What is Bioinformatics?
The genomic era
The genomic era has seen a massive explosion in the amount of biological
information available due to huge advances in the fields of molecular
biology and genomics.
Bioinformatics is the application of computer technology to the management and analysis of biological data. The result is that computers are being used to gather, store, analyse and merge biological data.
Bioinformatics is an interdisciplinary research area that is the interface between the biological and computational sciences. The ultimate goal of bioinformatics is to uncover the wealth of biological information hidden in the mass of data and obtain a clearer insight into the fundamental biology of organisms. This new knowledge could have profound impacts on fields as varied as human health, agriculture, the environment, energy and biotechnology.
Why is bioinformatics important?
The greatest challenge facing the molecular biology community today is to make sense of the wealth of data that has been produced by the genome sequencing projects. Traditionally, molecular biology research was carried out entirely at the experimental laboratory bench but the huge increase in the scale of data being produced in this genomic era has seen a need to incorporate computers into this research process.
Sequence generation, and its subsequent storage, interpretation and analysis are entirely computer dependent tasks. However, the molecular biology of an organism is a very complex issue with research being carried out at different levels including the genome, proteome, transcriptome and metabalome levels. Following on from the explosion in volume of genomic data, similar increase in data have been observed in the fields of proteomics, transcriptomics and metabalomics.
The first challenge facing the bioinformatics community today is the intelligent and efficient storage of this mass of data. It is then their responsibility to provide easy and reliable access to this data. The data itself is meaningless before analysis and the sheer volume present makes it impossible for even a trained biologist to begin to interpret it manually. Therefore, incisive computer tools must be developed to allow the extraction of meaningful biological information.
There are three central biological processes around which bioinformatics tools must be developed:
- DNA sequence determines protein sequence
- Protein sequence determines protein structure
- Protein structure determines protein function
Biological databases
Biological databases are archives of consistent data that are stored in a uniform and efficient manner. These databases contain data from a broad spectrum of molecular biology areas. Primary or archived databases contain information and annotation of DNA and protein sequences, DNA and protein structures and DNA and protein expression profiles.
Secondary or derived databases are so called because they contain the results of analysis on the primary resources including information on sequence patterns or motifs, variants and mutations and evolutionary relationships. Information from the literature is contained in bibliographic databases, such as Medline.
It is essential that these databases are easily accessible and that an intuitive query system is provided to allow researchers to obtain very specific information on a particular biological subject. The data should be provided in a clear, consistent manner with some visualization tools to aid biological interpretation.
Specialist databases for particular subjects have been set-up for example EMBL database for nucleotide sequence data, UniProtKB/Swiss-Prot protein database and PDBe a 3D protein structure database.
Scientists also need to be able to integrate the information obtained from the underlying heterogeneous databases in a sensible manner in order to be able to get a clear overview of their biological subject. SRS (Sequence Retrieval System) is a powerful, querying tool provided by the EBI that links information from more than 150 heterogeneous resources.
Biological applications
Once all of the biological data is stored consistently and is easily available to the scientific community, the requirement is then to provide methods for extracting the meaningful information from the mass of data. Bioinformatic tools are software programs that are designed to carry out this analysis step.
Factors that must be taken into consideration when designing these tools are:
- The end user (the biologist) may not be a frequent user of computer technology
- These software tools must be made available over the internet given the global distribution of the scientific research community
Similarity Searching Tools
Homologous sequences are sequences that are related by divergence from a common ancestor. Thus the degree of similarity between two sequences can be measured while their homology is a case of being either true of false. This set of tools can be used to identify similarities between novel query sequences of unknown structure and function and database sequences whose structure and function have been elucidated.
Protein Function Analysis
This group of programs allow you to compare your protein sequence to the secondary (or derived) protein databases that contain information on motifs, signatures and protein domains. Highly significant hits against these different pattern databases allow you to approximate the biochemical function of your query protein.
Structural Analysis
This set of tools allow you to compare structures with the known structure databases. The function of a protein is more directly a consequence of its structure rather than its sequence with structural homologs tending to share functions. The determination of a protein's 2D/3D structure is crucial in the study of its function.
