by New findings from the Stowers Institute for Medical Research uncover critical information about how a dangerous selfish gene, considered a parasitic portion 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 December 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 drive systems for pathogen pest control. Collective and collaborative progress in advancing understanding may one day lead to the eradication of pest populations that damage crops or even humans in the case of vector-borne diseases.
“It’s quite dangerous for a genome to encode a protein that has the ability to kill the organism,” said Stowers’ research associate SaraH Zanders, Ph.D. “However, understanding the biology of these selfish elements could help us build synthetic drivers to modify natural populations.”
Drivers are selfish genes that can spread in a population at higher rates than most other genes, without benefiting the organism. Previous research from the Zanders Lab revealed that a driver gene in yeast, wtf4, produces a poisonous protein capable of destroying all offspring. However, for the chromosome pair of a given parent cell, unity is achieved when wtf4 is found on only one chromosome. The effect is a simultaneous rescue of only those offspring who inherit the drive allele, by delivering a dose of a very similar poison-counteracting protein, 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 the timing of generating venom and antidote proteins to starting with wtf4 and its distribution patterns within developing spores are critical to the driving process.
The team have developed a model that they continue to investigate for how the poison works to kill the spore, the equivalent of a human egg or sperm in yeast. Their results indicate that the poisonous proteins clump together, which could disrupt the proper folding of other proteins needed for the cell to function. Because the wtf4 gene codes for both the poison and the antidote, the antidote is very similar in shape and is grouped together with the poison. However, the antidote has an additional part that seems to isolate the antidote groups from the poison by taking them to the cell’s garbage can, the vacuole.
To understand how selfish genes work during reproduction, the researchers looked at the beginning of spore formation and found poisonous protein expressed within all developing spores and the sac surrounding them, while the antidote protein was only seen at low levels. concentration in the whole bag. Later in development, the antidote was enriched within the spores that inherited wtf4 from the yeast parent cell.
The researchers found that the spores that inherited the driver gene made additional antidote protein within the spore to neutralize the poison and ensure its survival.
The team also discovered that a particular molecular switch that controls many other genes involved in spore formation also controls the expression of the venom, but not the antidote, of the wtf4 gene. The switch is essential for yeast reproduction and is inextricably linked to wtf4, which helps explain why this selfish gene is so successful in evading any attempts by the host to turn the switch off.
“One of the reasons we think these things have been around for so long: They’ve used this sneaky strategy of exploiting the very essential switch that turns on yeast reproduction,” Nidamangala Srinivasa said.
“If we could manipulate these DNA parasites to express them in mosquitoes and drive their destruction, it 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 supported by the Searle Award, the National Institutes of General Medical Sciences (awards: R00GM114436, DP2GM132936), the National Cancer Institute (award: F99CA234523), the 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.
