‘Junk DNA’ tells mice—and snakes—how to grow a backbone

Mutations in this mouse embryo’s noncoding DNA likely caused it to grow extra ribs.

R. Aires, et. al. Developmental Cell, 38, 2 (29 July 2016) © Elsevier Inc.

‘Junk DNA’ tells mice—and snakes—how to grow a backbone

Why does a snake have 25 or more rows of ribs, whereas a mouse has only 13? The answer, according to a new study, may lie in “junk DNA,” large chunks of an animal’s genome that were once thought to be useless. The findings could help explain how dramatic changes in body shape have occurred over evolutionary history.

Scientists began discovering junk DNA sequences in the 1960s. These stretches of the genome—also known as noncoding DNA—contain the same genetic alphabet found in genes, but they don’t code for the proteins that make us who we are. As a result, many researchers long believed this mysterious genetic material was simply DNA debris accumulated over the course of evolution. But over the past couple decades, geneticists have discovered that this so-called junk is anything but. It has important functions, such as switching genes on and off and setting the timing for changes in gene activity. 

Recently, scientists have even begun to suspect that noncoding DNA plays an important role in evolution. Body shape is a case in point: “There’s an immense amount of variation in body length across vertebrates, but within species the number of ribs and so forth stays almost exactly the same,” says developmental biologist Valerie Wilson of the University of Edinburgh. “There must be some ways to alter the expression of those [genes] regulating evolution to generate this massive amount of variation that we see across the vertebrates.”

To explore this question further, researchers led by developmental biologist Moises Mallo of the Gulbenkian Institute of Science in Oeiras, Portugal, turned to an unusual mouse. Most mice have 13 pairs of ribs, but a few strains of mutant mice bred by Mallo and colleagues have 24 pairs. Their rib cages extend all the way along their backbone, down to the hind legs, similar to those of snakes.

Snakes, such as this Gaboon viper, have can have more than 100 pairs of ribs.

Snakes, such as this Gaboon viper, have can have more than 100 pairs of ribs.

Stefan3345/Wikimedia Commons

The research team traced the extra ribs to a mutation deactivating a gene called GDF11, which puts the brakes on another gene that helps stem cells retain their ability to morph into many cell types. Without GDF11 to slow down that second gene—OCT4—the mice grew extra vertebrae and ribs. But GDF11 seemed just fine in snakes. So what was regulating vertebrate growth in snakes? The researchers decided to look at the DNA surrounding OCT4 to see whether something else was going on.

The OCT4 gene itself is similar in snakes, mice, and humans, but the surrounding noncoding DNA—which also plays a role in slowing down OCT4—looks different in snakes. To see whether this junk DNA gives snakes a longer-lasting growth spurt, Mallo and his colleagues spliced noncoding snake DNA into normal mouse embryos near OCT4. The embryos grew large amounts of additional spinal cord, suggesting that this junk DNA does indeed play a role in body shape regulation, the team reports this month in Developmental Cell.

But the researchers will have to do more to definitively confirm their findings, says developmental biologist and snake specialist Michael Richardson of Leiden University in the Netherlands, who was not involved in the study. Snakes would have to be genetically engineered with noncoding DNA that switches off OCT4 early, as it does in most other vertebrates. If this noncoding DNA is in fact the cause of snakes’ extra-long midsections, then snakes with that version governing OCT4 would be much shorter. Unfortunately, genetically engineering snakes is almost impossible because there’s no way to get access to very early embryos. “When the snake lays an egg, it’s already got a little head and about 26 vertebrate, so it’s already well on the way [to becoming a fully formed snake]. That way we miss out on the early genes,” Richardson explains.

Developmental biologists say OCT4 could be another example of evolution using noncoding DNA to change up animal anatomy. “We know that oftentimes it’s not the gene itself that changed—it’s the flanking regions or the regulatory regions,” Richardson says. “What they’ve shown quite clearly here is that the OCT4 gene isn’t different but the timing [of its expression] is prolonged.”

Snakes are an extreme variation. Almost all vertebrates have a head, a neck, a rib cage, and a tail (or tail region), but the lengths of those sections vary wildly among different species. “A flamingo has a very long neck, but snakes have a huge trunk. It’s not only the tail that’s longer,” Mallo explains. “The ingredients are not changing. The amounts and the timing of adding ingredients are.”