Scientists analyze mammoth and find fossil chromosomes for the first time

In a groundbreaking discovery from a new study, a piece of woolly mammoth skin was found containing fossil chromosomes after excavation in a Siberian permafost — which is, roughly speaking, ground that has been frozen for long periods.

Researchers have unearthed the remains of a 52,000-year-old mammoth in 2018, near the village of White Mountain in northeastern Siberia, where freezing temperatures helped preserve the makeup of chromosomes — tiny, threadlike structures that carry genetic material, or DNA — in minute detail.

Although samples of ancient DNA have been found on other occasions, they are usually highly fragmented and contain only hundreds of letters of the genetic code. Fossil chromosomes contain millions, offering a much more complete view of an animal’s genetic code .

“Fossil chromosomes have never been found before,” he said. Erez Lieberman Aiden professor of molecular and human genetics at Baylor College of Medicine and co-corresponding author of the study published Thursday (11) in the journal Cell.

In previous discoveries, the fragments also lacked an organized structure, Lieberman Aiden added. “Here, the fragments are clearly organized in 3D — essentially as they were in the original chromosomes in the living mammoth.”

According to Olga Dudchenko, assistant professor of molecular and human genetics at Baylor College of Medicine and co-first author of the study, the chromosomes, referred to as “unmineralized fossils, or subfossils” by the researchers, are in a state of preservation good enough to assemble the genome — or the sum of all genetic material — of an extinct species.

“We strongly believe that this will not only apply to the mammoth or to this specific mammoth,” said Dudchenko, who is also a senior research scientist at Rice University’s Center for Theoretical Biological Physics. “But in practice, it is the beginning of a new area of ​​research with great possibilities.”

DNA diffusion

In different cell types, DNA sits in distinct and specific 3D structures that provide insights into the particular properties or characteristics of that cell type, he said. Kevin Campbell professor of environmental and evolutionary physiology at the University of Manitoba in Canada, who was not involved in the study.

After death, the body’s cells degrade rapidly, and this 3D structure is lost within days or less, he added. In arctic animals like the woolly mammoth, degradation is slower due to freezing temperatures, but the DNA is still damaged and, over long periods of time, is expected to lose the structure and attributes that make up the species’ biology.

“However, this study is the first to demonstrate that this is not always the case,” Campbell said in an email. “DNA is a very long molecule, and after an animal dies, it begins to deteriorate and break down into smaller fragments,” Dudchenko explained.

“What you normally expect is that all these pieces would start moving relative to each other and dispersing, losing any organization that was there,” Dudchenko said. “But clearly in this particular sample, that didn’t happen.”

This loss of structure is called diffusion, and how to prevent it is well known to food scientists — and it’s not unlike the production of jerky, he added.

“Preventing diffusion is key to preserving food, so if you want something to be shelf-stable for a long time, you basically need a combination of dehydration and cooling,” she said. “Any shelf-stable food that isn’t canned is probably in a state of diffusion blocking.”

When the mammoth in the skin sample died, the conditions may have been just right to start this process naturally . “(The carcass) could have spontaneously undergone the same procedure we use commercially all the time,” Dudchenko said, “removing substantial amounts of water, blocking internal diffusion and fixing these pieces of chromosomes in place, allowing us to read them 52,000 years later.”

But although it was well preserved, the DNA was not completely intact . “Each chromosome, originally a single DNA molecule, has fragmented into millions of DNA molecules,” Aiden said in an email. “But the molecules haven’t moved much, even on a nanometer scale, so we call them fossil chromosomes.”

If this sample were a book, Lieberman Aiden said, the binding would have disappeared, leaving countless loose pages or DNA fragments. Diffusion is like the wind blowing the pages away, making it impossible to put them back in order. But in this sample, the pages were never blown away; they remained in a neat stack, exactly as they were before the binding was lost.

Tests on dried meat

Researchers confirmed this preservation theory performing some experiments with dried meat to see how far they could mistreat the food before the chromosomes lost their structure.

