In the very, very big picture, the story of a species can feel ponderous and slow. Over generations, mutations accumulate in our DNA—the code that produces our cells, our organs, and sets the broad patterns of our lives. It’s DNA that splits, recombines, and divides to pass down its knowledge—and any mutations that proved either neutral or potentially beneficial—to the next generation.
But on a smaller scale, in the iconic words from Ferris Bueller’s Day Off, “Life moves pretty fast.” Climates can switch from dry to wet, cold to warm. Food and shelter can appear and disappear, become rare or hyperabundant. Our DNA may have prepared us for some of it, but a set of As, Cs, Ts, and Gs can only reflect our past. It cannot predict our future.
And in the face of species-altering challenges within a single generation or two, DNA hits its limits. What picks up the slack, helping a species adapt and survive? The flexibility could come with epigenetics—the tags and tweaks that control how those genetic instructions become proteins, cells, and finally, organs. Evolution isn’t as simple as a change to a genetic letter. Instead, epigenetics might also allow a species to adapt on the fly, by tailoring the expression of already present genes to an ever-changing environment.
Those epigenetic changes could make the differences between whether a species survives and thrives—or whether it disappears.
Just two million years ago, the genus Homo spun off a branch of the primate family tree. Only 100,000 years ago, there were at least three known human variants hunting and gathering their way around Africa, Europe, and Asia. They weathered climates from tropical to icy, met, and interbred.
And then, by 40,000 years ago, there was only one left. Climate, resources, or something else brought an end to every human population but Homo sapiens. Within such a short span of time, it would have been epigenetics, not genetics, that adjusted our heights and builds. Epigenetics tweaked crucial proteins in the structures and functions of our brains.
From Ancient to Modern Human Brains
Liran Carmel, a computational biologist, and Eran Meshorer, a paleoepigeneticist, both at the Hebrew University of Jerusalem in Israel, have been steadily reconstructing the epigenetic markers on the DNA of modern and ancient humans. They have already used the results to predict how Denisovans might have looked slightly different from anatomically modern humans, from facial shape to pelvis, and how Neanderthals’ voice boxes and skull shapes might have compared to our own.
Now, with funding from the John Templeton Foundation, Carmel and Meshorer have been looking into how changes in epigenetics between modern and ancient humans might manifest in our brains. Using their techniques for detecting ancient genetic tags, they have identified places where DNA is regulated differently between us and our ancient kin—places involved in key neural functions that could make big differences in how anatomically modern humans encountered the world.
The epigenetic changes Carmel and Meshorer have found highlight how quickly large differences between species can arise—even before DNA drastically differs. “An emerging viewpoint now is that epigenetics serve as a first layer of response for a changing environment,” Carmel says. “It gives enough time to the genetics to respond.”
Our epigenetics, they reason, produced some of the features of the modern human brain, including benefits to language, cognitive processing, and brain cell survival. The new big brains bought us time on our planet in the face of changes that doomed our kin.
Marking Up the Genetic Instruction Manual
DNA has long told us that there’s very little that differs between us and our closest kin. Calculating the exact percentage points of DNA differences—98.9 percent between us and chimps—may be a fun exercise, but not always a useful one, explains David Reich, a geneticist at Harvard Medical School. “I think these percentage numbers are both helpful and confusing,” he says. Species could be very similar in terms of their DNA. But if the few changes they have are in genes that code for important proteins and cell functions, tiny changes could mean a lot.
Just as important as changes in our DNA itself, it turns out, is how that DNA is regulated. Every cell in the body contains the same DNA. But bone looks very different from muscle or brain. As a cell develops, it receives and sends signals that cause some of its genes to be expressed, while others sit quiet and unused. Something is controlling which parts of the manual each cell “reads,” and how much of that is produced as proteins and cell functions. Some of that control is from promoters and enhancers on the DNA itself. But much of it is from epigenetics.
Methylating the Manual
Epigenetics are structural changes in DNA that control where and how it is used. “A majority of the data has really been focused on changes in promoters and enhancers,” explains Megan Dennis, a genomicist at the University of California, Davis. These are regions of DNA that control other regions, promoting them to be transcribed more or suppressing them, reducing how much a gene’s DNA produces a protein.
One way to modify these promoters and enhancers is to make them more or less available for cellular machinery to transcribe. Genes bound up around histones, for example, are unavailable for transcription—a part of the instruction manual placed back on the shelf.
“But the most studied epigenetic change is methylation,” Dennis explains. Methylation—the popping of a methyl group onto a nucleotide—is largely an automatic process, says Meshorer. Specialized cellular machinery hunts for specific base pair patterns in DNA, and where it spots one, it methylates.
In general, to methylate areas of a promoter region is to render it less active. Methylation can occur during the adult life of a cell, but most of it occurs in development, making a cell into one specific for a tissue like bone or brain. But other enzymes can demethylate, or add more methylation later in a cell’s life, responding to changes in the environment, from changes in temperature to experiences that form memories.
