A ‘Selfish Gene’ That Can Poison its Host

Research on selfish genes provides new insight into meiotic drive systems and how they use the poison-antidote technique to function.

Highlights:

The selfish gene in yeast uses the ‘poison-antidote’ technique to function
The study focuses on the pathway by which ‘wtf4’ DNA functions
Manipulation of these DNA parasites to be expressed in mosquitoes and drive their destruction may help to control pest species

New research from the Stowers Institute for Medical Research sheds light on how a harmful selfish gene, which is thought to be a parasite fragment of DNA, functions and persists. Understanding this dynamic is an important resource for the larger group of meiotic drive system researchers ().

It demonstrates how a selfish gene in yeast employs a poison-antidote method to permit its operation and, most likely, its long-term evolutionary success. This technique is useful for scientists researching similar systems, such as teams developing synthetic drive systems for pathogenic pest management. Collective and collaborative progress on the understanding drive may one day lead to the eradication of pest populations that threaten crops or, in the case of vector-borne diseases, even humans.

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‘The ‘wtf genes’—a lineage that is expected to evolve to maximize its inclusive fitness and even kill its host.’

When the two alleles in a diploid organism are transferred to offspring at equal rates, natural selection works optimally. Despite this, selfish loci known as meiotic drivers are ubiquitous throughout eukaryotes, biasing their transmission into gametes. Drive is assumed to be a potent evolutionary force, but empirical evolutionary assessments of drive systems are constrained by the small number of meiotic drive genes that have been found. The wtf gene family is a family of 25 genes in S. pombe, some of which are involved in a meiotic drive by killing spores and not inheriting the driver genes ().

“It’s quite dangerous for a genome to encode a protein that has the capacity to kill the organism,” said Stowers Associate Investigator Sarah Zanders, Ph.D. “However, understanding the biology of these selfish elements could help us build synthetic drivers to modify natural populations.”

The Spreading Mechanism of ‘wtf4’ Gene

Drivers are selfish genes that can spread faster in a population than most other genes while providing no benefit to the organism. Previously Zanders Lab research demonstrated that wtf4, a driver gene in yeast, creates a toxic protein capable of harming all progeny. However, the drive is established when wtf4 is only located on one chromosome of a given parent cell. The result of administering a dose of a very similar protein that counteracts the poison, the antidote, is the simultaneous rescue of only those children who inherit the drive allele.

The study, led by former postdoctoral researcher Nicole Nuckolls, Ph.D., and current postdoctoral researcher Ananya Nidamangala Srinivasa in the Zanders Lab, discovered that differences in the timing of generating poison and antidote proteins from wtf4, as well as their distinct distribution patterns within developing spores, are fundamental to the drive process.

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The researchers have constructed a model for how the poison kills the spore, which is yeast’s equivalent of a human egg or sperm. Their findings suggest that toxic proteins cluster together, potentially interfering with the normal folding of other proteins necessary for cell function. Because the wtf4 gene encodes both the poison and the antidote, the antidote resembles the poison and clusters with it. The antidote, on the other hand, appears to isolate the poison-antidote clusters by transporting them to the cell’s garbage can, the vacuole.

To further understand how selfish genes act during reproduction, the researchers observed poison protein expressed within all growing spores and the sac surrounding them, but antidote protein was only identified in low concentrations throughout the sac. Later in development, the antidote was shown to be more abundant inside spores that acquired wtf4 from the parent yeast cell.

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The researchers discovered that spores with the driver gene produced extra antidote protein inside the spore to counteract the poison and secure their survival.

The researchers also discovered that a specific molecular switch that regulates the expression of many other genes involved in spore production also regulates the expression of poison, but not antidote, from the wtf4 gene. The switch is required for yeast reproduction and is intricately related to wtf4, which helps to explain why this selfish gene is so adept at eluding host attempts to deactivate the switch.

“One of the reasons we are thinking these things have stuck around for so long – they’ve used this sneaky strategy of exploiting the same essential switch that turns on yeast reproduction,” said Nidamangala Srinivasa.

“If we could manipulate these DNA parasites to be expressed in mosquitoes and drive their destruction, it may be a way to control pest species,” said Nuckolls.

Thus, further research on this can aid us in eliminating vector-borne infections and some genetic disorders.

References :

S. pombe wtf drivers use dual transcriptional regulation and selective protein exclusion from spores to cause meiotic drive - (https://pubmed.ncbi.nlm.nih.gov/36477651/)
Killer Meiotic Drive and Dynamic Evolution of the wtf Gene Family - (https://pubmed.ncbi.nlm.nih.gov/30991417/)

Source-Medindia