Myeloproliferative disorders are characterised by the overproduction of red and white blood cells, which increases the risk of strokes and heart attacks. Many cases of MPDs are caused by a mutation in a gene called JAK2. When the JAK2 gene has mutated, it sends abnormal messages to the blood stem cells to produce more and more blood cells.Scientists, funded by Leukaemia Research, have found that a particular region of chromosome 9 that carries the JAK2 gene is predisposed to acquiring mutations, but only in individuals with a particular genetic makeup. It is likely that this finding will lead to a much better understanding of how the JAK2 gene mutations happen and why they lead to an increased risk of someone developing an MPD.The study, carried out at the Wessex Regional Genetics Laboratory in Salisbury and the University of Southampton, has proved that people carrying this mutation-prone region of DNA on chromosome 9 that includes the JAK2 gene have triple the risk of developing an MPD.The chromosome 9 variant is present in 40 per cent of the UK population but only 1 in 20,000 people develop an MPD each year. Nonetheless, the new research has confirmed that the inheritance of this genetic variant can contribute to inherited susceptibility to develop an MPD.The study found that the link was especially strong in polycythaemia vera (PV), one of the main three MPDs. Professor Nick Cross, from the University of Southampton who led the research team, says: "This research provides strong evidence that at least half of the cases of PV diagnosed each year are linked to an inherited genetic variant on chromosome 9. Whilst this risk is still very small it nonetheless confirms that individual susceptibility to acquiring cancer-causing mutations is linked to genetic inheritance. Now that we have this evidence we can carry out studies to determine exactly how the variant contributes to this risk."Dr Shabih Syed, Scientific Director at Leukaemia Research, adds: "This is a very important step forward in our knowledge of the causes of myeloproliferative disorders. It helps us to understand why some people might be predisposed to acquiring genetic mutations that lead to cancers."
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"Once the data were together, it was very easy to see transcript structure across the genome," said Bergman. "We could see clear boundaries between transcribed and non-transcribed regions of the genome, which represent where individual transcripts start and stop. This was really exciting, because transcript boundaries tell us precisely where to find the regulatory sequences that govern gene expression, and these sequences are extremely hard to find otherwise."
The researchers also found that since RNA-Seq is essentially just a very high-throughput counting technique, it also provides a way of determining how abundant each transcript is in the cell. They showed that this approach is a much more sensitive way of measuring gene expression than the more conventional microarray-based methods.
"We can very easily see which genes are the most highly expressed, but we were also able to detect very rare transcripts - the ones that are only being produced by 1 in 100 or 1 in 1000 cells - and with this level of sensitivity we can actually get a glimpse of the random events that make individual cells different from one another," said Bergman.
Combining the structure and abundance information for every gene in a bacterial genome allows researchers to take a more rational approach to tasks like antibiotic discovery and microbial engineering, Bergman noted.
"Sequencing-based transcriptome profiling has several huge advantages over array-based profiling," sad Bergman. "Right now array-based methods are still a little less expensive, and take a little less effort in terms of the bioinformatics, but I don't think those obstacles will last long. I think we'll see a lot more studies taking this approach in the near future."
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