Over time, DNA can degrade into numerous short fragments that wiggle around. Eventually, the chromosome loses its original structure and genetic information to the ravages of time. However, researchers pondered whether fossil chromosomes that retained their original three-dimensional configuration existed.
To find out, an international team of researchers set off on an expedition in the frosty tundra of Siberia. In 2018, they discovered a promising, well-preserved skin sample from a giant titan of the Ice Age: a 52,000-year-old woolly mammoth.
Using a high-throughput technique to capture chromatin conformation (Hi-C) and DNA sequencing, molecular geneticists Erez Aiden and Olga Dudchenko at Baylor College of Medicine reassembled the three-dimensional structure of DNA and its genome—the first reconstruction of its kind. These findings, published in Cell, uncovered new biology and ushered in an exciting new chapter in paleogenomics.
Sampling from Fossil Chromosomes to Uncover Genetic Insights
Typically, ancient DNA fragments yield short snippets of DNA and provide an incomplete picture of the genomic puzzle. However, the woolly mammoth skin sample showed promise. Dudchenko observed that the sample was exceptionally well-preserved from macroscopic down to nanometer scales, with no molecular movement, and could potentially contain a more complete genomic picture.
To explore the 3D morphology of the existing chromosomes, Aiden modified an in situ Hi-C protocol, dubbed PaleoHi-C. This technique, adapted for ancient samples and combined with DNA sequencing, enabled the researchers to map the chromosome features, assemble a reference genome, and determine activation patterns across genes.
With this data, the team assembled the first 3D reconstruction of the woolly mammoth’s genome, which had 28 chromosomes; the order of genes was very similar to that of the Asian elephant. Then, upon analyzing the X chromosomes, they confirmed the specimen was a female woolly mammoth. They also observed inactive X chromosome (Xi) superdomains, a pattern resembling the bipartite architecture seen in humans and mice. However, to the researchers’ surprise, they uncovered new biology. Dudchenko noted that the mammoth “was a bit of an overachiever”, as its Xi exhibited a tetradic architecture. This pattern is also seen in modern elephants.
Next, they compared the degree of transcriptional activity of DNA between mammoth and elephant tissue. “We saw interesting differences in the genes related to hair follicle development and, more broadly, hair maintenance,” Dudchenko remarked.
By Laura Tran, PhD
Article can be accessed on: The Scientist