Shedding light on male infertility

An overlooked cellular structure gene may help scientists better understand male fertility and the forces that shape fast-evolving proteins. Dr. Courtney Schroeder, a postdoctoral fellow in the Fred Hutchinson Cancer Research Center lab of Dr. Harmit Malik, studies the causes and consequences of changes in protein sequence and function in the context of sperm development. She recently received a prestigious, five-year K99 Pathway to Independence Award from the National Institute of General Medical Sciences, a branch of the National Institutes of Health. Such awards recognize early-career researchers who are likely to become leaders in their field.

Schroeder studies proteins that comprise the cytoskeleton, the protein network that gives cells shape and facilitates nearly every cellular process, from movement to division. Though evolution shapes all genes, it doesn’t shape them all equally. Generally, genes that encode proteins that are fundamental to cell function are highly conserved, or very similar between different species. For example, actin, a key cytoskeleton protein, and similar actin-related proteins, or Arps, are conserved across species as dissimilar as humans and protozoa, animal-like single-celled organisms.

In contrast, some genes evolve rapidly.

In particular, “There’s a common phenomenon whereby reproductive proteins rapidly evolve,” Schroeder explained.

As minuscule sperm cells compete to fertilize an egg, every micrometer or microsecond makes a difference. If a genetic mutation helps a sperm beat out its competitors, it gets passed on to the fetus that arises once sperm and egg unite. This cutthroat environment encourages genetic innovation, or rapid changes in key proteins.

Schroeder showed that Arps fit into both categories: they’re both highly conserved and a hotbed of genetic innovation. While most cells use a tried-and-true Arp that evolves slowly, she found that developing fruit fly sperm use several different Arps that are changing quickly.

During her Ph.D. work, Schroeder had used conservation of protein sequences to predict important areas of proteins based on the assumption that if amino acids in a specific location on a protein are the same across many species, they must be important.

“I got interested in Harmit's work because we look at it from the flip side, which is that rapidly changing [amino acids] are equally as important [as conserved ones],” she said.

By studying sperm-specific Arps, Schroeder can simultaneously learn more about genetic innovation and shed light on the understudied area of male fertility.

“We don't really know a lot about fertility, particularly male fertility,” Schroeder said. “This phenomenon [of rapidly evolving Arps] that we're uncovering in flies, it's actually happening in mammals as well, and we have no idea what these proteins are doing.”

Schroeder has many questions that her Pathway to Independence Award will enable her to explore.

“Genetic innovation is a recurrent phenomenon,” she said. Though she is studying changing Arps specifically in the context of male fertility, Schroeder said her work addresses broader questions about how evolution “embellishes” on conserved proteins and will reveal both how changes to a protein’s sequence influence its function and how evolution shapes this process.

And because Arps are so essential to cell function, answering these questions will shed light on their role in cellular processes far beyond sperm development, which may include diseases like cancer, she said.

Schroeder’s Pathway to Independence Award will fund up to two years of postdoctoral research as she gains the skills and experience needed to set up her own laboratory, and then the first three years of her independent work.

“I am delighted for Courtney to get this award,” Malik said. “It rewards her courage in looking for signatures of innovation in a class of proteins everyone, including me, had assumed would be completely conserved. Looking beyond the dogma has allowed her to craft this unique, beautiful research program.”

Schroeder said she’s wanted to become a professor for a long time, and her K99 makes this dream more attainable. “Ever since I got it, I feel even more excited about what I'm doing. I feel empowered.”