Seeking Superpowers in the Axolotl Genome
The axolotl, sometimes called the Mexican walking fish, is a cheerful tube sock with four legs, a crown of feathery gills and a long, tapered tail fin. It can be pale pink, golden, gray or black, speckled or not, with a countenance resembling the “slightly smiling face” emoji. Unusual among amphibians for not undergoing metamorphosis, it reaches sexual maturity and spends its life as a giant tadpole baby.
According to Aztec legend, the first of these smiling salamanders was a god who transformed himself to avoid sacrifice. Today, wild axolotls face an uncertain future. Threatened by habitat degradation and imported fish, they can only be found in the canals of Lake Xochimilco, in the far south of Mexico City.
Captive axolotls, however, are thriving in labs around the world. In a paper published Thursday in Genome Research, a team of researchers has reported the most complete assembly of DNA yet for the striking amphibians. Their work paves the way for advances in human regenerative medicine.
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Many animals can perform some degree of regeneration, but axolotls seem almost limitless in their capabilities. As long as you don’t cut off their heads, they can “grow back a nearly perfect replica” of just about any body part, including up to half of their brain, said Jeramiah Smith, an associate professor of biology at the University of Kentucky and an author of the paper. To understand how they evolved these healing superpowers, Dr. Smith and his colleagues looked to the axolotl’s DNA.
At 10 times the size of the human genome, the axolotl genome was no small beast to tackle. “This thing’s huge,” said Melissa Keinath, a postdoctoral fellow at the Carnegie Institution for Science in Baltimore and an author of the paper.
Building off a previous study, Dr. Keinath and her colleagues mapped more than 100,000 pieces of DNA onto chromosomes, the structures that package DNA in the nucleus of each cell. Their axolotl genome is the largest genome to be assembled at this level.
The scientists used an approach called linkage mapping, which relies on the fact that DNA sequences that are physically close together on a chromosome tend to be inherited together.
To identify axolotl-specific DNA, the researchers juxtaposed axolotls with tiger salamanders, which are close relatives. Specifically, they crossed axolotls and tiger salamanders, then back-crossed these first-generation hybrids with pure axolotls.
Tracking patterns of gene inheritance across 48 of these second-generation hybrids, the researchers were able to infer which sequences of DNA belonged to axolotls and where they physically sat along the amphibian’s 14 chromosomes (humans have a greater number of chromosomes, but the axolotl’s are much larger).
It was like “putting together 14 linear puzzles,” said Randal Voss, a professor of neuroscience at the University of Kentucky and an author of the study.
In the process of validating their results, they identified a gene mutation that causes a commonly studied heart defect in axolotls, demonstrating that their research will speed up the process of scanning the axolotl genome for mutations in the future.
Ultimately, knowing how DNA is positioned along chromosomes “allows you to start thinking about functions and how genes are regulated,” Dr. Voss said. For instance, much of the genome consists of noncoding DNA sequences that turn genes on and off. Often, these noncoding sequences occur on the same chromosome as the genes they interact with.
“Once these relationships are known, then we can ask questions about whether the same kind of controls happen in other animals, like humans,” said Jessica Whited, a professor and limb regeneration expert at Harvard Medical School who was not involved in the study.
Over all, she added, that will help scientists understand whether there are predictable ways to “render humans more like axolotls,” fantastic regenerators of the animal kingdom.