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The dream of flying has always fascinated humanity. In evolutionary history, the ability to fly has emerged independently only three times: in birds, pterosaurs, and, uniquely among mammals, in bats.

Bat wings are structurally similar to human hands, containing bones, blood vessels, nerves, and tendons. The key difference lies in a flexible skin membrane called the chiropatagium, which stretches between the elongated digits II to V. Additional membranes, the plagiopatagium and uropatagium, extend between the front and rear extremities, and between the legs, respectively.

Unlike bird or insect wings, the wings of bats can be moved like a hand during flight, making them particularly efficient and agile flying artists. In evolutionary terms, this adaptation has been a major success: with about 1,400 species, bats (order Chiroptera) are the second most diverse group of mammals after rodents. They are found all over the world, except in extreme deserts and polar regions.

How such remarkable capabilities like flight arise, along with the associated anatomical and functional changes, and how they are encoded in the genome has been a central question in biology since Darwin.

As an extreme example of evolutionary innovation, the bat wing provides a unique model for studying the molecular basis of evolutionary novelties and morphological transformation. Using cutting-edge technologies, the researchers have uncovered surprising insights into the genetic programs that differentiate a hand from a wing and the morphological changes involved.

"We chose bats because they are an excellent example of phenotypic adaptation. The limbs are a beautiful model system to see how evolution produces different forms and functions," says Prof. Stefan Mundlos, corresponding author of the study. "Think of the limbs of a horse or the fins of a dolphin, or our hands or a wing. These are prime examples of how evolution takes one form and turns it into something completely different."

In their new study, in Nature Ecology & Evolution, the team analyzed the critical stages of limb development when wing morphology begins to form, comparing bat and mouse embryos. They conducted whole-genome and single-cell transcriptomic (scRNA-seq) analyses and applied sophisticated computational tools to interpret the data.

The work was a collaboration between the labs of Mundlos (Max Plank-Institute for Molecular Genetics, Berlin, Germany), Dario G. Lupiáñez (Max-Delbrück Center, Berlin, Germany and Centro Andaluz de Biología del Desarrollo, Sevilla, Spain) and Francisca M. Real (Max Planck Institute for Molecular Genetics and Centor Andaluz de Biología del Desarrollo).

A major challenge in this field of research is the comparison of single-cell and genomics data from different species—especially when working with non-model organisms such as bats. Nevertheless, this cutting-edge technology provides a unique insight into the gene activity of each individual cell within an organ during the different steps of development. By comparing the anterior (wing) and posterior (leg) extremities in bats and mice, the scientists were able to classify the cell types involved in wing formation, and made some unexpected discoveries.

"One of the biggest surprises for us was that all cell types and functions in the limb appear to be conserved between species. Initially, we thought that this technology and analysis would provide clear insights into some bat-unique cells forming the wings, since wings and mouse limbs are very different from each other," explains Real, corresponding author of the study.

The scientists demonstrated an important evolutionary concept operating during development: The same genetic programs are reused in other cells instead of inventing something completely new. In particular, it was shown that the cells that form the chiropatagium are not fundamentally different from other cells in other parts of the limbs. What changes is the timing and location of gene activation. In other species, these genes are typically switched on early in development and only in the proximal part of the limb bud. In bats, however, the same genes are reactivated later and in more distal regions of the developing limb.

"The cells present in the proximal part of the limb are similar in identity to the cells that later form the wing. This reflects how evolution works. The big question is, how this genetic program is precisely regulated in space and time. Can we identify significant differences in the genome that trigger this entire process from the beginning?" concludes Christian Feregrino, first author of the study.