“We decided to test how well this beautiful molecule resists stress and damage by asking a pitcher for the Houston Astros baseball team to throw a ball and fire a shotgun at it,” said Dr. Cynthia Pérez Estrada, co-first author of the study and a researcher at Baylor’s Center for Genome Architecture and Rice’s Center for Theoretical Biological Physics.

“The jerky was breaking down more and more, but the DNA structure was still there, telling us that DNA is extremely resilient and even more so in this kind of glass-like state (like in the sample), where the molecules are basically frozen and behaving like a crystal,” Pérez Estrada added.

With the new genetic information discovered in the skin samples, researchers determined for the first time that the woolly mammoth had 28 pairs of chromosomes, just like modern elephants.

But the structure allowed them to go further and see which individual genes were active in the animal. “Everyone wants to know what exactly made it woolly,” Dudchenko said. “We have some ideas thanks to the way these chromosomes were preserved.”

Dreams about mammoths

The researchers compared individual genes from the mammoth sample with their counterparts in modern elephants, noting differences in the activity of genes that regulate hair follicles. But elephant DNA was also needed to assemble the mammoth genome.

“Our hope and dream was to assemble the mammoth genome completely, but right now, that’s not quite where we are — we still use some information from its closest relatives to help, because the amount of data we were able to get from the mammoth was less than what is normally needed,” Dudchenko said. “But the fundamentals tell us that as we continue to work on this, we will be able to do it[without the help of elephant DNA].”

Could fossil chromosomes make the dream of resurrecting the woolly mammoth a reality? “The fundamental biology we learn from this will be useful, there’s no doubt about that,” Dudchenko said. “Are we any closer? One step closer, but there are still many steps ahead with all sorts of considerations that go beyond the basic science.”

The researchers also hope that the same methodology used on the mammoth sample can be applied to samples from other species.

“We expect to find chromosome structures in museum samples,” said Marcela Sandoval-Velasco, a guest researcher at the Center for Evolutionary Hologenomics at the University of Copenhagen in Denmark and co-first author of the study.

“Not just permafrost specimens, because that’s very limiting, but also samples from museum collections. There’s huge potential there,” he added, citing the woolly rhino, extinct lions and the passenger pigeon as some of the extinct species that scientists could learn more about this way.

This potential opens up more discoveries, according to Pérez Estrada. “It will take a huge effort to find suitable samples, so there will be a lot of work ahead — but I wouldn’t be surprised if we discovered something new and completely different from what we have now,” she said.

“That’s also a really exciting open question: What else and what other physical attributes (of DNA) can be preserved?” he added.

Exciting discoveries

Researchers not involved in the study expressed enthusiasm for the findings.

This study is the first to reconstruct the structure, or architecture, of a genome from an extinct species that lived during the last ice age, said Peter Heintzman, a paleogeneticist at Stockholm University in Sweden.

“This structural information provides insights into the functions of the woolly mammoth genome that were invisible using previous genomic methods,” Heintzman said in an email.

“This advance therefore helps open an exciting new frontier in paleogenomics, the study of ancient genomes, and is likely to provide further insights into how extinct species evolved, lived and disappeared.”

Given the substantial level of DNA degradation and fragmentation in ancient samples, it was surprising to see the high-quality, chromosome-level reconstruction of the mammoth genome reported in this study, he said. Dmitry Filatov professor of biology at the University of Oxford, UK.

“It is even more surprising that the researchers were able to infer which genes were active and which were off in the mammoth sample and compare this with gene expression in elephants,” Filatov said in an email. “This will certainly stimulate further paleogenomic research in other species.”

Hendrik Poinar director of the Centre for Ancient DNA at McMaster University in Ontario, called the paper “very exciting.” Typically, with fossil remains, researchers can’t do anything remotely close to assembling a genome, Poinar said.

“I don’t know how many tissue samples will be preserved to this level,” he added in an email. “But I think the method will make us think of new ways to extract DNA from tissue in ways that are different from what we are used to.”

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