Image Marcos Amend.
Scientists from across the globe have sequenced and compared the DNA of almost all forms of mammals, in the most massive and ambitious genetics project ever. In a package of 11 studies published on Thursday in a special issue of Science, researchers outline what they’ve learned from this formidable undertaking, dubbed the Zoonomia Project. Some of the highlights include narrowing the list of genes that potentially underlie diseases like cancer, and determining the genetic advantages that gave the famous sled-dog Balto an edge.
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But these examples are just a fraction of what’s possible when it comes to understanding ourselves and other mammals. The project has been dubbed as an “expansion of the mammalverse” by experts and whose applications and findings “promise to astound in coming decades”. Digging into this newly-assembled trove of data will help scientists investigate the genetic causes of human diseases, how we evolved, and the amazing abilities and variety of mammals on this planet. Where before researchers might have sequenced and then compared the genomes of a couple of species in a particular group, say for example bats, Zoonomia sequenced the DNA from 240 mammals covering 80 percent of all mammal families including more than 50 endangered species. The project hinges on a technique called sequence alignment, which cuts up each genome into chunks then reassembles them so they line up with each other. Researchers can then compare these aligned genomes to the animal group that all modern mammals evolved from, to see how genomes changed over time. The analysis was detailed enough to be able to see changes as small as one genetic building block.“We’re trying to figure out, in every single species, for each position in their genome, which position it matches to in the ancestor of all mammals. So, how it has changed since then,” explained Elinor Karlsson, one of the project’s leads and director of the Vertebrate Genomics Group at the Broad Institute of MIT, in a press briefing.
What scientists end up with, explains Karlsson, is a “three bears situation” where some areas of the genome are really similar across all mammals, some that have changed about as much as they’d expect (based on the fact that random mutations pop up pretty consistently), and some places where there’s suddenly a huge change a particular group of mammals. Each type of change tells researchers something important. A sudden change for example could show how a species is adapting to its environment and may explain some animals’ extraordinary abilities like hibernation or a highly sensitive sense of smell. “Mammals have adapted to almost every ecosystem on the planet,” said Karlsson. “So finding what’s underlying those adaptations would be really cool.”On the flipside, areas that show little change over time, or so-called constrained areas, tell evolutionary biologists that genes in those sections are doing something important. In evolutionary biology, if something’s important, it sticks around.Zoonomia researchers identified more than 100 million sections of genomes that are barely different across the 200-plus species. They think these areas are the ones that are crucial for the biology that makes all animals tick—things like the chemistry that drives our cells or how groups of cells grow and work together to make organs.In humans, they discovered that roughly 10 percent of our genome is constrained, meaning that roughly a tenth of it codes for proteins in the body or helps determine where in the body, when, and how many of those proteins get made. Previously, scientists thought that anywhere between 3 and 12 percent were functional.
“The human genome was sequenced more than 20 years ago but it’s still really hard to understand what the functional elements are,” said Zoonomia’s other lead, Kerstin Lindblad-Toh, who’s a professor of comparative genomics at Uppsala University in Sweden. “We’ve gotten incredibly good at sequencing genomes but it’s really hard for us to actually understand what they’re doing,” adds Karlsson.It’s vital for scientists to understand which sections of DNA serve a function and how our genes work to find treatments for inherited disorders like heart disease, schizophrenia or diabetes. Researchers, including Lindblad-Toh, have already used the information from Zoonomia to identify new gene mutations that increase a person’s risk of a particular type of brain cancer.Yet another notable study to come out of the Zoonomia Project so far is an analysis of famous sled-dog Balto’s DNA. Balto is known for leading a group of dogs on a mission to deliver a diphtheria antitoxin to a highly remote area of Alaska—a journey that required incredible physical resilience. To see what made Balto unique, researchers used the information they had from Zoonomia, on which parts of the genome were similar across dogs, to pick out sections where Balto was different. The analysis showed that Balto was less inbred than similar, modern dog breeds and he had fewer mutations to his genes that might have put him at risk of becoming sick. Still other studies in the collection cover questions around biodiversity and conservation, the evolution of brain size and when mammals first evolved.Karlsson and Lindblad-Toh say they hope these initial studies will blast the door open on more research about the plethora of mammals on our planet. “Humans are really good at studying humans... But when you get out into a lot of other species, we know surprisingly little about them and what they can do,” said Karlsson. They’re urging biologists to collect more genetic samples to grow the Zoonomia database. Hopes are running high for the possibilities for the project long-term. Deputy editor for research at the American Association for the Advancement of Science wrote “the Zoonomia project heralds a new era in which the joint production of genomes from hundreds of species will open the door to new ways of understanding mammals, mammalian evolution, and ourselves."