A ‘selfish gene’ that poisons its own host

Discovery of genes that divide two species in a simple fungus sheds light on complex evolutionary principles
Photo of Harmit Malik
Evolutionary biologist Dr. Harmit Malik has published a new study delving into a family of genes known as 'wtf.' Fred Hutch file

Scientists have a tendency to anthropomorphize their work, and not just the animals they study. Even molecules or scientific principles may be ascribed human attributes or logic.

Case in point: a family of genes dubbed “wtf” described in a study published Tuesday in the journal eLife. These genes don’t behave in the way biologists typically think about the building blocks of a cell or organism, said study author and Fred Hutchinson Cancer Research Center evolutionary biologist Dr. Harmit Malik, and that may be why they remained mysterious for so long.

According to Malik, the two dozen genes with the cheeky name do nothing for their host, a type of yeast. In fact, the fungus would be better off without them. (The wtf moniker, by the way, is a somewhat disappointingly banal acronym that derives from the genes’ location: “with Tf,” for their proximity to the genetic elements known as Tf transposons.)

When the wtf-bearing yeast sexually reproduce — yes, even single-celled fungi do it — one of those genes, wtf4, produces a precisely timed molecular poison that can kill these very offspring. Luckily for the baby yeast, wtf4 also makes an antidote to its own poison later in reproduction.

The end result of this complex reproductive dance?

Only yeast offspring bearing the chromosome with the wtf4 gene survive. Through this intricate coupling of sex and death, the gene and its wtf cousins also appear to have single-handedly driven the division of two very similar yeast species. The two types of fungus are nearly genetically identical but are unable to reproduce with each other due to the presence of this molecular poison, whose antidote only works on its own kind.

The evolutionary benefit to the yeast? Nada, said Malik.

The gene is “basically a parasite,” Malik said. “It’s found this opportunity to entrench itself in natural populations.”

Selfish genes and evolution

Wtf4 is a so-called “selfish gene.” There are other examples of selfish genes throughout biology, although not all are linked to reproduction, said Dr. Sarah Zanders, co-senior author on the study and a former postdoctoral fellow in Malik’s lab. But what’s unique about wtf4 is the bizarre poison-antidote system encoded in a single gene.

Photo of Sarah Zanders
Dr. Sarah Zanders, a former Fred Hutch postdoc, uses simple yeast in her lab at the Stowers Institute for Medical Research to understand complex evolutionary science. Photo by Robert Hood / Fred Hutch News Service

Most other selfish genes identified to date seem to stand alone, Malik said, while the wtf family is a large collection of selfish genes, and at least some of them seem to be acting together to drive the division of species.

While the wtf family seems to be specific to these particular yeast, the general concept of selfish genes — and the possibility that they could be affecting species’ evolution or even fertility — is likely universal. But it can be difficult to study this type of reproduction-linked evolution in organisms more complex than the single-celled yeast, Zanders said.

“Genes that are doing something similar to this are present in mammals,” said Zanders, who now runs her own research lab at the Stowers Institute for Medical Research in Kansas City, Missouri. “We can study our simple little genes in our simple little yeast and that can teach us some general principles about how [such] genes can work in more complex systems that are too hard to study.”

In a previous study, Zanders and Malik showed that the reproductive breakdown between the two types of yeast happens when chromosomes separate to daughter cells during meiosis, the special type of cell division that forms spores (in yeast) or sperm and eggs (in us). The poisonous gene results in spores with the wrong number of chromosomes, which kills the offspring.

Having the incorrect number of chromosomes is also a hallmark of miscarriage — and it happens more often than you might expect in humans, Malik said. (The rates of early miscarriage in U.S. women range from 15 to 50 percent, according to the National Institutes of Health.)

In their current study, they pinpointed the genes responsible and showed that the wtf4 poison is made early in meiosis — before the walls of the spore cells have formed so the poison leaches into every one of the daughter cells. But the antidote is made later in cell division, once the walls have formed around each tiny poison-filled sac. So those offspring without the wtf4 gene are out of luck.

There’s as yet no evidence that such reproduction-linked selfish genes could have anything to do with unexplained infertility in humans. But Malik is intrigued by the fact that humans “don’t seem to be doing as good a job at meiosis as you might think,” he said, pointing to the fact that rates of female infertility and miscarriage are much higher in humans than in many other mammals.

“That makes us wonder about human infertility,” he said.

A cell is not a Swiss watch

Their findings also point to the ways biology and evolution sometimes work in unexpected ways.

By their nature, selfish genes don’t contribute much or anything to their hosts, making discovering them through a traditional viewpoint difficult. Zanders, whose new lab is built around the study of selfish genes, said it can be a tricky viewpoint to explain to those who don’t study evolution.

“Most biologists spend their time studying genes that are good for you and the diseases that come about when those genes are broken. That general idea is an idea almost every biologist spends all day thinking about,” she said. “They come and talk to me and I say, ‘No, our genes are bad. You’d be better off if these genes were totally gone.’ That’s a tough sell.”

Even biologists can fall into the trap of thinking all genes should benefit their hosts, Malik said. In a simplistic sense, scientists might think that a gene that’s stuck around through evolution “must be doing something really important, which is why it’s kept around,” he said.

But much like a culturally embedded acronym, when it comes to wtf and other selfish genes, their hosts just can’t shake them.

“If you go in with the assumption that everything should be well refined, like a perfectly operating Swiss watch, everything is working perfectly well together” in a cell, you might miss something interesting, he said.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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