Some human tissues, like the liver and muscles, retain the ability to regrow after damage. But most of our bodies do not—if you lose a limb, the limb's gone. But elsewhere in the animal kingdom, regeneration is much more widespread. Many reptiles can regrow tails, and some salamanders can replace entire limbs. More distantly related worms called planaria can be cut into multiple pieces and see each piece regrow an entirely new body.
A couple of organisms have been extensively studied due to their ability to regenerate: the planarian Schmidtea mediterranea and a type of salamander called an axolotl (Ambystoma mexicanum). But those studies have been limited by the fact that we don't have a complete catalog of genes for these organisms. Attempts to correct that were bogged down by the fact that the genomes appeared to be littered with duplicate copies of virus-like DNA—in the case of the axolotl, enough to balloon its genome up to 10 times the size of our own.
Now, researchers have figured out a way to overcome that hurdle, and they have gotten high-quality copies of both the planarian's and the axolotl's genomes. Unfortunately, the copies don't shed much light on the animals' regeneration abilities. And all that extra DNA carried by the axolotl doesn't seem to be doing anything useful in particular.
Repetitive DNA and how to sequence it
Repetitive, seemingly useless DNA is present in almost every genome. The human genome, for example, carries more DNA that came from old virus infections than it uses to encode proteins. With a few exceptions, most organisms can tolerate a fair amount of DNA that isn't providing any useful function—often termed "junk DNA." But in some organisms, this goes to an extreme. The pines, for example, seem to have every chromosome stuffed up to the physical limits with repetitive DNA.
The axolotl, with 32 billion DNA bases in its genome, appeared to be in this camp. And, by salamander standards, it's a relative lightweight. Some of its relatives have 40 times the DNA of us puny humans.
While this doesn't appear to be a problem for the organisms that have all the superfluous DNA, it is a problem for anyone trying to figure out their sequences. DNA sequencing methods are generally effective for generating sequence reads that are a few hundred bases long. Software then recognizes overlaps in these fragments and pieces them together into longer contiguous sequences. But for a genome filled with repetitive DNA, similar-looking sequences could appear hundreds or thousands of times, scattered throughout the genome.
The software ends up badly confused and leaving the genome in hundreds or thousands of short fragments. That's exactly what happened with earlier attempts to sequence the planarian and axolotl genomes.
The current work relies on a relatively new method of sequencing DNA. It places a DNA-copying enzyme and a single molecule of DNA inside a tiny chamber and then watches as it uses fluorescently labeled bases to make a copy. The changes in fluorescent signal tell us which specific base was used at each step and thus what the sequence is.
The good news is that this method works for very long stretches of DNA, often over 1,500 bases long. The bad news is that it's relatively error-prone, so you can't really trust that it has gotten each individual base right.
The team behind the new work has developed software that combines the best of both sequencing methods. It uses the long reads to identify the probable sequence of the genome, since it is long enough to bridge over most repetitive DNA. But shorter, more accurate reads are used to fill in the details of the precise sequence. The result was a much more detailed look at the DNA these species carry.
Regeneration and other oddities
So, can these genomes tell us something about the incredible regeneration abilities of these organisms? The answer is a qualified "maybe." For the planarian, the researchers were able to identify roughly 1,000 likely genes that are probably specific to these organisms. Another 450 genes that are widely shared among animals were also missing. So something may be there, but that's a lot of genes to sort through to find out.
On the axolotl side, the researchers were able to identify five genes that aren't present in reptiles or mammals but are active in the stump of a regenerating limb. Two of these we already knew about, and the others don't give us much of a clue as to what they might be doing. So, while the gene list may make life easier for researchers studying regeneration, it doesn't provide much in the way of research on its own.
Both genomes drive home something that is becoming increasingly apparent: almost every organism is weird in some way. In vertebrates, there are two closely related genes (Pax3 and Pax7) that help direct the development of a large number of tissues. Axolotl seems to have lost one of them, and the one remaining gene does all the functions that normally require two genes.
One hundred and twenty-four of the genes missing from planaria are essential to humans and mice, but the worms seem to do fine without them. One of these is essential for checking whether all of a cell's chromosomes are ready for the cell to divide. The system still exists in planaria; it simply must use some other mechanism. Planaria also appear to lack a gene essential for making fats, meaning they must get them all from their diet.
Planaria also have the biggest piece of mobile DNA found outside of plants. The big plant version was called Ogre, so the researchers have named this one Burro, for "big, unknown repeat rivaling Ogre."
So, the research doesn't really solve much of the outstanding questions about regeneration. But it's an important step forward technique-wise, given that it shows we can now get a better handle on a large number of genomes that have previously caused our software to break down. And once again, it drives home that, for genomes, size doesn't matter.
Nature, 2018. DOI: 10.1038/nature25458, 10.1038/nature25473 (About DOIs).
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