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Embedded within the stretches of our genome, with no obvious function, are thousands of tiny genes with instructions to make small proteins. ��

These microproteins may interact with our immune systems, triggering false alarms and leading to autoimmune diseases. Or over time, the proteins could persist and potentially evolve useful functions, such as the ability to protect us from viral infections.

Before researchers can sort any of this out, they need a better understanding of the basics: Where in the body are these microproteins? How many are there? How does the immune system see them? A team of Pitt researchers is delving deep into these questions, powered by a five-year, $7,636,234 Director’s Transformative Research Award from the National Institutes of Health (NIH).

Of the four PIs on the award, three are from Pitt’s School of Medicine: Anne-Ruxandra Carvunis, associate professor in the Department of Computational and Systems Biology; Alok V. Joglekar, assistant professor in the Department of Immunology with a joint position in the Department of Computational and Systems Biology and core member of the Center for Systems Immunology; and Maninjay Atianand, assistant professor in the Department of Immunology. Rasi Subramanian, of the Fred Hutchinson Cancer Center in Seattle, is the fourth investigator.

The award is part of the , which supports transformative project proposals that are inherently risky and untested but have the potential to create or overturn fundamental paradigms.

“Are microproteins good for health because they help fight pathogens, or bad for health because they trigger the immune system, or both?” Carvunis asked. “We are looking forward to finding out. This will be fun!”

Microproteins are known as biology’s dark matter. “We don’t even know if they have a function, or if they’re just by products of random stretches of DNA,” Joglekar said.

The team wants to understand how these microproteins interact with the immune system: If they’re seen as invaders, they could be related to autoimmune diseases, disorders in which the body attacks itself.

“Take a microprotein made in the pancreas,” Joglekar said. “If the immune system thinks it’s foreign, then the immune system might attack it, thereby attacking the pancreas, potentially causing Type 1 diabetes.”

If microproteins are seen as part of the body and the immune system lets them survive, however, they may have evolved some useful functions. “Are they playing a role in defending us against viral infections?” Joglekar asked. “Are they playing a role in the innate immune system?”��

As part of their investigation, the team will catalog as many microproteins as they can. “We’re not just putting together a list, though,” Joglekar said. “For each microprotein we want to know where it’s expressed in the body; what is its evolutionary history; is it seen by the immune system as self or invader?”

This atlas of microproteins will not only help the team understand immune system interactions, but it will help other researchers who are trying to understand all aspects of microproteins — even researchers who haven’t heard of microproteins, but who are trying to understand autoimmune diseases or human genetic variation, which might be expressed in the creation of different microproteins.

“What makes a species unique? How does the body deal with the rapid evolution of novel microproteins?” Carvunis asked. “I’m delighted to work with an exceptional team on these blue-sky questions.”��

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— Brandie Jefferson, photography by Aimee Obidzinski