About 360 million years ago, our fishy ancestors moved from water to land. Along the way, fins turned into feet with toes. Millions of years later, the front pair evolved into hands.
To understand this profound evolutionary transformation, scientists have spent decades studying the fossils of extinct fish that sported limb-like fins. They have also compared the embryos of modern-day fish and land vertebrates to understand how their fins and limbs develop.
Now, precise DNA-editing technology known as CRISPR is letting scientists reconstruct this ancient evolutionary change in molecular detail. It turns out hands and feet were not the products of new genes doing new things. Rather, through natural selection, pieces of old genetic recipes for ancient body parts were cobbled together into new combinations.
This month, Aurélie Hintermann, a postdoctoral researcher at the Stowers Institute for Medical Research, in Kansas City, Missouri, US, and her colleagues showed just how old some of those pieces were.
They carried out their study by tracing the activity of genes in developing embryos. An embryo begins as a fertilised egg with a single set of genes; it then divides into new cells, each of which inherits those same genes. But along the way, the cells turn these genes on and off in different patterns, enabling them to become particular tissues and organs. The cells also send out molecules that trigger neighbours to change their own genetic melody.
Those signalling molecules switch genes on by grabbing DNA at a precise location, like a key turning in a lock. Many genes need several keys to open locks before they can become active.
Scientists have identified some of the locks that enable embryos of humans and other species to grow limbs. In 2011, biologist Denis Duboule discovered half a dozen molecular locks sitting side-by-side along a stretch of DNA called 5DOM. When 5DOM was snipped out of a mouse embryo’s DNA, it grew legs but failed to grow feet.
Duboule and his colleagues at the University of Geneva wondered how these locks evolved. Was it when our ancestors first came ashore and evolved limbs? Or even earlier?
Christopher Bolt, then a graduate student in Duboule’s lab, searched through the genome of the zebrafish and discovered that it, too, had 5DOM. Zebrafish and mammals share an ancient common ancestor that lived more than 400 million years ago. The Geneva team’s discovery suggested that this primordial ancestor already had 5DOM.
Hintermann, who took over the project while working in the Geneva lab, grew zebrafish embryos from which she had removed the 5DOM locks, using CRISPR. If the locks were important in the development of fish fins, then deleting them might reveal how. To her surprise, this had little effect on the developing fins. But it disrupted a region on the underside of the zebrafish’s tail, where there are two openings: the anus and a hole for the bladder and for sexual organs. This prompted researchers to take a closer look at the same region in mouse embryos. Here they got a second surprise: 5DOM unlocks the genes that built that region in mammals, too.
These and other experiments led the scientists to a new hypothesis for the evolution of fingers and toes. The story starts a half-billion years ago, with the earliest, simplest fish. Their bodies were little more than heads connected to long, ribbon-like bodies. They swallowed food, which made its way down a long digestive tract until the remnants escaped through the anus. A nearby opening was used for sex, and the release of urine.
The embryos of this protofish unlocked different genes to create different parts of its body. At the far end, 5DOM unlocked the genes for the anus as well as the opening for its urethra and sexual organs.
That genetic recipe hasn’t changed in a half-billion years. That’s why 5DOM still controls the development of that region in both zebrafish and mice — and us.
But 360 million years ago, scientists say, 5DOM underwent an evolutionary change. Now it could build not only our nether regions but our fingers and toes, too.
NYTNS
