Autoimmune conditions linked to reactivated X chromosome genes

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In female mammals, the genes on one copy of the X chromosome are generally inactivated.

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Female mammals have a higher risk of developing autoimmune diseases such as lupus because extra copies of genes that should be permanently turned off are reactivated as they age, a mouse study suggests.

Findings will likely apply to all mammals, including humans, says Celine Morey at Paris Cité University in France, and could explain why older women are more likely to develop diseases such as rheumatoid arthritis.

While male mammals generally have an X and a Y chromosome, most female mammals has two copies of the X chromosome. If all genes on both X chromosomes were active, women would receive a double dose of the gene products compared to men.

Instead, shortly after embryos begin 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.

Morey and his colleagues began studying this process by creating mice that lack one of the genes involved in X inactivation. This elimination does not completely prevent X inactivation – which would be fatal – but it reduces its strength.

At first, the mice appeared normal. “We had to wait for the mice to get older to finally see something wrong, because otherwise they would be happy,” says Morey.

In old age, the mice developed lupus-like symptoms, such as an enlarged spleen.

The team found that several key genes on the inactivated X chromosome in their immune cells were being reactivated as the mice aged. These genes regulate the immune system and one of them, called TLR7it’s already Known to affect people’s risk of developing lupus.

It is suspected that higher doses of genes such as TLR7 make people with two X chromosomes more resistant to many infectious diseases but also more prone to autoimmune diseases. The new study provides the strongest evidence yet that higher doses could occur due to a failure to maintain X inactivation.

Morey hopes the findings could lead to better treatments for autoimmune diseases such as rheumatoid arthritis, which is more common at older ages and in women compared to men.

“If we identify the genes involved, perhaps we can design some treatments that target specific key factors,” says Morey.

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