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James Noonan, Kent Professor of Genetics and Professor of Neuroscience takes a “uniquely human” path to genetics research

March 02, 2023
by Haleigh Larson

James Noonan, PhD was recently appointed Albert E. Kent endowed Professorship in Genetics at the Yale School of Medicine. Dr. Noonan’s appointment reflects both the accomplishments of his lab and his contribution to the academic community in the near 15 years he has been at Yale. His lab focuses on delineating the molecular basis of what makes us distinctly human, with a focus on brain development. The Noonan lab has made key contributions in identifying regions of DNA within the human genome that encode functions unique to humans.

As an accomplished scientist, some might be surprised to know Dr. Noonan’s circuitous route to Yale. He became the first in his family to attend college, studying literature at the University of Chicago; however, after just one year he was forced to take time off to work in order to afford his education. He eventually re-enrolled at SUNY Binghamton where he added a degree in Biology to the honors degree in English Literature he graduated with in 1997. After graduation, the pressure to make money brought Dr. Noonan to New York City where he worked as a lab technician in the lab of Norma Neff, PhD. It was as a technician that Dr. Noonan learned to think about science, design experiments and examine the literature. Dr. Neff, a yeast geneticist and biochemist, encouraged Noonan to attend graduate school. Until that point, Noonan hadn’t considered it, but was persuaded and eventually chose to attend Stanford for a PhD in genetics and hasn’t looked back since. “That was pretty much it, I was hooked” Noonan recalls. While at Stanford, he trained in a lab involved in the Human Genome Project. His thesis made heavy use of population genetics, genome sequencing and computational biology techniques – all of which he wished to continue working with. He then chose to pursue a post-doctoral position at the Lawrence Berkeley National Laboratory, after which, he made the journey to Yale.

Noonan’s background in genomics and work on the human genome contributed to an interest in the genetics of what makes us human. His post-doctoral work focused on how gene expression is controlled during development in humans and other mammals. For Noonan, his time in comparative genomics got him thinking about the origins of uniquely human biological traits – traits that we all share and distinguish us from our closest non-human relatives. Early on, his work involved defining the biological mechanisms that drive human uniqueness. Initially he investigated changes in morphology across species, particularly in limb development. As a rule, many animals develop limbs but each have unique biological features. Hence, these biological features are modifications to processes that are highly conserved across mammals. The question then, is how the differences, products of evolution, are encoded in the genome. Patterning of any tissue is governed by conserved features of development thus any change in gene expression, transcript and protein localization or quantity can have developmental consequences.

For Noonan, the brain is the ideal organ to study these perturbations in. We’re the only organisms on earth who have our brains. Compared to our closest relatives in the animal kingdom, our brains are bigger, have more synapses and increasingly complex neural circuitry - the results of an extraordinarily long period of post-natal development and other changes hidden in our genome. Evolution is the cause of much of this genetic change: it happens over long periods of time but leaves behind genetic clues if you know where to look.

Noonan and colleagues in the field have identified two classes of changes to the human genome that they believe have likely played a role in the evolution of our human brain: Human Accelerated Regions (HARs) and Human-Specific Gene Duplications (HSGDs). HARs are regions of the genome that are conserved across many species but show a high degree of sequence change in humans. Because these regions have been highly conserved, it is likely that they play a pivotal biological role. In fact, Noonan and colleagues have been able to show that these HARs often act to influence the dynamic spatial, temporal and quantitative dance of development by controlling gene expression. Much of this work has been driven by recent advances in techniques and approaches to study gene regulation and development. “When we started, we had a reference human genome that wasn’t finished and about eight other genomes that also weren’t great.” Noonan and colleagues identified HARs through alignment of these less-than-stellar genomes without a remote idea of their function. “We had assays where we could test the effects of those differences one by one, but it was very slow. Now we have much more high-quality genomes, rich datasets on gene regulatory function in human and mouse and other species in all sorts of cell types and tissues. That allows us to annotate these sites and what they’re doing.”

The second class of genetic changes implicated in human evolution, HSGDs, are a collection of about 30 genes that are uniquely duplicated in the human genome. These duplications can result in novel functions of the parent gene as they are more prone to sequence changes. Noonan’s collaborator, Dr. Franck Polleux, in the Zuckerman Institute at Columbia University, has shown that some of these gene duplications may have had an impact on human brain evolution. Noonan and his collaborators, including Polleux and Dr. In-Hyun Park at the Yale Stem Cell Center, believe that sequence changes in both HARs and HSGDs may be responsible for the evolution of the unique human brain. They have initiated a major project to investigate this hypothesis by studying the functional impact of HARs and HSGDs with a series of elegant experiments utilizing humanized mice and organoids.

Apart from questions of human uniqueness, Noonan is passionate about building supportive scientific communities. He is a founding member of the Department’s Diversity Advisory Committee, which was created by a mix of faculty and students in order to promote innovation, scientific discovery and creativity by transforming the institutional culture towards an inclusive environment that allows all people to thrive. Noonan is adamant about people finding a space that supports them in science – and if one doesn’t exist, to create it.

His advice for new scientists is to find excellent mentorship, to take ownership of one’s project and collaborate early on. Be creative, help others and listen to their suggestions. “Science truly is a team sport,” Noonan says, “Nobody does it well on their own.” Have curiosity and a true desire to pursue questions that are important to you, they don’t have to be important to everyone else. And accept failure, you have to be able to change your mind when your hypotheses aren’t supported by evidence and be willing and creative enough to develop new ideas. To young faculty, Noonan emphasizes the culture of the department as a key factor in success and enjoyment in science. “The Department has to be inclusive and supportive. Science is a community and has to support everyone that’s a part of it.” In addition, he recalls the importance of persistence when he was just starting out. “Stick to your vision. What’s worked for us is we had an idea we wanted to pursue and that’s what we’ve done…. find a profound question that engages you and changes how we think about biology. If you’re not doing that, I don’t know what the point is.”

Submitted by Neltja Brewster on March 03, 2023