'Mother's Curse' mutation — harmful to males but not females — ID'd for the first time in animals

Study in fruit flies identifies a mutation in mitochondria — the energy factories of our cells — that harms males but not females
Image of normal fruit fly sperm, and mutant, tangled sperm
Researchers have identified the first true 'Mother's Curse' mutation in animals — a genetic change harmful to males but not females. The mutation, discovered in fruit flies, renders male flies' sperm a "tangled mess," as shown above right, said Fred Hutch evolutionary biologist Dr. Harmit Malik. Images courtesy of the Malik lab

A long time ago, your ancestors did something bizarre.

Deep in the primordial ooze, your ancient ancestors, being just single cells (this was a really, really long time ago), slurped up some of their neighboring bacteria.

More than a billion years later, we still have those bacterial remnants — known as mitochondria — dozens to thousands of them in nearly every cell in our body. Researchers think of the story of their ancient origins as one of the most classic examples of symbiosis, or mutually beneficial co-existence, ever to be studied.

But there’s a strange flipside to mitochondria’s near-total assimilation into our cells (and the cells of every other animal, plant and fungus on the planet). They’re inherited completely maternally.

Now, a new study published Tuesday in the journal eLife identifies an unusual mutation in the mitochondrial DNA of fruit flies that renders males sterile but leaves the female insects completely unharmed. The mutation is proof of an evolutionary theory known as the “Mother’s Curse,” which posits the existence of genetic changes that are harmful to the males of a species but neutral or helpful to the females. Such mutations had previously been found in plants and some mutations harmful to males had been seen in fruit flies, but a true Mother's Curse mutation had never before been seen outside of the plant kingdom.

Mitochondria, which are responsible for generating all our energy, have their own genes. And unlike your nuclear genome — the DNA we usually think of when we talk about our genes, of which half originates from your mother, half from your father — all mitochondrial DNA comes from mom.

“Dad contributes nothing when it comes to mitochondria,” said Fred Hutchinson Cancer Research Center evolutionary biologist Dr. Harmit Malik. He led the eLife study along with Dr. Maulik Patel, a former Fred Hutch postdoctoral research fellow who now heads a research laboratory at Vanderbilt University. The mutation Patel, Malik, and their colleagues found specifically affects sperm development in the male flies — in the mutant flies, the sperm end up “a tangled mess,” Malik said.

Better understanding the Mother’s Curse could have implications beyond the insect world. Between 7 and 10 percent of men have a fertility defect, Patel said — these men are either completely sterile or, more commonly, have lowered fertility, despite not having any other obvious health problems. For most of these cases, the genetic causes are not known, but mitochondria have been implicated in some human male infertility. And some researchers even think the Mother’s Curse evolutionary principle could explain why men’s average lifespan is shorter than women’s.

When partners in crime can’t get along

In evolutionary terms, even though we live mostly in symbiotic harmony with our mitochondria, their unequal mode of inheritance “creates this battle of the sexes that’s being manifested through the mitochondria,” Malik said. Since mitochondria aren’t inherited from fathers, they have no impetus to protect males.

Photo of Maulik Patel in the lab
Vanderbilt's Dr. Maulik Patel said "males represent an evolutionary dead end" for mitochondria. Photo courtesy of Dr. Maulik Patel

In fact, it would be to mitochondria’s evolutionary advantage if a given population were dominated by females, since that increases the mitochondria’s chances of making it to the next generation — of people, flies, or any other mitochondria-bearing creature. That battle of the sexes is kept in check by an opposing evolutionary pressure from the rest of our genes, Malik said, which benefit from an even male-female split in the population since they are inherited from both parents.

The end result is a strange push-pull between two essential parts of our very cells: nucleus and mitochondria. The nuclear genome and mitochondrial DNA are typically “partners in crime,” Patel said. “But here we have a case where they’re actually in conflict with each other.”

Although the Mother’s Curse theory that described such a conflict seemed plausible, researchers hadn’t previously seen any convincing evidence of this evolutionary phenomenon in animals — and it was unclear how a mutation in such a fundamental part of our cells could specifically harm only one sex. So Malik and Patel set out to find it, operating mostly on a hunch, in what Malik described as one of the most labor-intensive experiments his laboratory team had ever conducted.

It took the research team, which included two dedicated fly technicians, Ganesh Miriyala and Aimee Littleton, one and a half years of breeding and analyzing hundreds of thousands of flies to home in on one tiny mutation in a few of those flies’ mitochondria. The mutation resides in a mitochondrial gene that codes for a key piece of the molecular machinery these cellular compartments use to make our energy. The mutation lowered the activity of that molecular piece by about a fifth, the researchers found.

Photo of Ganesh Miriyal, Harmit Malik and Aimee Littleton
Fruit fly technicians Ganesh Miriyala (left) and Aimee Littleton (right), working in the laboratory of Dr. Harmit Malik (center), sifted through hundreds of thousands of fruit flies to identify one Mother's Curse mutation. Behind the researchers sit vials of research flies. Photo by Aida de la Cruz

When they tested the effects of mutation, the researchers found it rendered the male flies sterile — tangled sperm and all — but only later in their five-week lifespan, or at higher than normal temperatures, implying that there was some kind of additive effect between the lowered activity of the energy-producing molecule and the stress of age or temperature, Patel said. It’s not yet clear how this mutation in such an essential part of the flies’ cells is affecting only sperm development, the researchers said. Through a series of rigorous fly health tests, they further showed that the mutation had no other ill effects on males and no negative effects on females at all.

Gender bias in laboratory research

Results like these point to the importance of studying both sexes in biological research, Malik said. In 2014, the National Institutes of Health took biomedical researchers to task for conducting the majority of their preclinical studies only on male animals — such studies could miss important clues on how women might react differently to new therapies.

It was a calling-out that seemed completely obvious to Malik. Much of his laboratory’s research is focused on the evolution that drives sexual dimorphism — the biological differences between males and females. If they hadn’t set out to understand how this particular mutation works in both sexes, they might never have grasped its true function, he said.

“If you looked only at males, you’d be like, yeah, this is a male-sterile mutation … If you looked only at females, you’d be like, this is totally uninteresting, not even worth looking at,” he said. “There is so much in biology that is sexually dimorphic in an interesting way that is also medically important.”

The researchers also had a hint that their results might eventually point to a new path for male fertility therapies. They found that the sterility-linked mutation only wreaked havoc in some types of fruit flies — when they introduced the mutant mitochondria into 12 different types of flies, eight of them remained perfectly fertile. This means that the nuclear genome has likely evolved to push back against this male-harming mutation, to suppress its negative effects.

The research team’s next step is to identify what that suppressing genetic factor is. If this fruit fly mutation is also linked to fertility problems in humans, the gene that can suppress those fertility problems could be a promising avenue to explore for new fertility treatments, the researchers said.

“The fact that nuclear suppressors exist suggests that there might be a way to intervene,” Malik said.

The study was funded by the National Institutes of Health, Howard Hughes Medical Institute and the Mathers Foundation.

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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