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Molecular biology involves analysing the interrelationships of DNA, RNA and proteins. To study and identify DNA sequences, the following techniques are used:
- Restriction enzymes which cleave DNA and isolate a particular sequence and gene;
- Polymerase chain reaction which amplifies DNA sequences;
- Sequencing which identifies the order of nucleotides in the DNA strand.
The human genome project, completed in 2003, mapped the genes shared by all humans. This was achieved in three ways: sequencing all the bases, mapping the location of genes for major sections of the chromosomes and producing linkage maps. This was followed by the NHS’s 100,000 Genome Project; 100,000 patients have been selected on the basis of having rare genetic conditions and their DNA is being analysed. The aims of this project are to improve the understanding of:
- The causes of such conditions;
- Whether testing all of someone's genes is a better way to identify the cause of illnesses (at the moment genes are tested one by one);
- If the cause of cancers are genetic, identifying which medicines would be most effective in treating individual cancers;
- How genomic variation affects the effectiveness of medicines.
This work is helping to develop the field of personalised medicine. Through combining individual-level genetic information with clinical and diagnostic information, medicine can be personalised to the individual, helping to detect illness earlier and determine the individual risk of developing disease. This can be achieved through the integration of genomic sequencing with other novel approaches such as wearable technology. This may then help inform the most effective interventions to help improve health and establish whether drugs are needed or a lifestyle choice is more effective. The approach is characterised by the four Ps of personalised medicine:
- Prediction and prevention of disease;
- More precise diagnoses;
- Targeted and personalised interventions;
- Participatory role for patients.
This field is advancing rapidly. Genomic profiling is already being used in some areas, for example in cancer medicine to aid with treatment decisions and providing a prognosis. However, the approach is costly and data intensive. It also has the possibility for misuse, with implications for insurance cover affected if an individual has a known genetic variant, irrespective of if they then go on to develop disease. It also has implications for personal privacy, with genetic information providing insight on family relationships as well as an association with certain traits and diseases.
While environmental and behavioural measures can make a major impact on incidence of infectious diseases, molecular research can help to identify potential new targets for drug therapies or vaccine development, explore the mechanisms of drug resistance developed by the pathogens and suggest new ways to overcome it.
Identifying the causative organism of disease can help to improve understanding of aetiology of disease, with identification of different strains providing context to variation in disease severity and/or medication susceptibility. Timely genome sequencing can also be vital in managing outbreaks through identifying linked cases, chains of transmission and information on drug resistance, for example in outbreaks of tuberculosis.
Pathogen genomes vary in size. Viral genomes are the smallest, ranging in size from a few thousand up to 1.2 million base pairs. While viruses contain RNA or DNA, the highest mutation rates are seen in those with the absence of RNA proof-reading mechanisms to correct errors of replication. Retroviruses such as HIV have RNA genomes which they transcribe into DNA in host cells by a viral enzyme (reverse transcriptase) and integrate into the host genome to aide replication. Influenza genes allow rapid exchange of surface antigens, preventing recognition by the host immune system. These changes happen continually over time as the virus replicates and is termed antigenic drift. Antigenic shift occasionally happens when there is a large change which results in most people having little or no protection.
Bacterial genomes are larger, ranging from 600,000 to around 10 million base pairs. Bacteria often also contain plasmids, additional non-genomic DNA that independently replicates. They contain genes that may confer virulence or antibiotic resistance and can be readily exchanged between different bacteria. This process underpins the development of antibiotic resistance.
Parasite genomes frequently possess multiple genetic loci that allow rapid switching of surface proteins to avoid immune recognition, a characteristic called antigenic variation.
The genome of the human population has co-evolved with pathogens, with resistance or susceptibility to infection a strong evolutionary selective pressure. In some cases, this results from a single genetic variant. An example is sickle-cell anaemia, where the mutant haemoglobin S allele is prevalent in areas with endemic malaria. The structural defect confers a protective effect against malaria infection, despite being a potentially very harmful allele.
In most cases, this susceptibility or resistance to a specific disease is likely to be associated with variation in several genes, each of which has a relatively weak effect.
© Public Health Genetics Unit 2006, H Green 2017