Sequence Analysis
This set of tools allows you to carry out further, more detailed analysis on your query sequence including evolutionary analysis, identification of mutations, hydropathy regions, CpG islands and compositional biases. The identification of these and other biological properties are all clues that aid the search to elucidate the specific function of your sequence.
Real world applications of bioinformatics
The science of bioinformatics has many beneficial uses in the modern day world.
These include the following:
1. Molecular medicine
The human genome will have profound effects on the fields of biomedical research and clinical medicine. Every disease has a genetic component. This may be inherited (as is the case with an estimated 3000-4000 hereditary disease including Cystic Fibrosis and Huntingtons disease) or a result of the body's response to an environmental stress which causes alterations in the genome (eg. cancers, heart disease, diabetes..).The completion of the human genome means that we can search for the genes directly associated with different diseases and begin to understand the molecular basis of these diseases more clearly. This new knowledge of the molecular mechanisms of disease will enable better treatments, cures and even preventative tests to be developed.
1.1 More drug targets
At present all drugs on the market target only about 500 proteins. With an improved understanding of disease mechanisms and using computational tools to identify and validate new drug targets, more specific medicines that act on the cause, not merely the symptoms, of the disease can be developed. These highly specific drugs promise to have fewer side effects than many of today's medicines.
1.2 Personalised medicine
Clinical medicine will become more personalised with the development of the field of pharmacogenomics. This is the study of how an individual's genetic inheritence affects the body's response to drugs. At present, some drugs fail to make it to the market because a small percentage of the clinical patient population show adverse affects to a drug due to sequence variants in their DNA.
As a result, potentially life saving drugs never make it to the marketplace. Today, doctors have to use trial and error to find the best drug to treat a particular patient as those with the same clinical symptoms can show a wide range of responses to the same treatment. In the future, doctors will be able to analyse a patient's genetic profile and prescribe the best available drug therapy and dosage from the beginning.
1.3 Preventative medicine
With the specific details of the genetic mechanisms of diseases being unravelled, the development of diagnostic tests to measure a persons susceptibility to different diseases may become a distinct reality. Preventative actions such as change of lifestyle or having treatment at the earliest possible stages when they are more likely to be successful, could result in huge advances in our struggle to conquer disease.
1.4 Gene therapy
In the not too distant future, the potential for using genes themselves to treat disease may become a reality. Gene therapy is the approach used to treat, cure or even prevent disease by changing the expression of a persons genes. Currently, this field is in its infantile stage with clinical trials for many different types of cancer and other diseases ongoing.
2. Microbial genome applications
Microorganisms are ubiquitous, that is they are found everywhere. They have been found surviving and thriving in extremes of heat, cold, radiation, salt, acidity and pressure. They are present in the environment, our bodies, the air, food and water.Traditionally, use has been made of a variety of microbial properties in the baking, brewing and food industries. The arrival of the complete genome sequences and their potential to provide a greater insight into the microbial world and its capacities could have broad and far reaching implications for environment, health, energy and industrial applications. For these reasons, in 1994, the US Department of Energy (DOE) initiated the MGP (Microbial Genome Project) to sequence genomes of bacteria useful in energy production, environmental cleanup, industrial processing and toxic waste reduction.
By studying the genetic material of these organisms, scientists can begin to understand these microbes at a very fundamental level and isolate the genes that give them their unique abilities to survive under extreme conditions.
2.1 Waste cleanup
Deinococcus radiodurans is known as the world's toughest bacteria and it is the most radiation resistant organism known. Scientists are interested in this organism because of its potential usefulness in cleaning up waste sites that contain radiation and toxic chemicals.
Microbial Genome Program (MGP) scientists are determining the DNA sequence of
the genome of C. crescentus, one of the organisms responsible for sewage treatment.
Increasing levels of carbon dioxide emission, mainly through the expanding use of fossil fuels for energy, are thought to contribute to global climate change. Recently, the DOE (Department of Energy, USA) launched a program to decrease atmospheric carbon dioxide levels. One method of doing so is to study the genomes of microbes that use carbon dioxide as their sole carbon source.
Scientists are studying the genome of the microbe Chlorobium tepidum which has an unusual capacity for generating energy from light.