The Ancient Epigenome
Where genetics is slow, Carmel explains, epigenetic changes like methylation can change within the lifespan of a single organism. “Basically, genetics responds very slowly because your DNA is totally stable, and you have to wait for generations to pass in order to see differences. Sometimes you need to respond much faster to changing environmental conditions, and the plastic nature of epigenetic patterns allows the body to respond much faster,” he says. Methylation changes could recur in subsequent generations, “and then eventually genetics would catch up.”
Understanding those changes and when they occurred could show researchers how humans became anatomically modern—how we became what we are today.
Carmel and Meshorer have been working for years to reconstruct methylation patterns. It’s a significant technical challenge, Carmel says. Methylation patterns aren’t preserved, only the marks of where they once were. Carmel has developed a method to identify these marks, creating a ghost map of the epigenome that existed when the DNA was whole.
Bone Collectors
Carmel and Meshorer wanted to create methylation maps for bone—the most frequently preserved tissue. That meant making maps for modern bones, as well as ancient ones. Samples from archaic humans were often drilled out of a single ancient tooth. Bone samples from great apes arrived in tiny dry slivers. But modern human bone arrived, er, fresh.
“When we started working with human bones, it looks white when it comes from the operation room,” Meshorer says. Inside, however, the fresh bone still contained marrow—which had made blood cells. “When we drilled it for the first time, it was like a slaughterhouse.”
Once the methods were fully validated—and relatively bloodless—Carmel and Meshorer began reconstructing DNA methylation patterns in ancient and modern humans, and used an algorithm to compare them.
Across anatomically modern humans, ancient humans, Neanderthals, and Denisovans, Carmel and Meshorer identified approximately 3,000 regions that showed significant methylation differences.
Carmel and Meshorer used their maps to “reconstruct” ancient anatomy. “We were able to zoom in on five very important developmental genes that are known to be involved in shaping the skeletal system,” Carmel says. “We think that together, they are responsible for the unique shape of the human face and voice box.”
The modern human face is much flatter, more retracted, than our Neanderthal cousins, Meshorer notes. A flatter face leads to a different voice box position—which leads to different capabilities of the voice itself. “People wonder whether Neanderthals, Denisovans, could speak,” he says. “Probably they could speak as well as modern humans. At least as much as we would be able to speak 50,000 to 150,000 years ago.”
But while we may have had similar powers of speech to our near relations, that doesn’t mean we had the same things to say.
From Bone to Brain
Carmel and Meshorer are especially interested in understanding how these epigenetic changes might have made the modern human brain possible. Dennis has also been studying methods of brain evolution, including faster changes to DNA such as gene duplications. More copies of a gene, she notes, can produce new versions. Duplications of genes, she has found, can increase connections between brain cells, increase learning and memory, and more.
Epigenetic changes, particularly during development, can also drastically increase or decrease the expression of genes. Carmel and Meshorer wondered if methylation changes might produce similar brain differences between anatomically modern humans and their near relatives. But their studies were in bone, and methylation can vary a great deal between different tissues. While scientists can, with great effort, get samples of ancient bones, preservation of soft tissues like the brain would be miraculous.
Given those constraints, Carmel and Meshorer began to ask if it would be possible to extrapolate some of the methylation findings from bone to the brain. Under very specific circumstances, it turns out, the answer is yes.
Their new techniques identified more than 1,850 differences in DNA methylation between ancient and modern neurons. Some were linked to brain volume and cognitive function. Others play important roles in early neuron survival. Still others are associated with language impairment, schizophrenia, and how the brain reacts to injury.
Evolution: Fast and Slow
“There’s a lot that’s not known about the drivers of human evolution,” Dennis says. “We only have a handful of examples where we feel relatively confident that they likely contributed to the phenotypes we have today.” Finding these DNA methylation changes, she notes, offers a direction to find more.
Carmel and Meshorer have many new candidates. But these are only signs that something was different in the methylation. Now, Carmel says, they have to go through and find out what the signals mean. Some of the genes are connected with brain volume or cognitive function—what happens if those methylation changes are applied now? What changes in a brain cell of a mouse, or a human?
The results could paint a picture of a species adapting on the run, balancing speedy epigenetic adaptation with the slower, permanent changes to DNA. Changing a gene in response to a sudden new environment is high risk, Meshorer says. “But if you have a subtle mutation that will just methylate and reduce its expression, then you can buy epigenetic means to find a much fitter balance.”
That balance could help scientists understand why modern humans managed to make it, when so many others like us did not.
Bethany Brookshire is an award-winning science journalist and author of the book, Pests: How Humans Create Animal Villains. Her work has appeared in Scientific American, The New York Times, The Washington Post, The Atlantic, and other outlets.
