Uncovered: an elusive marsupial gene linked to diseases in humans

17 June 2012

X Chromosomes of a human female

Image: X chromosomes of a human female©  Department of Clinical Cytogenetics, Addenbrookes Hospital/Science Photo Library

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 called Rsx (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 and Rsx genes to shed light on exactly how Xist initiates 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.

  • A marsupial gene that inactivates genes on one copy of the X chromosome in females has been pinned down after decades of uncertainty.
  • The discovery is expected to aid understanding of the human equivalent of the gene, and how the process goes wrong in human diseases including cancer.
  • Marsupials - including opossums, kangaroos and wallabies - give birth to relatively undeveloped young which then mature in a pouch. They are the second largest class of animals after the placental mammals (including humans) - so-called because developing foetuses attach to their mother's uterus by a placenta. There is also a third mammal group - the egg-laying monotremes, which includes platypuses and echidnas.
  • DNA provides the genetic instructions for almost all living organisms. It is found primarily in the nucleus of a cell. RNA transmits this genetic information into the rest of the cell. Its main job is to translate the genetic instructions into proteins to enable the cell to carry out its functions. RNA genes don't code for proteins, but instead produce molecules of RNA that have a function themselves, such as in gene regulation.