Three-dimensional genome architecture persists in a 52,000-year-old woolly mammoth skin sample

Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (†Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth’s death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale. [Display omitted] •3D genome architecture is preserved in a 52,000-year-old woolly mammoth sample•PaleoHi-C makes it possible to assemble the woolly mammoth’s genome•Chromatin compartments also persist, enabling study of mammoth gene expression•We propose that dehydration led to a glass transition arresting molecular movement Three-dimensional genome architecture is shown to be preserved in a 52,000-year-old woolly mammoth sample, enabling genome assembly and analysis of gene expression. Spontaneous freeze-drying of the mammoth carcass in the cold Siberian environment potentially led to a glass transition that preserved sample morphology across eight orders of magnitude in length, from the 3-m carcass to 50-nm chromatin loops.