Keedwell, E., Intelligent Bioinformatics: The Application of Artificial Intelligence Techniques to Bioinformatics Problems. Wiley, 2005. ISBN 0-470-02175-6 Kohane, et al. Microarrays for an Integrative Genomics. The MIT Press, 2002. ISBN 0-262-11271-X Lund, O. et al. Immunological Bioinformatics. The MIT Press, 2005. ISBN 0-262-12280-4 Michael S. Waterman, Introduction to Computational Biology: Sequences, Maps and Genomes. CRC Press, 1995. ISBN 0-412-99391-0 Mount, David W. Bioinformatics: Sequence and Genome Analysis Spring Harbor Press, May 2002. ISBN 0-87969-608-7 Pachter, Lior and Sturmfels, Bernd. "Algebraic Statistics for Computational Biology" Cambridge University Press, 2005. ISBN 0-521-85700-7 Pevzner, Pavel A. Computational Molecular Biology: An Algorithmic Approach The MIT Press, 2000. ISBN 0-262-16197-4 Soinov, L. Bioinformatics and Pattern Recognition Come Together (http://jprr.org/index.php/jprr/article/ view/8/5) Journal of Pattern Recognition Research ( JPRR (http://www.jprr.org)), Vol 1 (1) 2006 p.37-41 Tisdall, James. "Beginning Perl for Bioinformatics" O'Reilly, 2001. ISBN 0-596-00080-4 Dedicated issue of Philosophical Transactions B on Bioinformatics freely available (http://publishing. royalsociety.org/bioinformatics) Catalyzing Inquiry at the Interface of Computing and Biology (2005) CSTB report (http://www.nap.edu/ catalog/11480.html) Calculating the Secrets of Life: Contributions of the Mathematical Sciences and computing to Molecular Biology (1995) (http://www.nap.edu/catalog/2121.html) Foundations of Computational and Systems Biology MIT Course (http://ocw.mit.edu/OcwWeb/Biology/ 7-91JSpring2004/LectureNotes/index.htm) Computational Biology: Genomes, Networks, Evolution Free MIT Course (http://compbio.mit.edu/6.047/) Algorithms for Computational Biology Free MIT Course (http://ocw.mit.edu/OcwWeb/ Electrical-Engineering-and-Computer-Science/6-096Spring-2005/CourseHome/index.htm) Zhang, Z., Cheung, K.H. and Townsend, J.P. Bringing Web 2.0 to bioinformatics, Briefing in Bioinformatics. In press (http://www.ncbi.nlm.nih.gov/pubmed/18842678)

External links
Bioinformatics Organization (http://bioinformatics.org/) Bioinformatics Research Groups (http://www.google.com/Top/Science/Biology/Bioinformatics/ Research_Groups/) - Google Directory EMBnet (http://www.embnet.org/) Open Bioinformatics Foundation (http://www.open-bio.org/)

Article Sources and Contributors

Article Sources and Contributors

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