In female mammals, the gene on one copy of the X chromosome is normally inactivated.
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Female mammals are at higher risk of developing autoimmune diseases such as lupus because extra copies of genes that should be permanently turned off reactivate as they age, a mouse study suggests.
The study says the findings likely apply to all mammals, including humans. Celine Moret Researchers from Paris Cité University in France and their colleagues may explain why older women are more likely to develop conditions such as rheumatoid arthritis.
Male mammals usually have one X chromosome and one Y chromosome, but most female mammals have two X chromosomes. If all genes on both her X chromosomes are active, a woman will ingest twice the amount of her gene product compared to a man.
Instead, as soon as the embryo begins to develop, most of the genes on one of the two copies of the X chromosome are turned off, a phenomenon known as X inactivation.
Morley and colleagues began studying this process by creating mice lacking one of the genes involved in X inactivation. This deletion does not completely prevent inactivation of X – it is lethal – but it reduces the strength of X.
At first, the mouse appeared normal. “We had to wait until the mice were older and finally noticed something was wrong, because otherwise they were happy,” Morley says.
As the mice got older, they developed lupus-like symptoms, including an enlarged spleen.
The research team found that as the mice aged, several key genes on the inactivated X chromosomes of immune cells became reactivated.These genes regulate the immune system, and one of them is TLR7is already known to influence the risk of developing lupus.
It is suspected that the dosage of genes such as TLR7 People with two X chromosomes are more resistant to many infections, but they are also more susceptible to autoimmune diseases. The new study provides the strongest evidence so far that higher doses may result from a failure to maintain X inactivation.
Professor Morley hopes the findings could lead to better treatments for autoimmune diseases such as rheumatoid arthritis, which are more common in older people and women than men.
“If we can identify the genes involved, we may be able to design treatments that target specific key factors,” Morley says.
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Source: www.newscientist.com
