Â鶹ÒùÔº

Ancient DNA research aids de-extinction efforts and reveals surprising dire wolf ancestry

Last week, Colossal Biosciences made global headlines when they announced that they had successfully brought the dire wolf back from extinction, or at least a version of one. Colossal's team used pieces of the genetic code they uncovered in ancient dire wolf DNA samples to alter the genome of a common gray wolf to resemble that of its long-extinct cousin. The resulting pups are not exact replicas of their ancestors, but have many of their most distinctive traits.

Beth Shapiro, who while she was a professor at UC Santa Cruz and is currently serving as Colossal's Chief Science Officer, helped lead this milestone accomplishment.

"Ancient DNA is notoriously difficult to work with because it is often fragile and degraded, but paleogenomics has made tremendous leaps forward in the past 20 years, leading to the recent groundbreaking achievement of the world's first de-extinction with the birth of Colossal's dire wolves," Shapiro said.

"This amazing feat was possible because of Colossal's strong partnerships with academic institutions, like UC Santa Cruz, that have pioneered work in this field."

On April 11, a team of researchers from Colossal, UC Santa Cruz, Form Bio, and academic collaborators from around the globe, released a on bioRxiv of some of the research that the team conducted on ancient dire wolf genomes. The new study introduces an improved method for reconstructing ancient genomes, using the Minigraph-Cactus pipeline and Giraffe tool developed at the UC Santa Cruz Genomics Institute. This new method allowed the team to discover a surprising ancestry.

Researchers knew from fossil remains that dire wolves were larger than modern gray wolves, with stronger jaw muscles that likely helped them specialize as hunters of large Ice Age mammals. The new study reveals that these distinct features come from a surprising mix of two ancient canid groups.

Roughly two-thirds of the dire wolf genome seems to originate from an ancestor of wolves and coyotes, while the remaining third comes from an ancient lineage related to South American dogs. This finding suggests that the dire wolf arose through interbreeding between distantly related lineages approximately 4 to 5 million years ago.

Interbreeding between species to create an entirely new species is known as "hybrid speciation," and scientists believed it to be an extremely rare way for evolution to work. These new findings about the ancestry of the dire wolf, combined with an earlier finding co-authored by UC Santa Cruz about the evolutionary origins of the Columbian mammoth, suggest that it might be more common than we thought.

Understanding the dire wolf's evolutionary history contributes to our knowledge of the factors that may have contributed to their eventual extinction, which could have benefits for conservation. Shapiro and Colossal's CEO, Ben Lamm, have argued that the technologies they are developing in the process of de-extinction will help rescue endangered plants and animals from a global extinction crisis that threatens to wipe away 30–50% of the world's species in the next 25 years.

The advanced paleogenomic techniques employed in this study also provide a roadmap for future research on other extinct species that will offer insights into broader patterns of evolution on Earth.

"Our newest paper builds on decades of ancient DNA research to present an improved method for reconstructing ancient genomes, which allowed us to discover a surprising evolutionary history hidden in dire wolf DNA," Shapiro said. "I'm excited to see what else it will allow us to discover in the future, and how this new knowledge will help us to conserve Earth's amazing biodiversity."

The UC Santa Cruz Paleogenomics Lab, a dedicated ancient DNA lab established by Shapiro and Bioengineering Professor Ed Green as part of the Genomics Institute, conducted all of the careful early work to set up the samples for the study, including preparing an ancient dire wolf incisor tooth and skull from two separate specimens, extracting the DNA, constructing genomics libraries, and conducting quality-control sequencing. This delicate work required the skilled attention of a team of UC Santa Cruz researchers, including Jonas Oppenheimer, Molly Cassatt-Johnstone, and William Seligmann.

"It is exciting to see how Colossal has made use of tools Beth Shapiro and others at UC Santa Cruz have been developing to study ancient DNA to accomplish a truly remarkable feat of genetic engineering," said Genomics Institute Executive Director Lauren Linton.

"It shows the incredible power that can result from collaborations between industry and academia, and I know that Beth is working hard to harness that power to benefit our planet at a time when it is in desperate need of that help. With the rate at which the field is advancing, I am sure that Colossal's dire wolves are only the beginning."