Zoonomia’s Genomics of Scale

By sharing as many wildlife reference genomes as possible, can the Zoonomia Project provide early warnings about animals in danger of extinction?

  • By Robin Tricoles
  • Conservation
  • Dec 30, 2023

Beyond the southern resident orcas (above right), which are known to be in peril, “There may be species out there which look like they’re doing OK,” says Fred Allendorf, conservation biologist and University of Montana professor emeritus. “But when we look at them genomically, we may see indications there are going to be problems in the future.” A stylized phylogenetic tree (detail, left) illustrates evolutionary relationships among animals, such as the mammals in the Zoonomia Project’s database. (Phylogenetic tree illustration by 360 Design/Courtesy of Zoonomia Project; Photo by Heather MacIntyre)

CONSERVATIONISTS HAVE KNOWN FOR DECADES that southern resident orcas are in trouble. Despite being covered by the Marine Mammal Protection Act since 1972 and listed under the Endangered Species Act since 2005, the whales’ numbers continue to decline. Per the Marine Mammal Commission, only 74 individuals remained as of 2023.

The whales, which spend summer and fall in Puget Sound along the coast of Washington state, have been subject to culling, contaminants and harassment. Noise pollution from vessels interferes with the whales’ ability to locate food, chiefly Chinook salmon, whose numbers also have declined precipitously. What’s more, the whales are so inbred that recovery is extremely unlikely without genetic intervention, according to conservation biologist Fred Allendorf, professor emeritus at the University of Montana.

Inbreeding, or mating between close relatives, leads to undesirable traits that make a species less robust, decreasing genetic variation and lessening the odds that offspring will survive and reproduce. Artificially inseminating females from one orca population with sperm from another population could help. But the whales’ extreme circumstances, and the expense and difficulty associated with intervention, raise the question of how many resources should be allotted to save a species that’s considered a long shot.

Some say the relatively new and cost-effective tools of genomic sequencing and analysis could have revealed signs of a weakened population long before other stress factors appeared. “Genetic data can tell us if a population or a species is in trouble,” says Nicole Foley, a research scientist at Texas A&M University. Had the orcas’ genomes been sequenced and analyzed years before, the findings might have made a difference in their conservation status, according to Marty Kardos, a research geneticist at NOAA’s Northwest Fisheries Science Center, headquartered in Seattle.

While sequencing may be too late for southern resident orcas, the use of genomic data could help other wildlife from reaching such dire straits. “There may be species out there which look like they’re doing OK,” Allendorf says. “But when we look at them genomically, we may see indications there are going to be problems in the future.”

Others caution that genomic sequencing isn’t a silver bullet and researchers must avoid drawing unwarranted inferences about a population’s viability. “People are really excited about trying to predict extinction by using genomes,” Kardos says. “The reality is more complex than we’d like it to be.”

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An image of southern resident orcas.

In analyzing sequence data from southern resident orcas and comparing it to new data from genetically distinct northern resident orcas, Canadian researchers aim to evaluate inbreeding effects on the northern residents. Unlike the southern population, the number of northern resident orcas is starting to increase following legal protection.

The origin story

Twenty years ago, the Human Genome Project published the first sequence of a human genome, or the complete set of DNA found in a cell. By providing a genetic blueprint, the estimated $3 billion global endeavor accelerated the identification, prediction and treatment of diseases such as diabetes and certain cancers. Since then, sequencing has become cheaper and faster, with scientists regularly sequencing the genomes of viruses, bacteria, plants and animals.

In 2015, Kerstin Lindblad-Toh, a comparative geneticist at the Broad Institute in Massachusetts and Uppsala University in Sweden, led the creation of a database that would use comparative genomics to better understand mammalian evolution and, in turn, human diseases. Today scientists from all over the world access the database, now known as the Zoonomia Project, for research on topics ranging from extending human longevity to wildlife conservation.

Because Zoonomia is in the public domain, scientists can download data from previously sequenced genomes for further analysis. They can also sequence genomes from samples they’ve obtained separately and upload that information to Zoonomia. Elinor Karlsson, who studies cardiomyopathy in captive meerkats, sequenced a meerkat reference genome and then made it available to other researchers—just one of the more than 400 species now among the project’s portfolio.

Karlsson, director of the Vertebrate Genomics Group at the Broad Institute and a professor of biology and bioinformatics at the University of Massachusetts Chan Medical School, joined Zoonomia soon after its launch. Together with Lindblad-Toh, she helped wrangle the database’s first mammalian genomes, courting sources of DNA data from the National Institutes of Health to the San Diego Zoo Wildlife Alliance’s Frozen Zoo, which stores living-cell cultures, oocytes, sperm and embryos from thousands of species.

