Mitonuclear conflict — a struggle between the genes in a cell’s nucleus and those in its mitochondria — might sometimes split species in two.
originally appeared in Quanta Magazine
In the complex cells of humans and other organisms, two different genomes collaborate to sustain life. The larger genome, with DNA encoding thousands of genes, resides in the cell nucleus, while copies of the much smaller one sit in all the energy-producing organelles called mitochondria. Normally, they work in quiet alliance.
Over the past five years, however, scientists have begun focusing on the consequences of mismatches between the two. Emerging evidence shows that this “mitonuclear conflict” can drive a wedge between organisms, possibly turning one species into two. It’s too soon to say how frequently mitonuclear conflict acts as a force in speciation, but researchers agree that better understanding of that tension may help to solve mysteries about what barricade separates some apparently similar populations into distinct species.
More than 1.5 billion years ago, an ancient bacterium snuggled inside a fellow simple cell. Instead of digesting the interloper, the larger cell let it stick around for the valuable energy that it produced. In exchange, the invader got refuge and protection from predators, and over thousands of generations evolved into the mitochondrion, which produces energy in the form of a molecule called ATP. Thus began the complex eukaryotic cell, a primordial partnership that has evolved into one of life’s most successful endeavors.
Proof of the mitochondrion’s origins survives in the remnant genome that mitochondria still carry — a small ring of DNA very much like that in bacteria. Over hundreds of millions of years, some of the mitochondrial genes moved into the long, linear genome in the eukaryotic cell’s nucleus, but the mitochondrion hung on to a handful of genes that remained essential for the organelle’s functioning. (Human mitochondria carry just 37 genes.) The cell assembles the protein complexes that help mitochondria produce ATP with building blocks from both mitochondrial and nuclear genes. This requires the nuclear and mitochondrial genomes to cooperate and adapt in tandem.
More and more studies are pointing to that co-adaptation as an essential but mostly overlooked factor in the health and survival of organisms. “And that has big implications for our concept of species and natural selection,” said Geoffrey Hill, an ornithologist and evolutionary biologist at Auburn University.
For the past 40 years, the marine evolutionary geneticist Ron Burton has stalked tide pools along the Pacific Coast, armed with an aquarium fish net in his search for a tiny crustacean named Tigriopus californicus. Populations of this orange copepod live from the Baja California peninsula to Alaska, and Burton has spent his entire career looking at genetic differences among these groups. Not surprisingly, the copepods Burton found outside his lab at the Scripps Institution of Oceanography in San Diego were more closely related to the specimens he scooped out of tide pools in Baja California than those more than 2,000 miles north on the coast of Alaska. Burton wondered what the significance of their genetic differences might be.
To find out, he and his colleagues bred copepods from populations sampled all along the coast. They didn’t just breed copepods from the same population; they also put together males and females of different groups. The first generation of these hybrid offspring — the F1 — appeared normal and healthy when the lab began these experiments in the late 1980s. When Burton then bred the F1 generation with itself, however, problems appeared.
That second generation, the F2, had fewer young and didn’t survive some environmental stresses as well as non-hybrids did. Those results meant that although interbreeding between the geographically separated copepod populations was technically possible, the evolutionary cards were stacked against the long-term survival of hybrid offspring in the wild.
The researchers wanted to know why the second generation did so poorly. For Burton, only mitochondrial problems could possibly explain these difficulties. His previous work had shown that not only did the nuclear genomes of T. californicus vary among populations, so did their mitochondrial genomes. Since proper mitochondrial functioning required the interaction of proteins made by both genomes, Burton hypothesized that a mismatch between mitochondrial and nuclear DNA sat at the heart of the F2’s problems.
“The people thinking about mitochondrial function were not evolutionary biologists, and evolutionary biologists weren’t thinking about mitochondria, so no one was really putting these two ideas together,” Burton said. His copepods and his guess revealed how the forces of natural selection could act on one of life’s central processes.
Evolution by natural selection hinges on the mutability of the genome. If DNA is writ in stone, natural selection has no variation on which to act. Not long after the discovery of the mitochondrial genome in the 1960s, scientists hypothesized that the genes encoded by this DNA were so central to cellular function that they had to resist further shaping by natural selection. The forces of nature had no room to experiment. Or so the theory went.
“I always thought this was a bad idea,” Burton admitted. Instead, evidence is emerging that mitochondrial DNA is far more mutable than researchers thought. Because mitochondrial DNA lacks capabilities for checking DNA for errors and repairing it, in animals it mutates on average 10 times as frequently as its nuclear counterpart does. (The difference varies considerably: In copepods, the mitochondrial DNA mutates 50 times as frequently.) That mutability doesn’t mean anything goes. The conservative evolutionary forces acting on mitochondria are so strong that the wrong changes to their DNA sequence can create problems. Witness the severity of mitochondrial disease, caused by defects in mitochondria, which in humans can cause seizure, stroke, developmental delays or even death.
To evolutionary biologists, this high mutation rate posed an interesting question: How does the nuclear genome respond to this mitochondrial variability and its sabotage of their partnership? Moreover, an organism inherits its mitochondrial DNA only from its mother, instead of from both parents like its nuclear genome. This different pattern of inheritance gives mitochondrial genes a different evolutionary agenda than nuclear DNA does.
