How fish gill genes helped create your ears

The outer ears that sit on the sides of your head share an unexpected genetic heritage with the gills of fish. According to research published in the journal Nature by scientists from the University of Southern California, the genes that provide the instructions for human ears once directed the formation of gills in our ancient aquatic ancestors, giving us a new and incredible example of genetic recycling. “When we started the project, the evolutionary origin of the outer ear was a complete black box,” said Gage Crump, professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC and senior author of the study. Because elastic cartilage which makes up the outer ear rarely fossilises, the history of how it evolved over time has not been known. Scientists know that elastic cartilage-supported external ears must have already existed in a common ancestor of placentals (mammals like us) and marsupials (mammals like kangaroos) before these two groups diverged from one another on the tree of life some 160 million years ago, but earlier evidence of their existence has not been found. In the new study, researchers used powerful technology to analyse thousands of individual cells at once (considering which genes are active and how DNA is organised within each cell). They focused their effort on individual cells from zebrafish- which is a model laboratory fish species that scientists love to work with- and humans. What they found was surprising. The cells that form human ear cartilage and fish gill cartilage showed very similar patterns of gene activity, despite coming from entirely different animals. The key to their discovery involved studying “gene enhancers” which are stretches of DNA that control when and where specific genes are active. The researchers did a clever experiment to test the function of these enhancers. They took enhancers from human ear cells and inserted them into zebrafish DNA alongside a gene for a glowing protein. The results were striking: the human ear enhancers caused the zebrafish’s gill cells to glow, meaning it was able to turn those genes on. Since they couldn’t insert fish genes and enhancers into humans, they turned to lab mice. When they did the reverse experiment putting fish gill enhancers into mice, those enhancers became active in mouse ears. This would happen only if the cellular environments in fish gills and mammalian ears were similar enough that they could recognise and respond to each other’s genetic instructions. The researchers identified a family of genes called DLX as particularly important to this shared program. These genes act like molecular architects, directing other genes involved in shaping both gills and ears. Taken together, this is strong evidence of a shared evolutionary origin. When they studied the enhancers more closely, they found something fascinating. Enhancers that activate early during development had nearly identical sequences across species, while those active later showed more variation. To trace this evolutionary story further, the team looked at animals that bridged the gap between fish and mammals. In tadpoles, both human ear and fish gill enhancers showed activity in their gills. In lizards, a related program was active in a small bone-like structure in their middle ears. This evolutionary progression showed that genetic instructions for gills gradually repurposed over millions of years, first in aquatic vertebrates, then contributing to ear development in land animals. The shift from water to land environments created new selective pressures for hearing, driving the transformation of these once-aquatic structures into specialized sound-detecting organs. And hence we’ve got ears! The researchers also discovered this genetic program may have even deeper roots. When they studied horseshoe crabs, creatures that have remained largely unchanged for 400 million years, they found a similar genetic program active in their book gills. And when they put horseshoe crab enhancers into zebrafish, they saw activity in the fish’s gills, suggesting this genetic blueprint emerged before vertebrates and invertebrates split, potentially dating back more than 500 million years. This evolutionary repurposing of genes that gave rise to gills becoming parts of our ears shows just how thrifty nature is. Rather than inventing entirely new genetic programs for new structures like ears, living things often modify and reuse existing blueprints that were originally used for something else. Examples of repurposed genetic tools are scattered throughout mammalian evolution. One example is the bones of our middle ear. The tiny bones that transmit sound from your eardrum to your inner ear were once part of the jaw in distant ancestors. As mammals evolved, these bones shifted from chewing to hearing, while new jaw bones developed to handle eating. In fact, this connection between the middle ear and jaw bones is what inspired the current research. It’s remarkable how interconnected life really is. From ancient ocean creatures to modern mammals, we carry within us the genetic echoes of our evolutionary past, repurposed and refined over hundreds of millions of years yet still recognisable across vastly different species. Anirban Mahapatra is a scientist and author, most recently of the popular science book, When the Drugs Don’t Work: The Hidden Pandemic That Could End Medicine. The views expressed are personal.

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