image: Illustration illustrating the mechanism and distribution of the antidote and the expression of the poison. At the start of meiosis, both proteins are expressed. Later, the antidote is only found outside the spores, while the toxic protein is ubiquitous. Finally, mature spores that inherit wtf4 contain poison and antidote, while other spores are destroyed.
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Credit: Stowers Institute for Medical Research
KANSAS CITY, MO—Dec. Feb. 7, 2022—New findings from the Stowers Institute for Medical Research reveal critical insights into how a dangerous selfish gene thought to be a parasitic part of DNA functions and survives. Understanding these dynamics is a valuable resource for the broader community studying meiotic drive systems.
A new study published in PLoS genetics on Dec. 7, 2022, reveals how a selfish gene in yeast uses a poison-antidote strategy that enables its function and likely facilitated its long-term evolutionary success. This strategy is an important addition for scientists studying similar systems, including teams designing synthetic training systems for pathogen pest control. Collective and collaborative advances in understanding motivation could one day lead to the eradication of pest populations that harm crops or even humans in the case of vector-borne diseases.
“It’s dangerous enough for a genome to encode a protein that has the ability to kill the organism,” said Stowers associate researcher SaraH Zanders, Ph.D. “However, understanding the biology of these selfish elements could help build synthetic engines to modify natural populations.”
Drivers are selfish genes that can spread through a population at higher rates than most other genes, without benefiting the organism. Previous research from Zanders Lab revealed that a driver gene in yeast, wtf4, produces a toxic protein capable of destroying all offspring. However, for a given parent cell’s chromosome pair, the reader is reached when wtf4 is only on one chromosome. The effect is a simultaneous rescue of the only offspring who inherit the training allele, by delivering a dose of a very similar protein that neutralizes the poison, the antidote.
Building on this work, the study, led by former predoctoral researcher Nicole Nuckolls, Ph.D., and current predoctoral researcher Ananya Nidamangala Srinivasa at Zanders Lab, found that differences in generation timing poison and antidote proteins from wtf4 and their unique distribution patterns within developing spores are fundamental to the propulsion process.
The team developed a model that they are continuing to study to determine how the poison works to kill the spore, the yeast equivalent of a human egg or sperm. Their findings indicate that toxic proteins clump together, potentially disrupting the correct folding of other proteins necessary for cell function. Because the wtf4 gene codes for both poison and antidote, the antidote has a very similar shape and clusters with the poison. However, the antidote has an extra part that seems to isolate the poison-antidote clusters by bringing them to the cell’s trash can, the vacuole.
To understand how selfish genes work during reproduction, researchers looked at the onset of spore formation and found a toxic protein expressed in all developing spores and the sac around them, while the antidote protein did not. was observed only in low concentration throughout the bag. Later in development, the antidote was enriched inside the spores which inherited wtf4 from the parent yeast cell.
The researchers found that spores that inherited the driver gene made an additional antidote protein inside the spore to neutralize the poison and ensure their survival.
The team also discovered that a particular molecular switch that controls many other genes involved in spore formation also controls expression of the poison, but not the antidote, wtf4 gene. The switch is essential for yeast reproduction and is inextricably linked to wtf4, helping to explain why this selfish gene is so successful in evading any attempt by the host to turn off the switch.
“One of the reasons we think these things stuck around for so long – they used this sneaky strategy of exploiting the same critical switch that turns on yeast reproduction,” Nidamangala Srinivasa said.
“If we could manipulate these DNA parasites to express them in mosquitoes and cause them to kill, that could be a way to control pest species,” Nuckolls said.
Other authors include Anthony Mok, María Angélica Bravo Núñez, Ph.D., Jeffery Lange, Ph.D., Todd J. Gallagher, and Chris W. Seidel, Ph.D.
This work was funded by the Searle Award, National Institutes of General Medical Sciences (award: R00GM114436, DP2GM132936), National Cancer Institute (award: F99CA234523), Eunice Kennedy Shriver National Institute of Child Health and Human Development (award : F31HD097974) from the National Institutes of Health (NIH), and institutional support from the Stowers Institute for Medical Research. The content is the sole responsibility of the authors and does not necessarily represent the official views of the NIH.
About the Stowers Institute for Medical Research
Founded in 1994 through the generosity of Jim Stowers, founder of American Century Investments, and his wife, Virginia, the Stowers Institute for Medical Research is a nonprofit biomedical research organization focused on basic research. Its mission is to expand our understanding of the secrets of life and improve the quality of life through innovative approaches to the causes, treatment and prevention of disease.
The Institute consists of 17 independent research programs. Of the approximately 500 members, more than 370 are scientific staff members who include principal investigators, technology center directors, postdoctoral scientists, graduate students and technical support staff. Learn more about the Institute at www.stowers.org and its graduate program at www.stowers.org/gradschool.
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Research method
Experimental study
Research subject
cells
The title of the article
S. pombe wtf drivers use transcriptional dual regulation and selective spore protein exclusion to induce meiotic drive
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