Freeze-dried woolly mammoths share their genetic secrets with scientists

A 52,000-year-old woolly mammoth was impeccably freeze-dried by nature, its swatches of fur remaining intact – remarkably enough – and allowing a global team of scientists to reconstruct the creature’s three-dimensional genome for the first time.

A study published Thursday in the journal Cell about mammoths inspires a new way of looking at ancient DNA samples that may hold more information about the past than previously thought.

“Look at that woolly mammoth. It’s beautiful,” said Erez Lieberman Aiden, an author of the study and professor of molecular and human genetics at Baylor College of Medicine, where he directs the Center for Genome Architecture. “The hair is still on it, and you see long stretches of its skin.”

The authors suggest that the mammoth was found in such a well-preserved state because of the dry and cold winters of Siberia, where it was found. In those conditions, the mammoth probably entered a dehydrated stated shortly after death, protecting it from being colonized by fungi and bacteria.

The researchers studied a small skin sample from the back of the mammoth’s ear. By zooming into the mammoth’s hair follicles – which have not been visualized before – the authors found that skin cells remained intact. Zooming in further, scientists found that chromosomes in each cell were still organized into clear territories, giving experts insight into which genes were switched on and off while the mammoth was alive.

“This work is about the fact that under certain circumstances, ancient samples can be preserved in this special way about which we didn’t know,” said Olga Dudchenko, another study author and assistant professor at Baylor College of Medicine.

Most ancient DNA samples are severely fragmented because DNA starts to decompose after an organism dies. Previous work showed that ancient DNA often degrades into segments made of fewer than a couple hundred base pairs – the building blocks of all DNA. For context, the human genome is made of about 3 billion base pairs, and the mammoth genome has more than 4 billion.

As a result, most ancient DNA research relies on mapping these small fragments to an existing genome containing DNA from a similar animal. While this one-dimensional DNA sequencing has provided tons of useful information, it does not give scientists the ability to zoom out and gain a three-dimensional view of the genome’s structure.

“Knowing the structure of the genome, you can figure out which genes were active in that particular animal at the moment that it died and which genes were repressed,” said Marc A. Marti-Renom, an author of the study and professor at the National Center for Genomic Analysis in Barcelona.

The researchers realized that although the ancient DNA in their mammoth sample had fragmented during the past 52 millennia, the diffusion of the fragments throughout the skin cells was relatively modest.

“The idea that molecules as small as the ancient DNA fragments can get stuck for long periods of time – so the geometry can survive tens of thousands of years later – is surprising. It’s physically remarkable,” Aiden said.

The authors found a similar preservation of chromosome structure in another woolly mammoth sample: a piece of skin from a 39,000-year-old mammoth named Yuka, who is regarded as one of the most well-preserved mammoths ever discovered.

The authors hypothesized that the chromosome arrangements were preserved by a process known as a glass transition, whereby all the components of a material become frozen in place below a certain temperature.

Glass transition is what makes shelf-stable food products possible. Things like cereal and instant coffee are trapped in a glasslike state, keeping their components from breaking down and allowing them to last longer.

The authors developed a new technique, called Paleo Hi-C, that allowed them to interpret the 3D structure of the mammoth’s genome. They found that the mammoth had 28 pairs of chromosomes, just like its closest living relative: the elephant.

Anders Sejr Hansen, an associate professor of biological engineering at MIT who was not involved in the study, said figuring out how to organize fragments of DNA into a full genome is like solving a puzzle.

“You have lots of small puzzle pieces, but how do you stitch them together?” Hansen said.

3D genomics can provide a picture on the puzzle box. 3D sequencing techniques, such as Paleo Hi-C, help researchers piece together DNA by taking into account where the fragments are located in the cell.

“This allows you to computationally reconstruct the genome to a much better extent,” Hansen said.

By using information about where chromosomes were located within the cells, the authors could spot genes that may be responsible for differences between the mammoth and the elephant – namely, the genes that led to hair growth and the mammoth’s ability to stay warm in cold environments.

In addition to advancing the field of genomics, the findings from Thursday’s study could play a role in animal conservation efforts.

“To assess how poorly or how well species are doing in terms of genetic diversity and their overall genetic health, it’s important to understand … what is ‘natural’ for them,” said Patrícia Chrzanová Pečnerová, an assistant professor of evolutionary genetics at the University of Copenhagen who was not involved in the study.

“If we want to be able to understand what is natural, we have to go back in the past,” Pečnerová said. “We have to study how the species and how the population looked like before, for example, people started hunting it a lot or before climate change happened.”

Eriona Hysolli, head of biological sciences at Colossal Biosciences – a company working to reintroduce a version of the woolly mammoth to the Arctic – said the 3D chromosome structures the authors found “could reveal features of the genome that might be relevant to mammoth de-extinction.”

The authors said they hope their work will inspire similar studies on other dehydrated tissues, including those hot-air dried by nature or intentionally mummified.

The study is “good news for the history of life on Earth, which is that it’s still out there,” Aiden said.