“We wanted to get as many branches or families of mammals represented as we could,” Karlsson says in an email. “We had to go out and talk to a lot of scientists working with a lot of weird species to try and get DNA from them.”

Over time, scientists aim to add more reference genomes to the database. Unlike the Human Genome Project, which allows for genomic comparison among humans, Zoonomia lets researchers compare a sequenced genome from one mammalian species with genomes from other mammalian species—for example, comparing data from macaques, rats and bats to examine how vocal behavior has evolved across mammals. “The Zoonomia Project is really different from a lot of other conservation projects that are really species-centric,” says Megan Supple, a project scientist at the University of California Santa Cruz who looks at genetics across mountain lion populations.

Comparing genomes can reveal whether a common evolutionary function or dysfunction exists and how genomes change over time or don’t. In turn, that information could help scientists better understand species hardiness, with implications for wildlife conservation—and human health.

“A genome on its own is just a long string of As, Cs, Ts and Gs,” Karlsson explains. “We learn what that sequence of letters does (and which parts are important) by comparing it to other species—and the more species the better.”

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A collage containing a photo of frozen white rhino DNA and  a photo of two white rhinos.

Despite the inclusion of northern white rhino DNA in the San Diego Zoo Wildlife Alliance’s Frozen Zoo (left)—and its genomic data in Zoonomia’s portfolio—the subspecies (right) is now considered functionally extinct, with only two females remaining.

Superstars and wallflowers

For various reasons—funding and public interest among them—wildlife conservation favors charismatic species such as seals and big cats. Similar preferences show up in genetic research: Data are plentiful for dogs, cats and koala bears, in part because we have an affinity for them, and for livestock, because we have a monetary stake in their health.

While Zoonomia’s portfolio includes favorites like pandas and gorillas, scientists intentionally seek out less glamorous species as well. The brown rat and the banded mongoose are now getting their very own reference genomes, for example. Some scientists see that diversity, and genomics itself, as a way to triage wildlife that otherwise might be overlooked.

“There are a lot of species who don’t get the money and attention, and so this is a good way to identify some of those before they slip through the cracks,” Supple says. Plus, by collecting data on mammals from various branches of the evolutionary tree, scientists can distinguish differences that make a species particularly distinctive—and potentially vulnerable. If a species with no close genetic relatives goes extinct, an entire evolutionary lineage disappears, as does scientists’ ability to learn from it. Identifying these genomic outliers can make them priority candidates for conservation.

Pinpointing susceptible species while they’re still doing relatively well also can help conservation scientists take action early on, when intervention can be more cost-effective. That’s important because wildlife conservation is about more than protecting a single species, environmentalists say. It’s about protecting entire ecosystems.

“The principal behind conservation biology for the last 50 years is that we should conserve all species and let natural selection sort things out in the wild, and the way to do that is to maintain natural levels of connectivity and to limit habitat loss,” Kardos says.

“One of the things I find exciting about genomes is they have a whole history embedded in them.” –Megan Supple


The science of trouble-spotting

Animals encounter many threats in the wild, from habitat loss to climate change, pollution, illegal trafficking and human predation—all of which can result in population shrinkage and inbreeding, as with the orcas. To establish a species’ hardiness in the face of those obstacles, conservationists observe individuals over time, keeping data about when an animal was born, when it died, who its parents were and how many offspring it had. By knowing an individual’s pedigree, conservationists can determine its fitness.

When data indicate an entire population is in trouble—from inbreeding, for example—conservation scientists might decide an approach known as genetic rescue is in order. Genetic rescue involves introducing DNA from a healthy population to a declining one, with the goal of revving up genetic diversity and thereby rates of reproduction and offspring survival. (In a classic case study from the 1990s, genes from Texas pumas were introduced to the endangered Florida panther population.)

But genetic rescue can be controversial. Even as it addresses inbreeding, it lessens genetic distinctiveness: Introducing northern resident orca genes to southern residents would blur the lines between the two populations. For that reason, many conservationists champion responses that support “natural” gene flow, such as the Santa Monica wildlife crossing, which aims to bolster an inbred population of mountain lions by improving habitat connectivity rather than by artificial insemination.

