Deep in our basement, lives the Crick’s opossum colony. These rat-sized, nocturnal creatures originated in South America, and have become well-known in scientific research as the ‘model organism’ to represent all marsupials.
The colony at the Crick was originally kept at the University of Glasgow, but was rescued by Crick group leader James Turner in 2009 when there were plans to close it down. More than 100 opossums made the move from Glasgow to the MRC National Institute for Medical Research in north London, and then into the Crick in 2017.
The team in the Crick’s animal research facility are writing the book on how to care for opossums. Because there are only a handful of other groups used for research around the world, the technicians who care for them are used to testing new and improved ways to feed and clean them. They also experiment with keeping them stimulated by providing a regular rotation of toys such as balls and chews, and adding new ones into the mix to keep the animals active.
James was keen to provide a home for the opossums as they are well-suited for research, contributing to a number of different areas of science, including neuroscience and tumour biology.
One of their most important features is that young opossums or joeys are born relatively under-developed compared to other mammals. They latch on to their mothers’ abdomens where they stay for the next eight weeks, meaning that scientists can keep an eye on their development without having to perform invasive procedures or use complex imaging techniques.
But James is interested in a feature which originated millions of years ago. Marsupials’ branch of the genetic family tree split off from our own 160 million years ago, and it includes animals like kangaroos and koalas. Because marsupials have evolved alongside our own branch of mammals, comparing their genome to ours lets us see how evolution has affected our genetic makeup.
There are three main things that we can look for when comparing the opossum genome to our own. Firstly, there are the similarities: genes that have stayed constant and made it through millions of years of evolution. Then there are differences: genes that are found in both mice and humans, but not in opossums, might not be quite as important as they appear.
But the most interesting things are ones that have evolved separately in both branches of the family tree. The evolution of echolocation in both bats and dolphins is the most famous example of this. This convergent evolution points researchers towards important features that are probably the most effective way to do something, rather than just an evolutionary fluke.
James’s group at the Crick studies sex chromosomes, including X-chromosome inactivation, the automatic ‘turning off’ of one of the X chromosomes in every cell in female mammals.
The process evolved separately in both opossums and other mammals, but not in our shared ancestor, so it’s an example of convergent evolution and a successful strategy. And we know that problems in X-chromosome inactivation can cause developmental disorders and cancer. By examining the genetic makeup of opossums and the differences and similarities in our chromosomes, the team are answering important questions about fertility and development in mammals.
Tangled up in DNA
Jasmin Zohren is a postdoc in the lab specialising in bioinformatics. She is working on a project focused on DNA folding – the process that makes sure that two metres of DNA can fit into a space that’s only one millionth of a meter wide. Even though it seems like this would create a tangled mess, researchers have seen in mice that the arrangement of this ‘nest’ of DNA isn’t random at all.
“There are certain bits of DNA that will always be next to each other, no matter how the rest of it is arranged,” explains Jasmin. “The two sections that control X-chromosome inactivation is one of these bits. There’s a signal that starts the process and a signal that stops it and in both opossums and mice, these sections will always end up near each other once the DNA is folded up, even if they’re nowhere near each other when the DNA is arranged in a straight line.
“Comparing opossums and other mammals gives us so much more information than if we had just looked at mice and humans. It could hold the key to fully understanding this really complex and important process of DNA folding and how it’s been shaped by evolution.”
Bryony Leeke and Valdone Maciulyte are two researchers in the lab who are also working with opossums, and examining differences between them and us. Bryony studies DNA methylation and has been comparing the process in different animals. Methylation is a marker on our DNA that indicates whether it should be read or ignored. It protects our DNA, and DNA can become more fragile when it’s damaged.
In humans and mice, DNA methylation is ‘reset’ in the genome during the early stages of development, and the embryo has a clean slate on which to develop. Up until recently, it was thought that the process probably happened in all mammals, but not in other animals, like fish. Bryony is studying the process in opossums and filling in the picture about when and why DNA methylation resetting evolved.
“If we don’t look at other groups of animals to find out more about the process, we won’t know how important it is for the slate to be wiped clean at the start of embryo development,” explains Bryony. “We need to look at our most distant relatives to see the full picture.”
Valdone is studying a different process called spermatogenesis, the development of young male germ cells into mature sperm.
She’s using RNA sequencing to identify the key genes that control spermatogenesis in opossums and comparing them to the key spermatogenesis genes in other species. This means that she can find which genes have survived in the genomes of mammals over millions of generations of evolution.
“If we understand more about spermatogenesis and the genes involved, we could learn how to control the process and find new targets for contraception and infertility treatment,” she explains.
When we’re working with animals in research, it might seem like we would always want to use animals that are as similar to humans as possible. But opossums show us how much we can learn from our distant relatives.