Why I use marsupials in research
We use animals in research because they’re so similar to humans. So what can be gained from using marsupials, such as opossums and wallabies, that are so far from humans on the evolutionary family tree? James Turner, a researcher at the MRC National Institute for Medical Research (MRC NIMR), tells us why finding similarities in these more distant relatives can lead to important and surprising results.
For many years, scientists have used laboratory mammals such as monkeys, mice and rabbits to understand how human diseases develop and how they can be treated. The DNA make-up, or genome sequence, of these animals is very similar to that of humans, and we’re all members of the largest class of mammals (the ‘eutherians’), so they make good experimental models.
But during the past few years, my group at the MRC NIMR, along with other researchers, have started using a more unusual type of mammal, the ‘metatherian’, or marsupial, to understand human biology. Marsupials, such as opossums and wallabies, can provide us with a level of insight that other mammals cannot.
Marsupials diverged from our branch of the evolutionary tree 148 million years ago, so their genome sequences differ from ours markedly. So why do we use marsupials to understand our own biology? Importantly, although our genomes differ, most aspects of development, physiology and behaviour are similar, meaning that any genes that are shared, or ‘conserved’, between humans and marsupials are much more likely to be important in fundamental biological processes.
So by comparing marsupial and human DNA sequences, a process known as comparative genomics, we can make huge leaps in scientific knowledge.
We recently made such a discovery in the understanding of X-chromosome inactivation; the way in which female mammals silence one of their X chromosomes in each cell, to prevent a potentially dangerous double dose of genes (females have two X chromosomes, while males have an X and a Y). When X-inactivation goes wrong it can cause cancers of the blood or intellectual disability, so understanding how X chromosome inactivation works is important for human health.
In humans, X-inactivation is carried out by a gene on the X chromosome, discovered in the early 1990s, called Xist. The Xist gene is unusual in many ways. For example, unlike other genes it is used only in females, and rather than making a molecule called an RNA which then leads to a protein, it makes an RNA that physically “coats” one of the two X chromosomes to silence its hundreds of genes.
A big mystery is how this Xist RNA coats and silences a whole chromosome. It must contain some special sequences that give it these unique properties. But because it’s so large (around eight times the length of most other RNAs) these sequences have been difficult to identify.
The marsupial X chromosome does not contain a Xist gene. Nevertheless, my lab recently discovered another gene on the metatherian X chromosome, called Rsx, which is used only in females, and coats the inactive X chromosome.
At a glance, we were surprised to see that the sequence of the Rsx RNA was completely different to that of Xist. However, on closer inspection, we found that both Rsx and Xist carry a short stretch of sequence repeated multiple times, suggesting that this is the functionally important part of the Xist and Rsx RNAs. I believe that this discovery will help us and other scientists in the field to make more rapid progress in unravelling how X-inactivation works at the molecular level.
As you can see from this example, working with unusual animals can pay large dividends, and I hope that as time passes more scientists will realise their potential.
I believe that experiments using marsupials could generate big leaps in understanding in other areas of science, such as stem cell research. An enormous amount of progress has been made recently in this field, with the creation of induced pluripotent (iPS) cells by ‘reprogramming’ adult differentiated cells.
How stem cells are able to continually renew themselves, yet also generate any tissue in the human body, is mysterious.
We are attempting to generate iPS cells from marsupials, so that we can compare the expression of their genes with those from humans and mice, and understand how these unique properties arise.
This article is one of two about research using opossums at the MRC NIMR. You can read about then institute’s opossum colony and why opossums are useful laboratory animals in Making a name for itself: the laboratory opossum.
*The image used in this article has not been released under our Creative Commons Attribution 3.0 Unported Licence.