Chiroptera, the mammalian order to which all bats belong, is Greek for “hand wing" — a fitting name for animals that fly using elongated, webbed fingers. As the only mammals with powered flight, the evolutionary history of their wings has been poorly understood. However, research published Monday in Nature and PLoS Genetics has provided the first comprehensive look at the genetic origins of their incredible wings.

But to appreciate the genetics of their wing development, it’s important to know how crazy a bat in flight truly looks.

Try a little experiment: Stick your arms out to the side, palms facing forward, thumbs pointing up toward the ceiling. Now imagine that your fingers are long, arching down toward the floor like impossibly unkempt fingernails — but still made of bone, sturdy and spread apart. Picture the sides of your body connecting to your hands, a rubbery membrane attaching your leg and torso to those long fingers, binding you with strong, stretchy skin. Then, finally, imagine using your muscles to flap those enormous hands.

Bats, man.

As marvelous as bat flight is to behold, the genetic origins of their storied wings has remained murky. However, new findings from an international team of researchers led by Nadav Ahituv, PhD, of the University of California at San Francisco, Nicola Illing, PhD, of the University of Cape Town in South Africa and Katie Pollard, PhD of the UCSF-affiliated Gladstone Institutes has shed new light on how, 50 million years ago, bats took a tetrapod blueprint for arms and legs and went up into the sky.

Using a sophisticated set of genetic tools, researchers approached the question of how bats evolved flight by looking not only at which genes were used in the embryonic development of wings, but at what point during development the genes were turned on and off, and — critically — what elements in the genome were regulating the expression of these genes. Genes do not just turn themselves on without input; genetic switches, called enhancers, act to regulate the timing and levels of gene expression in the body. In other words, enhancers determine whether and when a gene is turned on to make the stuff that does the stuff. So figuring out how genes are regulated is just as important as pinpointing the genes themselves.

In studying the genetic blueprint of bat wings, scientists first sequenced the entire genome of the Natal long-fingered bat (Miniopterus natalensis), a species found in eastern and southern Africa. The genome refers not just to genes themselves, but to all of the genetic information encoded in the DNA — including the parts that are not translated into protein, as genes are, but those that play supporting roles as enchancers. The researchers then used these data and genomic analysis of bat embryos at specific stages of development to look at what parts of the genome were used, and when, to grow those big, flying hands.

What they found were thousands of wing development genes, but also thousands of genetic switches that drive wing development. And not only did they find these switches, but they discovered that at these key developmental stages, there were major differences in activity between forelimbs and hind limbs.

So how different are patterns of forelimb and hind limb development in bats, as compared with other mammals? The answer depends on how you look at the question.

“On one level, a bat is using the same basic set of genes in its wings and hind limbs that a mouse [or person] uses. So on that level the two are very similar,” explained Stephen Schlebusch, a PhD student in Illing’s lab who was closely involved in the newly published research.

“On the other hand, there aren’t many major differences between the forelimb and hind limb of most mammals. One might be larger or longer, but by and large they are fairly similar and their development follows a similar process. In comparison, a bat’s limbs could hardly be more different,” he said, citing the the elongation in the wing, the presence versus absence of webbing and the asymmetrical pattern of the wing versus the symmetrical hindlimb. “The thousands of differentially expressed genes we identified are testament to how substantially different the two really are.”

So where did these differences start to appear during development?

Until a certain stage, the authors say, bat forelimbs and hind limbs develop with a similarity more typical of mammals. Then, at specific points in development, “the forelimbs go crazy and lose symmetry, and the hind limbs stay normal and is very similar to other mammals and doesn’t change," Ahituv said.

But scientists haven't quite figured out exactly what makes a bat wing go wacky.

“The limitation is that everything we find is potentially causative. We have a nice genomic blueprint of all the different components that could potentially be causing the development of the wings,” Ahituv explained. Testing their findings to determine what genetic components actually cause these tweaks gets a little more complicated.

“The classic genetic experiment is to take something and knock it out in an organism and see what happens,” he said, referring to the practice of removing some genetic information from an organism and seeing whether it results in the anticipated outcome. In this case, scientists might remove certain genes to see which were necessary for the key runaway forelimb development.

That’s not actually possible in bats, as they are not an animal model used in labs. “That being said, one thing that you can do is stick these sequences into mice and replace the mouse sequence for the bat sequence and see what happens in the mouse," Ahituv said.

That’s not to imply that the future work is limited to building an army of bat-mice. The researchers also plan to study bats more closely throughout the developmental process, perhaps following the functional changes that occur as certain genes are expressed.

The research also has implications for our understanding of human limb malformations.

Humans can present a variety of limb malformations, including longer digits or webbing between them, but these conditions are not well understood. By learning about the development of bat wings, we now have new tools to understand how some of these limb malformations occur.

“By understanding how the bat does this, we can go and try to find in patients with limb malformations and maybe see how that same system might be used,” Ahituv said. His lab has DNA samples from about a thousand patients with limb malformations. The hope is that with this new understanding of how a baby bat grows its wings, scientists are one step closer to shedding light on how human limb formation can go astray.

Leigh Cowart is a freelance journalist covering science, sex and sports. She is fully vaccinated for rabies.

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