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Cheating to win

The wtf meiotic driver gene family has been cheating—and winning —for over 100 million years

08 November 2022

Microscopy image

By Rachel Scanza, Ph.D.

Most genes follow the rules, rules discovered by a 19th century monk named Gregor Mendel to be exact. However, as in any society, or genome if you will, civilized or not, rule breakers will always exist. A recent collaboration between the Stowers Institute for Medical Research and the National Institute for Biological Sciences in Beijing, China, revealed that a rule-breaking selfish gene family has persisted for over 100 million years, transforming how we may search for similar genes in other species.

Selfish or driver genes which acquire the ability to break the rules, or what geneticists term drive, are your common, run-of-the-mill criminals. During the specialized cell division called meiosis which gives rise to reproductive cells like sperm and eggs, these genes cheat to gain an unfair transmission advantage over their law-abiding partners—one of the two variations or alleles of a particular gene in a pair of chromosomes—in violation of Mendel’s 50 percent rule. The most vicious criminals in a genome are called killer meiotic drivers. Without remorse, regret, or conscience, they transmit their genetic information to most or all progeny, poisoning and killing the reproductive cells that do not inherit the drive allele.

Illustration from the Zanders lab depicting selfish genes in yeast that were found to be more than 100 million years older than originally thought.

Three unique fission yeast species, S. octosporus, S. osmophilus, and S. cryophilus diverged from S. pombe over 100 million years ago, with each species containing wtf genes.

Genomes generally evolved law enforcement for these heinous genes, helping to make their criminal sprees short-lived from an evolutionary timespan. Suppressor genes evolve to stop driver transmission for the good of the species. Drivers that manage to outrun suppressors can spread to all members of the population (fixation). This too stops driver genes as they decay when there are no longer competing alleles they can “cheat.”

“What makes this finding so interesting is that this family of drive genes have persisted at least ten times longer than what was thought possible,” said SaraH Zanders, Ph.D., an associate investigator at the Stowers Institute.

However, in a recent study published in eLife on October 13, 2022, led by Predoctoral Researchers Mickael De Carvalho, Ph.D., from the Zanders Lab, and Guo-Song Jia from the lab of Li-Lin Du, Ph.D., discovered that the killer meiotic gene family, wtf, in the fission yeast, Schizosaccharomyces pombe, are also present in three different fission yeast species, having managed to evade local, federal, international, and Darwinian law enforcement for over 100 million years.

Fission yeast divides into two cells via splitting down its rod-shaped center and is an excellent research organism for studying sexual reproduction and genetics. Fission yeast can also mate with each other, producing a diploid cell that undergoes meiosis to yield four spores, yeast’s analog to sperm or egg cells in humans.

All extant yeast species shared a common ancestor around 220 million years ago. Comprehensive evolutionary analyses of all living species reveal compelling and novel evidence that wtf meiotic drivers were born about 100 million years later and have been causing drive for the last 119 million years. Specifically, the wtf meiotic drivers are still present in four living species—S. pombe, S. octosporus, S. osmophilus, and S. cryophilus—and are actively causing drive in at least two, S. pombe and S. octosporus.

Wtf, the rather impertinent name for these genes stands for with transposon fission and is derived from the genes’ association with long strands of repetitive DNA sequences (transposons) that can easily change locations within a genome. In this highly mutable gene family, drivers and suppressors are likely constantly at war, each rapidly evolving to outsmart the other; wtfs always manage to stay one step ahead of Darwinian law enforcement, hence their genetic persistence.

“This changes the way we look for these types of genes,” said Zanders. “Before now, I would never have thought to look for novel drivers in old, evolutionarily conserved candidate genes.”

Illustration of bird made from flames over the letters WTF

A model for how wtf drivers evade extinction is via a continuous death-rebirth cycle, similar to the immortal Greek mythological phoenix, rising from the ashes of suppressed or fixated wtfs.

How these meiotic drivers have managed to outrun extinction is not only due to the difficulty for suppressors to keep up with rapidly evolving wtf drivers. In all four fission yeast species, the researchers found that wtf genes are present in massive numbers of copies throughout their respective genomes, with the number of potential drivers ranging between 5 and 83, species-dependent.

A model for the evolutionary complexity of wtfs proposes that long-term persistence is driven by a continuous cycle of death and rebirth allowing wtf genes to short-circuit suppression and fixation. In addition, despite their reputation as genetic parasites, meiotic drive systems are major propellors of genome evolution.

“The idea that they can exist for long periods of time suggests that their impact on shaping the genome is also long-lived,” said Zanders.

Even among scientists, it is not widely understood or appreciated that not all pieces of a genome are beneficial. The notion that natural selection will always eliminate genes that are detrimental may in fact be a very narrow understanding of how evolution works.

“What we are seeing is that “bad stuff” in a genome can flourish, which is very satisfying given how many times I’ve been “corrected” on my understanding of evolution,” said Zanders. “I think this is an excellent example of natural selection’s limitations.”

Additional authors include Ananya Nidamangala Srinivasa, R. Blake Billmyre, Ph.D., Jeffery J. Lange, Ph.D., and Ibrahim M. Sabbarini.

This work was funded by the New Innovator Award of the National Institutes of Health (award: DP2GM132936), institutional support from the Stowers Institute for Medical Research, the Chinese Ministry of Science and Technology, and the Beijing Municipal Government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

New research from the Zanders Lab, published in eLife, has uncovered a selfish gene family that has survived for over 100 million years – casting new doubt on established beliefs on how natural selection and evolution tackle these threatening sequences.

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