Despite studying the animal for years, Nathan Clark has never laid eyes on an Australian marsupial mole.
Spotted only five to 10 times per year in the remote deserts of western Australia, these elusive, blind, burrowing creatures hold secrets in their DNA that could help uncover new genes tied to human eyesight.
By teaming up with Australian researchers to sequence and analyze the mole’s genome, Clark, an associate professor at the University of Pittsburgh’s biological sciences department, and his fellow researchers are proving that even animals we’ve never seen can shed light on the inner workings of our own biology.
The research team has spent the past seven years studying how animals evolve in response to extreme environmental changes, focusing especially on subterranean tunneling species. Their research aims to uncover the genetic adaptations that enable these creatures to thrive underground. The team had previously identified four groups of mammals that evolved to become dedicated underground dwellers, until they found a fifth, the Australian marsupial mole.
Clark noted two primary reasons his studies are important. “One is just out of evolutionary scientific curiosity: ‘How did they do it?’”
Secondly, the research provides a way to identify genes related to eyesight in humans. All mammals, including humans, share a core set of genes responsible for producing and maintaining our eyes. In these blind subterranean species, however, those genes are degrading. By studying their DNA sequences, the changes are clearly illustrated, and it has led the team to identifying eye-related genes that had never been discovered before, Clark said.
“If something falls out of use [such as eyesight in the marsupial mole], the remnants of that gene stick around for a while, and we can see that,” said Clark, whose Pitt lab focuses on molecular evolution and comparative genomics. “Part of our mission is to uncover new parts of the genome that help us form and maintain our eyesight. It turns out that we have a lot of different eye abnormalities that are genetically encoded, and it depends on which disease, but roughly half of those go undiagnosed at the genetic level.”
To better understand the genetics behind the degeneration of the marsupial mole eyes, the researchers started with human genes because “they are some of the best characterized and studied version of the genes in science,” explained Sarah Lucas, a postdoctoral research associate at the University of Münster in Germany and a member of the research team that recently published the report. “For this study we wanted to focus on the eye, so we restricted the genes we were interested in to those which are only expressed in the human eye and in no other tissue. Next, we had to determine which of those genes are also found in marsupials.”
That left the team, she said, “with 30 genes to study.”
Once the focus was narrowed, the team then honed in on “helping fill out that catalog of ocular genes so that we can locate [the culprit gene or genes] when things go wrong,” Clark said.
For example, an ophthalmologist can plainly see that a part of a newborn’s eye never developed in utero, but can’t tell the parents why the anomaly happened, Clark said. Knowing what gene is responsible for the problem could lend important clues in developing treatments for the condition and possibly preventing the condition from happening to other children in the future.
Among the notable discoveries are “two positions in the marsupial mole in which the corresponding change in humans results in an eye disease,” Lucas said. “Both positions reside in the GJA8 gene, which encodes for a protein necessary for the growth and maturation of the lens. A human possessing either one of these variants is likely to go on to develop cataracts, or cloudiness of the eye.”
According to the team’s paper, the northern marsupial mole is distributed in northwestern Australia and very rarely seen. The southern marsupial mole can be found across central and southern Australia, with rare but occasional sightings recorded within the Uluru-Kata Tjuta National Park. Efforts to capture and study the moles in captivity have been wholly unsuccessful. Their endangered status also hindered collection efforts. The team instead obtained a female marsupial mole specimen from the South Australia Museum in Adelaide.
The researchers discovered that marsupial moles’ eyesight started to deteriorate little-by-little millions of years ago.
It didn't happen all at once. Imagine: Millions of years ago the animal starts to build little burrows. He likes them and starts to spend most of his time hidden below ground but still exits occasionally. And so “different parts of the eye degraded at different times. The first thing to go was the lens,” Clark said, indicating that eyesight was likely becoming less crucial to the mammal. After that, the species lost color vision.
“And then the very last thing to go, relatively recently, just one million years ago maybe, was the black and white kind of dim light vision that we all have: night vision.”
Because their eyesight has deteriorated recently, evolutionally speaking, more noticeable changes are present in the marsupial mole gene compared to the other marsupials, Lucas explained.
“This is in contrast to when a human experiences rare congenital disease affecting their vision,” she said. “Affected individuals won’t have multiple changes to their eye-related genes. They typically have one rare or two uncommon changes that are not observed in the general public.”
This gradual degradation of the marsupial mole’s eyesight isn’t just a fascinating evolutionary story. It’s part of the bigger picture of how biological systems adapt when certain functions are no longer essential — which could be a particularly relevant piece of the puzzle for ophthalmologists diagnosing and treating human conditions, like Ken Nischal, executive vice chair of UPMC Ophthalmology and a pioneer in pediatric corneal transplants.
“You don't need your eyes if you're living underground, because you're using touch, feel. We started to look at the accelerated rates of mutations in these mammals and, behold, there were genes that we know make photo receptors in the retina that had huge rates of accelerated mutation rates,” Nischal said.
Even more importantly, other genes, which the researchers did not know the function of, also had huge rates of mutations. “And so we assumed that they must have some kind of role in eye disease,” Nischal explained. "What [Clark is] doing in our collaboration, to me, is the perfect example of translational research.”
Although Nischal did not participate in the genome research of the mole, he and Clark have been collaborating for about eight years on translating the DNA decoding into real-world applications for patients. First, Nischal, the clinician, presents a problem: A patient has a condition, but the usual suspect genes are not responsible. From there, Clark and his research team analyze the genome to identify putative genes that might be involved.
The combined goal is to identify the specific gene responsible for the condition and use that knowledge to inform future care.
“This kind of work is really going to be what's going to open up curing congenital childhood blindness,” Nischal said, “Because if we can figure out from an evolutionary point of view why animals lose their eyesight, then when these babies are born who have no corneas … it would be great to make that connection.”
Genetic mapping potentially holds the key to unlocking many medical mysteries, from heart disease to congenital defects, Lucas said.
“The goal of gene therapy and other gene editing techniques is to replace the improperly functioning/nonfunctional copy of the gene with one that functions more typically. In order to do that work, you first need to know which gene needs replacing. Research on the marsupial mole can help researchers narrow down the candidate pool quicker. This type of information turns a reported variant in a patient from being one of hundreds ‘Variant of Unknown Significance’ into a candidate for further testing to see if it is ‘Pathogenic’ and disease causing,” Lucas said.
Clark said genetic research and mapping has advanced tremendously but still has a ways to go: “We're missing a lot of these cases. We don't have all of them yet in our toolkit: finding all the genes involved.”
First Published: January 25, 2025, 10:30 a.m.
Updated: January 27, 2025, 1:43 p.m.
