School of Medicine

Computer model IDs roles of individual genes in early embryonic development

Software developed at Washington University School of Medicine in St. Louis can predict what happens to complex gene networks when individual genes are disrupted in specific ways. Shown on the left is a representation of the development of normal zebrafish axial-mesoderm cells, which form a precursor to the spine. The right animation shows what happens when a single key gene in this development pathway is disrupted. (Image: Kenji Kamimoto/School of Medicine)

Computer software developed at Washington University School of Medicine in St. Louis can predict what happens to complex gene networks when individual genes are missing or dialed up more than usual. Such genetic networks play key roles in early embryonic development, guiding stem cells to form specific cell types that then build tissues and organs. Mapping the roles of single genes in these networks is key to understanding healthy development and finding ways to regrow damaged cells and tissues. Likewise, understanding genetic errors could provide insight into birth defects, miscarriage or even cancer.

Such genetic experiments — typically conducted in the laboratory in animal models such as mice and zebrafish — have been a mainstay of developmental biology research for decades. Much can be learned about a gene’s function in animal studies in which a gene is missing or overexpressed, but these experiments are also expensive and time-consuming.

In contrast, the newly developed software called CellOracle — described Feb. 8 in the journal Nature — can model hundreds of genetic experiments in a matter of minutes, helping scientists identify key genes that play important roles in development but that may have been missed by older, slower techniques. CellOracle is open source, with the code and information about the software available at this link.

“The scientific community has collected enough data from animal experiments that we now can do more than observe biology happening — we can build computer models of how genes interact with each other and predict what will happen when one gene is missing,” said senior author Samantha A. Morris, PhD, an associate professor of developmental biology and of genetics. “And we can do this without any experimental intervention. Once we identify an important gene, we still need to do the lab experiments to verify the finding. But this computational method helps scientists narrow down which genes are most important.”

CellOracle, which was included in a recent technology feature in the journal Nature, is one of a number of relatively new software systems designed to model insights into cellular gene regulation. Rather than simply identify the networks, CellOracle is unique in its ability to let researchers test out what happens when a network is disrupted in a specific way.

Morris and her team harnessed the well-known developmental processes of blood cell formation in mice and humans and embryonic development in zebrafish to validate that CellOracle works properly. Their studies, in collaboration with the lab of co-author and zebrafish development expert Lilianna Solnica-Krezel, PhD, the Alan A. and Edith L. Wolff Distinguished Professor and head of the Department of Developmental Biology, also uncovered new roles for certain genes in zebrafish development that had not previously been identified.

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