Woolly mammoth genome rebuilt in 3D from freeze-dried skin

While the frozen remains of some woolly mammoths discovered in Siberia look as if they’ve only just died, this illusion is only skin deep.

This is because the DNA of these animals rapidly fragments after death, producing a genomic jigsaw puzzle that is difficult to put back together. However, a new discovery suggests this isn’t always the case.

Samples taken from a 52,000-year-old mammoth have found its genome frozen in time. It’s believed this occurred after the animal was rapidly freeze-dried by the Arctic air, causing its chromosomes to enter a glass-like state that stopped the DNA from splintering.

This made it easier for the researchers to reassemble the structure of its genome, something Dr Olga Dudchenko, the co-first author of the study, describes as ‘game-changing’ for scientists researching extinct animals.

“These ‘fossil chromosomes’ show that certain information is not lost to time and entropy,” Olga explains. “In the right circumstances, the 3D structure of the chromosomes isn’t lost, and can be read off and studied.”

“We don’t think this is something unique to mammoths. Any dehydrated remains, whether in permafrost or the desert, might have DNA preserved in this form. I certainly hope that they do, and finding them would offer a treasure trove of information about their genome.”

Professor Ian Barnes, who studies ancient DNA at the Natural History Museum and was not involved with the study, says this research opens a variety of new possibilities.

“The key here is not that the DNA is in exceptional condition in terms of its length or quantity, but because it’s easy to relate to the mammoth’s chromosome structure,” Ian says. “This means we can understand much more about how evolution has acted on that species.”

“It gives us new ways to ask questions we couldn’t before, like whether mammoths became more inbred over time, or which of their genes were under stronger natural selection at different times.”

The findings of the study, published in the journal Cell, may also have implications for a project to ‘resurrect’ the woolly mammoth announced in 2021.

DNA structure – more than just a double helix

While it’s tempting to imagine DNA as one long strand inside our cells, there’s one problem in that it wouldn’t fit. The average human cell, for example, needs to contain at least 205 centimetres of DNA in a space that’s two million times shorter.

To get around this problem, DNA is coiled around small proteins known as histones like beads on a necklace. In turn, these ‘beads’ are coiled even more tightly with other proteins to form compact packages of DNA.

The resulting 3D structure affects how easy it is to read specific genes. If the DNA is tightly wound, then genes in that area can’t be read. On the other hand, coiling can bring other sections of DNA known as enhancers closer to genes, which makes it more likely they’ll be active.

By studying the shape of the DNA in living organisms, researchers can figure out which genes are on and off. However, after death this structure is one of the first things to break down meaning it hasn’t been possible to do this for extinct species until now.

Fortunately for the scientists, a mammoth found in 2018 contained exactly what they needed. A DNA sample taken from behind its ear revealed that its genome structure was still largely intact, having been rapidly dehydrated tens of thousands of years ago.

“Compared to its closest relative, the Asian elephant, the genome of this mammoth seems to have moved very little,” Olga says. “We think this is because it has gone through a glass transition, a process that is used to preserve food all the time, from beef jerky to tortilla chips.”

“It turns out that this also prevents the DNA from moving, a state we dub chromoglass. This preserves the 3D genome architecture, giving us a lot of information we didn’t have before.”

To test how resilient these chromosome fossils were, the team left dried beef at room temperature for a year. Dr Marcela Sandoval Velasco, the study’s other co-first author, says that the chromosomes in the dehydrated samples remained well-preserved, even after being physically damaged.

“To see how robust the chromoglass was, we put dehydrated beef samples through a range of ‘intense experiments’,” Marcela says. “Through shooting it, smashing it, immersing it in acid and even running it over with a car, we found that the genome architecture is extremely resilient.”

What does mammoth DNA reveal?

After piecing together the 3D structure of the mammoth’s DNA, the researchers were then in a position to answer some of the most fundamental questions about their genetics.

One was simply how many chromosomes a mammoth has, with the researchers counting 28 pairs. This is the same as modern elephants, allowing the team to make comparisons with the mammoth’s living relatives.

While most of the active genes were the same between mammoths and elephants, around 3% were in a different state. For example, a gene that has been linked to sweat glands was found to be turned off in mammoths. This might have been an adaption to the cold and dry environments they were living in.

Also inactivated was a gene known as EGFR, which Marcela says could help to explain why mammoths have a thick woolly coat.

“EGFR plays a critical role in the development and maintenance of hair follicles, and when it is inhibited in humans, it causes excessive hair growth,” Marcela explains. “This could be one of the reasons why woolly mammoths have a hairier appearance than their modern relatives.”

While these initial findings seem like convincing reasons to explain how mammoths were adapted to the cold, the researchers are cautious to point out that the elephant DNA wasn’t taken from behind the ear. This means that the differences in gene expression could be the result of different parts of the body activating different genes, rather than evolutionary changes.

What is more certain is that the same dehydration process that preserved this mammoth’s DNA could be found in other remains. The team found that both freeze-drying and heat-drying could cause chromoglass to form, meaning the remains of a variety of species might retain their genetic structure.

The team speculate that museum specimens, including preserved animals and human mummies, would be a good place to start looking for fossil chromosomes. If this is the case, it could provide an unprecedented window into the lives of the distant past.