Missing copies of important genes may increase risk of developing diseases
16 February 2006
New research has found that each person may be missing hundreds of thousands of base pairs or "letters" of the genetic code which can make them more at risk of different diseases. Scientists, studying the disease systemic lupus1, have found that the variation in the number of copies of the same gene in our genome may account for susceptibility to specific diseases.
The human genome project is giving us the promise of a new understanding of the genetic causes of common human diseases. In this week's Nature, Professors Tim Aitman and Terry Cook of the MRC Clinical Sciences Centre and Imperial College report that structural rearrangements of the human genome sequence account for part of the genetic susceptibility to kidney failure in the disease systemic lupus.
In this disease the body’s immune defences, which normally protect against infection, turn on the body’s own cells to cause damage to the kidneys and other organs. Starting with work on a special strain of rats which develop a kidney disease almost identical to that found in systemic lupus, Aitman and Cook identified a novel rat protein, Fcgr3-rs, that dampens down the immune response to prevent over-activity. In the rat model, they found that absence of Fcgr3-rs leads to an over-active immune response and susceptibility to kidney failure. They were able to show that absence of this protein was due to loss of the entire Fcgr3-rs gene from the genome of the rat strain used in the study.
Having shown that loss of this gene from the genome causes kidney failure in rats, they looked at the corresponding gene in the human genome, called FCGR3B, and found that humans also vary in the number of copies of this gene carried in their genomes. Finally, they looked to see if loss of the FCGR3B gene led to human kidney disease and were able to show a strong association with kidney disease in systemic lupus in humans, indicating that patients with systemic lupus who have a low number of FCGR3B genes in their genome are more susceptible to kidney failure compared to those with a higher number.
The findings suggest the possibility that increasing the expression of the gene FCGR3B could help to reduce the frequency or severity of kidney disease in patients with systemic lupus and possibly other immune causes of kidney disease. The study also shows for the first time that structural rearrangements of the genome – such as loss of entire genes from the genome or simply a variation in gene copy number can be a cause of this common immune disease, and is therefore a likely cause of other common human diseases.
Professor Colin Blakemore, Chief Executive of the Medical Research Council said: "This important new discovery is a great example of the way in which the massive investment into deciphering the entire human genome is paying off. Scientists are now beginning to explain the genetic basis for human health and disease. These new findings show that susceptibility to a common human disease can be caused by variation in gene copy number and suggest that many common diseases may be caused by this type of structural rearrangement in the genome”
Professor Tim Aitman of the MRC Clinical Sciences Centre added: "Since the recognition in the past two to three years that all of our genomes contain large differences, including duplication and loss of entire genes, it has seemed likely that such large differences could account for individual characteristics including predisposition to common diseases. By showing that variation in gene number can predispose to kidney failure in the common human disease systemic lupus, our studies have shown that this newly recognised type of sequence variation in the genome is a cause of at least one common human disease. This study will set the scene for a cascade of studies showing the dynamic nature of our genomes and how this impacts on susceptibility to common diseases.”
For further information, or to request an interview with Professor Tim Aitman, please contact the MRC press office on 020 7670 5139 or laure.thomas@headoffice.mrc.ac.uk.
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