Even before the reign of the dinosaurs ended in a mass extinction event about 65 million years ago, mammals had already gotten a humble but solid foothold.
That's just one of the findings from a close examination of DNA from 240 different mammalian species, an ambitious effort to understand how hairy, milk-producing mammals — including humans — evolved to have such an astonishing array of sizes, shapes, and special abilities.
Scientists know of around 6,500 living mammal species, inhabiting practically every environment on Earth — from frigid oceans to high deserts. This international project, called Zoonomia, set out to collect genetic material from across the entire mammalian family tree.
Researchers obtained DNA from all kinds of mammalian critters, like caribou, armadillos, bats, and bison. Their genetic menagerie eventually included 52 endangered species, like the giant otter and the Amazon river dolphin, as well as primates like chimps and humans.
"We're still only looking at a tiny portion of mammals, but it is the largest project we've ever done like this," says Elinor Karlsson, professor at the UMass Chan Medical School and the Broad Institute of MIT and Harvard, who notes that 80 percent of the mammalian families are represented in their collection.
After determining the sequence of chemical "letters" that made up the genetic code of each species, researchers then "aligned" those sequences so that they could be comprehensively compared. That let them spot which genetic regions had been unchanged over millions of years of evolution, suggesting that these contained essential biological instructions for making mammals.
They were also able to tease out genetic differences between mammalian species, which allowed them to probe the possible genetic underpinnings of unique traits such as the ability to hibernate, or an extremely sensitive sense of smell.
"It turns out that there's a weird little South American rodent that nobody seems to know very much about that has a huge number of olfactory genes and receptors," says Karlsson. "It sort of points out what we can discover when we are just looking at everything."
She and her colleagues have now published 11 research reports in the journal Science that lay out some of their first efforts to understand what exactly, at the genetic level, makes a mammal.
And intriguingly, they found some clues about how one mammal, Homo sapiens, evolved to have such a unique brain — the kind of brain that can ponder mammals and devise complex computational programs to compare and contrast the massive amounts of data in all of this genetic code.
When mammals started to emerge
Scientists have long debated exactly when mammals first appeared on Earth and how and why they began to diversify, eventually establishing themselves in almost every possible habitat and ranging in size from tiny bats to enormous whales.
"The reality is, from an evolutionary point of view, we don't know as much about mammals as we do know about how birds diverged," says Nicole Foley of Texas A&M University.
In the past, many researchers used the fossil record to insist that all of the real action for mammals occurred after the mass extinction of the non-avian dinosaurs, she explains.
But this vast new collection of mammalian DNA gave Foley and her colleagues a chance to look at this in a different way, by analyzing so-called neutrally-evolving sites, where random changes in the genetic code over time can serve as a kind of clock.
"With all of this data, we can kind of get to the point where we have a much more accurate timeline for mammalian diversification," says Foley.
What they saw indicates that the earliest mammals were walking around under the feet of the dinosaurs — even though mammals hadn't really had a chance to take off yet.
"Mammalian evolution kind of starts off slow back in the Cretaceous, but it's there," says Foley. "Mammals are established in the Cretaceous."
These creatures may have been small, and found in low numbers, but they were the predecessors of everything from bats to primates, says Bill Murphy, also of Texas A&M. "They only started to look like the modern bats and the modern primates," he says, "once the dinosaurs were gone."
From hibernation to a hero dog
Today's mammals share many features, but they also differ in important ways. For example, only some can hibernate, which Karlsson notes is an amazing activity.
"Basically animals are able to get super obese, climb into a hole, not move a whole lot for months on end. And then they lose all that weight and they come out and they don't have blood clots and they don't have strokes and they don't have diabetes," she says.
That's why one of the first things the researchers did is compare the genetic code of hibernating species to their non-hibernating relatives. "And that ended up finding some genes involved in some interesting traits, including aging," says Karlsson.