“What’s good for one genome might not be good for the other,” said Elina Immonen, an evolutionary geneticist and researcher at Uppsala University. “Males and females also might have different evolutionary interests.”
The mismatch of evolutionary forces on mitochondrial and nuclear genomes could be seen in Burton’s F2 copepods. He extracted mitochondria from their cells and measured their mitochondria’s energy output in the form of ATP. The F2 hybrids produced significantly less ATP than their nonhybrid counterparts did, a clear indication of mitochondrial dysfunction.
Confirmation of the mitonuclear conflict occurred when the researchers bred F2 males with females from the original maternal populations. This “backcross” again paired the right nuclear genes with their historically right mitochondrial genes, and it rescued the resulting F3 generation: Those offspring did not suffer the shortened lives and reduced fertility of their F2 fathers. (Because mitochondria are inherited only from the mother, paternal backcrosses had no beneficial effect.)
These experiments established some of the first evidence for the importance of mitonuclear conflict in wild animals. Other work in the fruit fly Drosophila melanogaster revealed another aspect to mitonuclear conflict. Jonci Wolff at Monash University in Australia and colleagues irradiated male flies to generate large numbers of DNA mutations, and then mated these flies with females that had identical nuclear genomes but one of six different mitochondrial genomes. As the researchers described in a paper published in April on bioRxiv, the percentage of each female’s eggs that hatched varied by which mitochondrial genome she carried.
That result showed that the mitochondrial genome normally plays a major role in the DNA repair pathway, but also that mutations in the mitochondrial DNA can affect how well it interacts with the nuclear DNA. “There’s a huge contrast between the small size of its genome and how important the mitochondrion is,” Wolff said.
Neither of these studies was sufficient to show that this force could divide a group of organisms into two separate species. That evidence lay along the eastern coast of Australia.
A Mitonuclear Wedge Between Populations
When the day’s first rays of sun hit Australia after their long journey over the endless blue Pacific, the silvery peals of the Eastern Yellow Robin greet them with enthusiasm. As the American robin is in the United States, the Eastern Yellow is a common backyard bird from Melbourne to Brisbane, its bright yellow belly providing a flash of color against a blue-gray head and back. Around two million years ago, the common backyard bird began splitting into a southern group that lives in the more temperate climes of Victoria and New South Wales, and a northern group that lives in more tropical Queensland. The sheer size of their territory keeps most of the northern and southern robins separate.
When the evolutionary biologist Hernán Morales was a graduate student at Monash, he sequenced the Eastern Yellow Robin’s DNA. His sequencing showed that starting around 270,000 years ago, birds along the cold, wetter coast started diverging from birds that lived inland, where it is hotter and drier. Morales found that the coastal and inland groups differed in their mitochondrial genomes, and a small portion of their nuclear genome, including a handful of changes to proteins in the energy-producing electron transport chain. He became curious about the interactions between mitochondrial and nuclear genomes as potential wedges forcing apart the coastal and inland robins.
“It’s a very nice example of mitonuclear co-evolution, and the perfect system to ask if there are nuclear genes with mitochondrial function that also have this geographic distribution,” said Maulik Patel, a geneticist at Vanderbilt University. “If you were to find this, it would suggest you have co-evolution between mitochondrial and nuclear genes.”
Morales and colleagues identified 565 genetic markers that differed between coastal and inland birds. Many of these differences cluster on a chromosomal region that encodes for nuclear genes that interacted with mitochondrial genes. Natural selection had weeded out variability around these genes, which suggested that the coastal and inland birds had hit upon a narrow combination of compatible nuclear and mitochondrial genes. Because this combination is so specific, hybrids with the wrong combinations are likely selected out, which keeps the coastal and inland populations of robins largely separate. To call these coastal and inland birds different species would be a reach, but they do seem to be adapted to their local conditions and to have differentiated from one another. (Morales, now at the University of Gothenburg in Sweden, and his colleagues published a description of this work on bioRxiv in June. Because that paper is under review with a scientific journal, Morales was unable to speak to Quanta about his work.)
“The mitochondrial and nuclear genomes are going down different pathways, which selects against hybrids and could create the reproductive isolation needed for a new species,” said Darren Irwin, an evolutionary biologist at the University of British Columbia.
To Geoffrey Hill of Auburn, Morales’s study points to the importance of mitonuclear co-adaptation as a major evolutionary force. In an April article in The Auk, Hill outlined what he called the mitonuclear species concept, which states that a species is a group of organisms with co-adapted mitochondrial and nuclear genomes.
“This isn’t a side note to other ideas. This is as central as you get,” Hill said.
Burton doesn’t argue with the idea that mitonuclear conflict and co-adaptation can be powerful evolutionary forces, even ones that assist with the formation of new species. But he cautions that not enough evidence exists to support the idea that mitonuclear conflict alone can create new species. Nor have researchers studied enough systems and performed enough sequencing and other experiments to say with any confidence how common mitonuclear conflict really is.
Immonen agreed with that view. “The jury’s still out on this,” she said.
If the idea does hold up — and Burton and Patel both believe in its importance — it would provide fundamental new insights on how species evolve. “Scientists know how important the mitochondrion is,” Patel said, “but this work would show its importance in evolution.”
Ryan Garcia for Quanta Magazine