After decades of speculation, researchers at the MRC's National
Institute for Medical Research (now part of the Francis Crick
Institute) have identified the gene responsible for a
process called X chromosome inactivation in marsupials. The finding
has clinical implications for a diverse range of diseases,
including cancer and mental disability.
While most chromosomes and their associated genes are common to
males and females, the sex chromosomes (X and Y) are an exception.
Females have two X chromosomes while males have one X and one Y.
This means that genes on the X chromosome are present in twice the
dose in females as they are in males. Most female mammals
compensate for this imbalance through a process called X chromosome
inactivation - or the silencing of genes on one of the two X
chromosomes.
Normally, X chromosome inactivation is random, with an equal
chance of affecting one or the other of the two X chromosomes. But
it sometimes becomes skewed and preferentially affects one of the
chromosomes - this has been associated with a diverse range of
diseases. This is because the effects of a gene with a mutation on
one of the X chromosomes can become exaggerated if the normal
version on the other chromosome is preferentially silenced.
In placental mammals (such as humans and mice), X chromosome
inactivation is controlled by an RNA gene called Xist. The
gene that corresponds to Xist in marsupials has remained elusive
until now and it was thought that the two mammal groups might use
fundamentally different mechanisms.
However a recent study by James Turner's group at NIMR
found that, in the opossum, the female inactive X chromosome shared
common features with that of placental mammals. This made it likely
that a similar gene initiates X chromosome inactivation in both
mammal groups.
Now, the researchers have found the likely gene. In three
species of marsupial they identified an RNA gene calledRsx (RNA-on-the-silent X) and showed that it exhibits all
the properties expected for it to be involved in X chromosome
inactivation.
"We analysed the expression of many genes on the marsupial X
chromosomes. One of the RNAs studied, Rsx, showed an
unusual pattern that suggested it could function in X chromosome
inactivation. We then introduced Rsx into a mouse cell -
the gene was expressed and resulted in inactivation of the mouse
chromosome, showing that it does indeed act to silence genes on the
X chromosome," said Dr Turner.
"It will now be possible to compare the Xist andRsx genes to shed light on exactly how Xistinitiates X chromosome inactivation in humans and other placental
mammals. This work has taken us a step closer to understanding how
this process goes wrong in diseases caused by abnormal X chromosome
activation, such as cancer, and how we might be able to stop this
happening."
The work was carried out by an NIMR team led by James Turner
working with collaborators from the USA, Australia and New Zealand.The paper, ' Rsx is a metatherian RNA with Xist-like properties in X-chromosome
inactivation', by Jennifer Grant et al is published in
Nature.