Researchers also tried to use the information in their mammalian DNA collection to see if they could make predictions, such as exploring what species might be susceptible to the pandemic coronavirus. Some of their predictions, such as the likelihood that deer would be affected, did indeed pan out.
One group of researchers at the University of California, Santa Cruz, used this dataset — along with hundreds of genomes of modern dogs — to try to find out something about a very special dog from the past.
They collected DNA from a sled dog named Balto, who famously helped transport precious medicine across Alaska during a diphtheria outbreak in 1925. A statue of him stands in New York City's Central Park, and his stuffed body is in a Cleveland museum.
It turns out that Balto was less inbred than dogs from modern breeds, and possibly had adaptations that helped him stay active in harsh conditions. For example, he had variants in genes related to things like joint formation and skin thickness.
What's missing in humans
The uniqueness of humans has long fascinated scientists, and researchers have compared human DNA to that of our close relative, chimpanzees, as well as other species to try to learn what sets the human brain apart.
Steven Reilly of the Yale School of Medicine says that he and his colleagues wanted to know what bits of foundational mammalian DNA had been lost in humans.
"We asked, what has been around across millions of years of evolution, and that if you look in a dolphin or you look at a dog or you look at a donkey, it's all there, but then suddenly in humans — poof! — we don't have it," explains Reilly.
They identified about 10,000 bits of DNA that exist in most other mammals but not humans, and most of these deletions occurred in parts of the genetic code that are thought to be in regulatory regions, where they can act like dimmer switches that turn the activity of other genes up or down.
Many of the human-specific deletions occurred near genes related to the development of the brain, says Reilly, but it wasn't clear which of them might actually be doing something.
So his group then did experiments in a wide range of cell types, to see which deletions could actually produce changes in gene activity. They found about 800 cases where the human version of the DNA produced a different outcome than the chimp version.
When they took a cell from a human nervous system and added a deleted bit of DNA back in, they could sometimes see wide-ranging effects. For example, they saw that the activity of one gene went down, and this had a cascading effect on the activity of around 30 other genes, ones that are associated with the formation of a kind of insulation around brain cells — a process called myelination. The brains of humans and chimps are known to differ markedly in the speed of this myelination (humans go slower).
"The fact that this one change seems to cause a reduction in all of these genes that would promote myelination means that this might be one of the genetic links towards this known difference between humans and chimps," says Reilly.
He called it "almost a little humbling that we don't have a lot of new fancy bells and whistles to build a brain. It's largely using the same building blocks that go into making a chimp brain. Just in a slightly different way."
Where genetic changes speed up
But some parts of the human genome do seem to have evolved particularly quickly. That was the focus of one study that wanted to understand the stretches of DNA that are nearly identical among humans, but that differ from all other mammals.
Scientists have looked for these regions in the past, but this new collection of mammalian genomes gives that search new power.
It turns out that many regions of accelerated genetic changes in humans cause DNA to fold differently compared to other primates, says Katie Pollard, director of the Gladstone Institute of Data Science and Biotechnology in San Francisco. That's important because different kinds of folding can dramatically affect what genes get turned on and off and how they all interact.
"DNA is a very long, skinny molecule. You can think about it as a thread and imagine taking more than a meter of thread and trying to scrunch it down into the nucleus of a cell," says Pollard. "It doesn't just get randomly scrunched in and folded up. It actually folds in a concerted way. And the way it folds is predictable from the sequence of the DNA."
Many years ago, says Pollard, biologists thought that human genes might be radically different from chimp genes. Instead, what they've learned is that the protein-producing genes themselves are pretty similar, but the way they're regulated and even packaged-up in three-dimensional space might be profoundly altered in humans.
"I think it's important to remember that what makes us human is not one change, but many, many changes," says Karlsson.
What's more, she says, humans have traditionally been very good at studying humans and other primates, "but when you get out into a lot of other species, we know surprisingly little about them and what they can do."
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