Meet WTF4: A Gene So Selfish It Poisons All Its Offspring

[Image by Wokandapix via Pixabay and Creative Commons 2.0 License.]

Imagine you’ve been invited to a fancy dinner at a millionaire’s house. The table is set. The silverware gleams. The guests are chitchating about who does what for work and the season finale of Game of Thrones when the dinner host arrives and announces that he has poisoned himself.

The confusion turns to terror when the dinner party host reveals that he has not only poisioned himself but everyone else in the room.

Such a scenario sounds silly, but if you’re a gene in the game of inheritance, “you win or you die.” (Or at least, risk disappearing from the gene pool.) And sometimes the most extremely “selfish genes” are the ones that survive.

Case in point: Some strains of kombucha yeast, the friendly fungus that makes fermented kombucha tea, carry a gene called “wtf4“. (Yes. That is its real, technical name.)

[A jar full of mature kombucha tea. Image via Wikimedia Commons]

As far as scientists know, wtf4 offers no benefits to its carrier. It doesn’t help kombucha ferment tea leaves or survive refrigeration. It doesn’t boost tendril growth or amp up spore production or even coast along as a neutral passenger. In fact, wtf4 is poisonous to the sex cells (aka “gametes”) of the yeast it lives in. (But not to humans.)

wtf4‘s poisonous nature mainly comes into play during meiosis–the process of typical cells dividing into sex cells with only half the total complement of chromosomes.

Genetics researchers at the Stowers Institute noticed that when yeasts that had just one copy of wtf4 (as opposed to 2 copies) went through meiosis, over 90% of the viable sex cells came out carrying wtf4.

All else being equal, you would expect the sex cells to have a 50-50 chance of inheriting wtf4 from a heterozygous parent. Something was killing off the gametes that didn’t inherit wtf4.

Further investigation revealed that the wtf4 gene was encoding both a poisonous protein…AND the antidote to that poisonous protein.

(For the technically inclined: For a gene to be expressed, it has to have a “transcription start site” where RNA-builder proteins can land and start making an RNA copy of the gene. Gene sequencing revealed that wtf4 actually has two transcription start sites, so the wtf4 can make both a long version and a short version of its protein. The short version is poisonous, but the long version is the antidote…A single gene encoding multiple proteins isn’t strange, but a gene encoding a poison and its own antidote is.)

“Dr. [Sarah] Zanders, our advisor, likens it to a murder mystery party where the host poisons everyone including himself,” says grad student Nicole Nuckolls of the Stowers Institute. “But then the host brings an antidote and saves only himself. That’s a really risky move by this driver, to poison himself and everyone, because if it doesn’t somehow also make the antidote and save itself, it’s dead.”

Nuckolls calls the gene’s behavior “very sneaky but very successful” because its inheritance rate is nearly 100%.

In follow-up experiments, the researchers attached a glowing protein to both WTF4 proteins so that they could see where the WTF4s were turning up in the cell. Much to their surprise, the wtf4-bearing cells released the poison first.

“I thought it was going to be the opposite: you turn on the antidote before you get poison,” says grad student María Bravo Núñez , also of the Stowers Institute. “But it’s just like, ‘No, let’s just kill everyone and hope that I turn on this thing on time and be able to save myself.”

The team published their findings in the journal eLife alongside a separate study by a team at Tsinghua University in China that identified two more genes (cw9 and cw27) in the wtf gene family as serial poisoners that also code for their own antidotes.

Humans don’t have any genes that correspond to wtf4, but we likely do carry some genes that “cheat” at meiosis–aka “meiotic drivers”–albeit in less dramatic ways. Scientists think that selfish meiotic driver genes may contribute to infertility in humans, a condition that affects 1 in 7 human couples.

Sorting out which gene does what in a genome is a time-consuming process, so spotting parasitic genes–even the extreme examples like wtf4–is difficut, but the researchers hope that understanding wtf4 will make it easier to study meiotic driver genes in humans and eventually address infertility.

“If a couple is struggling with infertility, one of the reasons could be due to selfish genes and genetic conflict,” says Nuckolls. “It’s not because they didn’t do something that was healthy or because they didn’t drink that super-helpful juice that one time...If our work gets even one couple peace-of-mind that their infertility isn’t something they’ve done–it’s just something going on in their biology–then that to me is worth it.”

tl;dr:

A yeast gene called wtf4 cheats at meiosis by encoding both a poison and the antidote to that poison…It’s weird, but understanding its behavior could yield insight into infertility.

Papers Referenced:

Nuckolls, Bravo Núñez, et al. “wtf genes are prolific dual poison-antidote meiotic drivers” eLife, 2017. DOI: 10.7554/eLife.26033

Hu et al. “A large gene family in fission yeast encodes spore killers that subvert Mendel’s law” eLife, 2017. DOI: 10.7554/eLife.26057