Genomic sequencing, like genetic rescue, draws a number of the same criticisms. But proponents see sequencing as an opportunity to speed up the observation process. “That’s one really powerful way of using genomics in conservation,” Kardos says. “We can see if inbreeding is compromising fitness, and we can do something about it. We don’t need a pedigree that extends many generations into the past.”

Supple agrees: “One of the things I find exciting about genomes is they have a whole history embedded in them.”

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An image of a ground pangolin foraging for termites.

Scientists say the act of sequencing can call attention to an imperiled species such as the pangolin, a frequent victim of illegal trafficking, pictured here in Mozambique.

Costs and opportunities

Although genetic analysis can save time in wildlife conservation, it isn’t cheap. A Tasmanian devil has 14 chromosomes while a coyote has 78, and the cost of sequencing varies accordingly—typically thousands of dollars on the low end. Comparative analysis costs thousands more and, according to some, is where the real effort begins.

“The difficult work is in the analysis of the genome. When you sequence a genome, you don’t really know anything much about what it does,” says Christopher Balakrishnan, a program director at the National Science Foundation (NSF). “You have to compare it to other things, and you have to identify what parts of the genome are important or not.”

Just as sequenced data don’t reveal much without further analysis, no amount of genetic analysis can save a troubled species without real-world intervention. “It’s one tool to add to the ecological research and other research that’s being done on the ground,” Supple says. Genetics can shed light on an animal’s fitness, its potential for adaptation and whether it’s carrying diseases, but only traditional field work can reveal where and how an animal lives, when it breeds and the size of its territory. “It’s not one or the other,” says Carolyn Hogg, a conservation biologist at The University of Sydney who researches incidents of cancer among Tasmanian devils.

Neither is genomic sequencing fail-safe and, as with any new technology, bugs remain. In recent years, sequences could be fragmented and incomplete, although Karlsson says accuracy improves all the time. Supple, too, acknowledges that data gleaned from genomes may contain errors, but because her work often takes a broad view of a species, “if there are errors, they don’t have a big influence.” She emphasizes that scientists keep mistakes in mind when applying genomic information toward conservation decisions.

Even so, “There’s a lot of irrational exuberance about genome sequencing and its ability to advance conservation,” Kardos says. “I’m a strong advocate for using genomic data for conservation, but I’m also trying to instill more caution than some people are using right now when it comes to the application of genetic data.”

Because Zoonomia is still in its infancy, scientists say it’s way too soon to attribute any conservation successes to the database or related research. But some see an immediate benefit: Certain charisma-challenged wildlife are already receiving increased attention. “They got a genome,” says Foley, of Texas A&M. “We’re now able to address some of the ones that are most in danger, like the pangolin,” a prime target of overseas trafficking. A sequenced genome could be a first step toward green-lighting further study and funding.

Zoonomia itself has been funded by an array of sources: some that invest in basic science, like NSF, the Swedish Research Council, and the Knut and Alice Wallenberg Foundation; and some that focus on medicine and human health, such as the National Human Genome Research Institute, NIH, the Broad Institute and others.

As for whether future funding might prioritize wildlife species that could offer insights into human health over those in need of conservation, scientists interviewed for this story say they see little cause for concern. Different institutions bankroll different types of research, and Zoonomia draws on “a big group of people that are sort of pooling resources and methods and expertise to answer all different kinds of questions using those resources,” Balakrishnan says. What’s more, because Zoonomia collects only data—no DNA samples or genetic material—the database isn’t subject to domestic or international regulations that might apply to lab research.

According to Oliver Ryder, director of conservation genetics at the San Diego Zoo Wildlife Alliance, for wildlife conservation to succeed ethically, it takes “lots and lots of people”: conservation biologists, genetic ecologists, epidemiologists, lawyers, bioinformaticians, computer scientists, policymakers and funders from all over the world. And for wildlife conservation to remain the end goal, he says Zoonomia data must remain accessible and in the public domain: “It’s important to do [comparative genomics] rapidly, do it comprehensively and to do it on a global scale, and in a way that is equitable and inclusive.”

Hogg emphasizes that Zoonomia and its data do nothing for wildlife without subsequent action. “If you buy a book and you put it on the shelf, it has had absolutely no impact or influence on your life,” she says. “But the moment you take the book off the shelf and you start to read it, that’s when it starts to have influence and impact, and it is exactly the same for a reference genome.”

Robin Tricoles, an independent science writer based in Tucson, teaches at The University of Arizona’s journalism school.

More from National Wildlife magazine and the National Wildlife Federation:

Connecting the Florida Wildlife Corridor »
The Endangered Species Act at 50 »

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