Hunting Down the Enhancers of Evolution: How Does a Fin Become a Limb?

A little skate egg case with embryo inside. Credit Dee Sullivan

91לLittle skate91ם may sound humble enough, but this funny looking shark relative  91ד with giant fins fused around its flat head  -- is aiming for the big time.

On a recent summer day in their MBL Whitman Center lab,  and  are proudly wearing T-shirts emblazoned with a little skate. And they are happy to talk about their goal to bring the little skate into the elite group of animals  91ד along with human, mouse, a few others -- whose full complement of DNA (genome) has been mapped and functionally characterized to a high degree.

Tetsuya Nakamura of Rutgers University and José Luis Gómez-Skarmeta of Centro Andaluz de Biología del Desarrollo with a little skate hatchling in their MBL Whitman Center lab. Credit: Megan Costello
Tetsuya Nakamura of Rutgers University and José Luis Gómez-Skarmeta of Centro Andaluz de Biología del Desarrollo with a little skate hatchling in their MBL Whitman Center lab. Credit: Megan Costello

The little skate91יs genome map will be 91לa huge resource for understanding human evolution and our vertebrate ancestry,91ם Nakamura says. Sharks and skates are ancient creatures that sit near the very base of the vertebrate lineage on the evolutionary tree. They are much more similar to humans than are zebrafish which, despite being a common model organism in biomedical research, sit on a more divergent branch of the tree of life.

91לHaving the skate genome will open a lot of new research questions in evolutionary and developmental (evo-devo) biology  91ד and people will come to MBL to answer them!91ם Gómez-Skarmeta says.

The Marine Resources Center at the MBL is the one of the only places in the world that collects this species of skate and breeds them for study, primarily for evo-devo biologists. These scientists compare how embryonic development is genetically regulated across many animal species, looking for the emergence of novel features, such as fins evolving into animal limbs.

Neil Shubin (center left) of University of Chicago with members of the Gómez-Skarmeta, Nakamura and Shubin labs in the MBL Whitman Center. Neil Shubin (center left) of University of Chicago with members of the Gómez-Skarmeta, Nakamura and Shubin labs in the MBL Whitman Center.

What makes this quest so challenging is the fact that 91לmost animals are constructed with the same toolkit of genes,91ם Gómez-Skarmeta explains. Among vertebrates, for instance, only 2 to 3 percent of the genome is protein-coding genes, and those genes are essentially the same in fish, mouse, and human. Somewhere in the rest of the animal91יs genome, sometimes called the 91לdark matter,91ם are the instructions for how those genes will function -- and these instructions will be very different across species.

91לThe way different life forms are generated 91ד why a fish doesn91יt look like a human 91ד is by using the same genes in different ways. These is done by regulatory elements in the genome that turn genes on or off during the life of the animal,91ם Gómez-Skarmeta says. 91לTo a great extent, evolution is the history of changing the regulation of gene expression during development.91ם

Cartilage staining of little skate embryo. Credit: T. Nakamura and J.L. Gómez-Skarmeta Cartilage staining of little skate embryo. Credit: T. Nakamura and J.L. Gómez-Skarmeta

It91יs no accident Gómez-Skarmeta, an expert in finding regulatory elements (also called enhancers) in the dark corners of a genome, and Nakamura, a developmental biologist, share a bustling Whitman Center lab. Their collaboration was first orchestrated in 2015 by , an evolutionary biologist at the University of Chicago and current interim co-director of the MBL. Shubin studies the evolutionary origin of vertebrate features, especially appendages such as fins and hands. In 2004, Shubin and colleagues startled the scientific world when they unearthed a 375-million-year-old fossil in arctic Canada that had features of both fish and amphibians 91ד a fish with limbs. This rare find of a transitional fossil -- from the time when marine organisms first ventured onto land --  would later become widely known through Shubin91יs book, 91לYour Inner Fish,91ם and a  with the same name.

Nakamura was a postdoctoral researcher in Shubin91יs lab when they realized that one path for exploring the genetic origins of innovation in fins (and in paired appendages) would be to find out what controls fin formation in the odd-looking little skate.

91לThe skate is really unique. Its pectoral fins are super wide,91ם Nakamura says. 91לIn humans, if the hand develops too wide and it has 5 or 6 fingers, it91יs a serious disease. So, we thought, if we could identify what genes regulate the formation of this super-wide fin in the little skate, it would help us understand [the generation of diversity] in an ancestral vertebrate and also a human disease.91ם

Shubin sent Nakamura to the MBL Whitman Center to work with skate embryos. That year, they pinpointed several genes in the little skate that also exist in limbed animals, but function differently. These genes, they suspected, generate the unusually wide pectoral fin ().

Diversity and evolution of fins and appendages. Skates (top left), sharks and rays belong to an ancient ancestral group of cartilaginous fishes. Tiktaalik is the transitional fish-amphibian fossil that Neil Shubin and colleagues found. By comparing how embryonic development is genetically regulated in different vertebrates, scientists can spot the evolution of novelty in the lineage 91ד such as fins transitioning into limbs. Illustration by J. Westlund Diversity and evolution of fins and appendages. Skates (top left), sharks and rays belong to an ancient ancestral group of cartilaginous fishes. Tiktaalik is the transitional fish-amphibian fossil that Neil Shubin and colleagues found. By comparing how embryonic development is genetically regulated in different vertebrates, scientists can spot the evolution of novelty in the lineage 91ד such as fins transitioning into limbs. Illustration by J. Westlund

Now the team is sequencing the entire little skate genome at several genomics centers across the world. In parallel, Gómez-Skarmeta is looking for the regulatory elements that fine-tune expression of their target skate fin genes.

The MBL, they agree, is essential to their work. 91לThis Marine Resources Center is the best in the world,91ם Nakamura says. 91לWe would never be able to breed this kind of huge marine organism somewhere else.91ם

Since Nakamura is based in New Jersey and Gómez-Skarmeta in Spain, they also appreciate the MBL as a place for 91לcommunity, collaboration, discussion. Not only among skate researchers, but you meet a lot of scientists here working on many different species,91ם Nakamura says. 91לWe can share techniques, we can talk about morphological or molecular diversity together. It91יs just a really amazing place.91ם