The genetic detective – Pharmacogenomics and personalized medicine

 THe following interesting study was published at  article is from royal society of chemistry website

A selective way to detect genetic variations could help scientists develop personalised medicine.

“[This method] should allow several thousands of single nucleotide variations, at different positions within a person’s genome, to be analysed in parallel.”
– Andreas Marx

Variations in our genetic make-up are responsible for some diseases and are known to be major players in an individual’s predisposition to drug side effects. Convenient and rapid detection of these variations could help doctors to adapt therapies for each patient. This idea has prompted Andreas Marx and colleagues at the University of Konstanz, Germany, to devise a high-throughput technique to detect variations between single nucleotides in genetic sequences. 

Marx’s system uses a microarray of oligonucleotide probes to analyse the DNA. The probes are attached by their 5′ end to a glass surface and treated with an enzyme, a DNA polymerase. The enzyme can add further nucleotides to the unattached ends of the probes. If a probe’s terminal base complements the DNA under investigation, the oligonucleotide chain continues to form; if the base is a mismatch, the chain does not extend further.

A microarray of oligonucleotide probes

Oligonucleotide probes are used to analyse DNA to detect variations between single nucleotides

‘Conventional enzyme-based strategies for detecting single nucleotide variations often lack sufficient selectivity,’ said Marx. The oligonucleotide chain can continue to form even when there is a mismatch. The team was able to increase the selectivity by modifying the terminal nucleotide of the probe with a methoxymethylene group. 

In human DNA, approximately one single nucleotide variation occurs per 1000 bases. This method ‘should allow several thousands of single nucleotide variations, at different positions within a person’s genome, to be analysed in parallel,’ said Marx. ‘This is still a challenging task that none of the present systems is able to achieve reliably.’

Oliver Seitz, an expert in DNA diagnostics at Humboldt University in Berlin, Germany, believes that Marx’s work could have a significant impact in developing diagnostic probes for DNA. ‘The method brings high specificity to the high-throughput format,’ said Seitz. ‘The challenge now is to combine multiplex analysis with specificity and signal amplification in a miniaturised format, to enable point-of-care diagnostics.’

Alison Stoddart

References

Increased single nucleotide discrimination in arrayed primer elongation by 4′C-modified primer probes

J Gaster, G Rangam and A Marx, Chem. Commun., 2007

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