The archaeon Archaeoglobus fulgidus and the bacterium Thermotoga maritima have potential for practical applications in industry and government-funded environmental remediation. These microorganisms thrive in water temperatures above the boiling point and therefore may provide the DOE, the Department of Defence, and private companies with heat-stable enzymes suitable for use in industrial processes. Other industrially useful microbes include, Corynebacterium glutamicum which is of high industrial interest as a research object because it is used by the chemical industry for the biotechnological production of the amino acid lysine. The substance is employed as a source of protein in animal nutrition. Lysine is one of the essential amino acids in animal nutrition. Biotechnologically produced lysine is added to feed concentrates as a source of protein, and is an alternative to soybeans or meat and bonemeal.
Xanthomonas campestris pv. is grown commercially to produce the exopolysaccharide xanthan gum, which is used as a viscosifying and stabilising agent in many industries.
Lactococcus lactis is one of the most important micro-organisms involved in the dairy industry, it is a non-pathogenic rod-shaped bacterium that is critical for manufacturing dairy products like buttermilk, yogurt and cheese. This bacterium, Lactococcus lactis ssp., is also used to prepare pickled vegetables, beer, wine, some breads and sausages and other fermented foods. Researchers anticipate that understanding the physiology and genetic make-up of this bacterium will prove invaluable for food manufacturers as well as the pharmaceutical industry, which is exploring the capacity of L. lactis to serve as a vehicle for delivering drugs.
Scientists have been examining the genome of Enterococcus faecalis a leading cause of bacterial infection among hospital patients. They have discovered a virulence region made up of a number of antibiotic-resistant genes that may contribute to the bacterium's transformation from a harmless gut bacteria to a menacing invader. The discovery of the region, known as a pathogenicity island, could provide useful markers for detecting pathogenic strains and help to establish controls to prevent the spread of infection in wards.
Scientists used their genomic tools to help distinguish between the strain of Bacillus anthracis that was used in the summer of 2001 terrorist attack in Florida with that of closely related anthrax strains.
Scientists have recently built the virus poliomyelitis using entirely artificial means. They did this using genomic data available on the Internet and materials from a mail-order chemical supply. The research was financed by the US Department of Defence as part of a biowarfare response program to prove to the world the reality of bioweapons. The researchers also hope their work will discourage officials from ever relaxing programs of immunisation. This project has been met with very mixed feeelings, and more.
2.2 Climate change
Increasing levels of carbon dioxide emission, mainly through the expanding use of fossil fuels for energy, are thought to contribute to global climate change. Recently, the DOE (Department of Energy, USA) launched a program to decrease atmospheric carbon dioxide levels. One method of doing so is to study the genomes of microbes that use carbon dioxide as their sole carbon source.
2.3 Alternative energy sources
Scientists are studying the genome of the microbe Chlorobium tepidum which has an unusual capacity for generating energy from light.
2.4 Biotechnology
The archaeon Archaeoglobus fulgidus and the bacterium Thermotoga maritima have potential for practical applications in industry and government-funded environmental remediation. These microorganisms thrive in water temperatures above the boiling point and therefore may provide the DOE, the Department of Defence, and private companies with heat-stable enzymes suitable for use in industrial processes. Other industrially useful microbes include, Corynebacterium glutamicum which is of high industrial interest as a research object because it is used by the chemical industry for the biotechnological production of the amino acid lysine. The substance is employed as a source of protein in animal nutrition. Lysine is one of the essential amino acids in animal nutrition. Biotechnologically produced lysine is added to feed concentrates as a source of protein, and is an alternative to soybeans or meat and bonemeal.
Xanthomonas campestris pv. is grown commercially to produce the exopolysaccharide xanthan gum, which is used as a viscosifying and stabilising agent in many industries.
Lactococcus lactis is one of the most important micro-organisms involved in the dairy industry, it is a non-pathogenic rod-shaped bacterium that is critical for manufacturing dairy products like buttermilk, yogurt and cheese. This bacterium, Lactococcus lactis ssp., is also used to prepare pickled vegetables, beer, wine, some breads and sausages and other fermented foods. Researchers anticipate that understanding the physiology and genetic make-up of this bacterium will prove invaluable for food manufacturers as well as the pharmaceutical industry, which is exploring the capacity of L. lactis to serve as a vehicle for delivering drugs.
