The adorable and enigmatic axolotl is capable of regenerating many different body parts, including limbs, organs, and even portions of its brain. Scientists hope that a deeper understanding of these extraordinary abilities could make this kind of tissue regeneration possible for humans.
Axolotls have tiny aquatic salamanders whose only native habitat is a lake near Mexico City. Many animals, such as frogs, sea stars, and flatworms, are capable of tissue regeneration, but the axolotl is unique in that it can regenerate many different body parts over the course of its entire life cycle, including limbs, tail, heart, lungs
In a scientific first, researchers from the University of Kentucky have assembled the axolotl genome, the details of which were published today in Genome Research. On its own it may not sound so impressive, as many animals have had their genomes sequenced in recent years. But consider the sheer size and complexity of the axolotl genome, which consists of 32 gigabases, or 32 billion base pairs.
"The axolotl genome is 10 times larger than the human genome and is divided into 14 chromosomes. "Prayag Murawala, a genetician at the Institute of Molecular Pathology in Vienna, who was not involved with the puzzle, is the ultimate goal of creating 14 big pictures from the individual pieces of the puzzle. new study, told Gizmodo. "Building blocks of these 14 puzzles can be obtained by various sequencing technologies. However, the sequencing results do not tell you where each building block belongs. "
Indeed, previous work in the axolotl genome has yielded a tremendous amount of genetic data, but the challenge has been to correctly place each puzzle block in the correct location. A genome must be assembled in the correct order for scientists to truly understand how it works.
Genome sequencing and assembly are iterative processes, according to Randal Voss, co-lead author of the new study and professor at the University of Kentucky's Spinal Cord and Brain Injury Research Center. Last year, his team reached a point where they had a manageable number of pieces to work with, about 125,000 large chunks of DNA, but they still had to organize these pieces into 14 extremely long linear DNA puzzles.
"We did this using one of the most fundamental concepts in genetics-linkage mapping, "Voss told Gizmodo. "If you find that pieces of DNA tend to be inherited together, then they must map each other."
To do genetic linkage analysis, Voss used tissues that were generated and frozen 18 years ago by crossing axolotls to tiger salamanders . It took him three years to perform these crosses. The first generations of crosses were made in 1997 and the second generation of crosses were made in 2000. Using these crosses, Voss, with co-lead author Jeramiah Smith, identified genomic regions in the mapping sense sense to explain certain aspects of axolotl growth and development. Other genetic mapping studies have continued over the next several years.
"Fast forward to 2015, Jeramiah … had the clever idea to sequence DNA from individuals of these crosses," Voss explained, "and build a genome map that allowed the ordering of approximately 125,000 large DNA pieces into entire chromosomes. It worked! "
Now that researchers have a near-complete axolotl genome – the new assembly still requires a bit of fine tuning (more on that in a bit) -they, along with others, can now go about the work of identifying the genes responsible for axolotl tissue regeneration. By doing so, scientists may eventually be able to regenerate tissues in humans, facilitating limb and skin regrowth, spinal cord repair, and organ healing. This is no idle speculation; the study was funded by the U.S. National Institutes of Health and the United States Department of Defense
"We need all of the data to begin to understand how salamanders are able to regenerate tissue," said Voss. "The DOD is committed to sustaining the axolotl for regenerative medicine research given its promise to reveal regenerative repair therapies for finger and hand injuries in battle. "
Murawala is particularly excited by the potential for cardiac-related breakthroughs
" Axolotls are known for their ability to regenerate their hearts, " he told Gizmodo. "
During their research, Voss and Smith discovered a mutant axolot who was unable to repair his heart. This led to the identification of a mutation in its tnnt2 gene. The identification of this gene, along with others required for axolotl generation, will in future allow scientists to identify "regenerative roadblocks in mammals," in the words of Murawala
"As an axolotl research community, we should all be excited "
Jessica Whited, an assistant professor at Harvard University's Department of Stem Cell and Regenerative Biology, described the new work as a" landmark study " that, on its own, it is a valuable resource, but also serves as an important proof-of-concept for genetics research into axolotls.
"Here, they have made a physical map that relates many spots in the genome to one another, identifying, for example, which genes reside on the same chromosome and about how far apart they lie there," Whiti told Gizmodo. "It is likely that increased resolution will come with the further application of these techniques. However, as an axolotl research community, we should all be excited about this current work because it is a resource that we can all use in our biological studies. "
As noted, genome sequencing and assembly is an iterative process, so there's still work to be done. Building and chromosome level assembly for the axolotl is a major accomplishment, no doubt, but Voss and his colleagues are now looking to the next step, which is to make the assembly even better.
Nature is amazing, and it's already solved a lot of problems for us. We just have to figure out the nuts-n-bolts of it all. Ultimately, tissue regeneration in humans may not work exactly like it does in salamanders, but if we can harness it in a broad way, it will be a shift paradigm for medicine.