2.5 Antibiotic resistance
Scientists have been examining the genome of Enterococcus faecalis a leading cause of bacterial infection among hospital patients. They have discovered a virulence region made up of a number of antibiotic-resistant genes that may contribute to the bacterium's transformation from a harmless gut bacteria to a menacing invader. The discovery of the region, known as a pathogenicity island, could provide useful markers for detecting pathogenic strains and help to establish controls to prevent the spread of infection in wards.
2.6 Forensic analysis of microbes
Scientists used their genomic tools to help distinguish between the strain of Bacillus anthracis that was used in the summer of 2001 terrorist attack in Florida with that of closely related anthrax strains.
2.7 The reality of bioweapon creation
Scientists have recently built the virus poliomyelitis using entirely artificial means. They did this using genomic data available on the Internet and materials from a mail-order chemical supply. The research was financed by the US Department of Defence as part of a biowarfare response program to prove to the world the reality of bioweapons. The researchers also hope their work will discourage officials from ever relaxing programs of immunisation. This project has been met with very mixed feeelings, and more.
2.8 Evolutionary studies
The sequencing of genomes from all three domains of life, eukaryota, bacteria and archaea means that evolutionary studies can be performed in a quest to determine the tree of life and the last universal common ancestor. For more interesting stories, check the archive at the Genome News Network (GNN).
For information on structural, functional and comparative analysis of genomes and genes from a wide variety of organisms see The Institute of Genomic Research (TIGR).
3. Agriculture
The sequencing of the genomes of plants and animals should have enormous benefits for the agricultural community. Bioinformatic tools can be used to search for the genes within these genomes and to elucidate their functions. This specific genetic knowledge could then be used to produce stronger, more drought, disease and insect resistant crops and improve the quality of livestock making them healthier, more disease resistant and more productive.3.1 Crops
Comparative genetics of the plant genomes has shown that the organisation of their genes has remained more conserved over evolutionary time than was previously believed. These findings suggest that information obtained from the model crop systems can be used to suggest improvements to other food crops. Arabidopsis thaliana (water cress) and Oryza sativa (rice) are examples of available complete plant genomes.
3.2 Insect resistance
Genes from Bacillus thuringiensis that can control a number of serious pests have been successfully transferred to cotton, maize and potatoes. This new ability of the plants to resist insect attack means that the amount of insecticides being used can be reduced and hence the nutritional quality of the crops is increased.
3.3 Improve nutritional quality
Scientists have recently succeeded in transferring genes into rice to increase levels of Vitamin A, iron and other micronutrients. This work could have a profound impact in reducing occurrences of blindness and anaemia caused by deficiencies in Vitamin A and iron respectively.
Scientists have inserted a gene from yeast into the tomato, and the result is a plant whose fruit stays longer on the vine and has an extended shelf life,and more.
3.4 Grow in poorer soils and drought resistant
Progress has been made in developing cereal varieties that have a greater tolerance for soil alkalinity, free aluminium and iron toxicities. These varieties will allow agriculture to succeed in poorer soil areas, thus adding more land to the global production base. Research is also in progress to produce crop varieties capable of tolerating reduced water conditions.
4. Animals
Sequencing projects of many farm animals including cows, pigs and sheep are now well under way in the hope that a better understanding of the biology of these organisms will have huge impacts for improving the production and health of livestock and ultimately have benefits for human nutrition.
5. Comparative studies
Analysing and comparing the genetic material of different species is an important method for studying the functions of genes, the mechanisms of inherited diseases and species evolution. Bioinformatics tools can be used to make comparisons between the numbers, locations and biochemical functions of genes in different organisms.
Organisms that are suitable for use in experimental research are termed model organisms. They have a number of properties that make them ideal for research purposes including short life spans, rapid reproduction, being easy to handle, inexpensive and they can be manipulated at the genetic level.
An example of a human model organism is the mouse. Mouse and human are very closely related (>98%) and for the most part we see a one to one correspondence between genes in the two species. Manipulation of the mouse at the molecular level and genome comparisons between the two species can and is revealing detailed information on the functions of human genes, the evolutionary relationship between the two species and the molecular mechanisms of many human diseases.
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