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https://www.quantamagazine.org/genetic-struggles-within-cells-may-create-new-species-20170927/ September 27, 2017

Genetic Struggles Within Cells May Create NewSpeciesMitonuclear conflict — a struggle between the genes in a cell’s nucleus and those in its mitochondria— might sometimes split species in two.

By Carrie Arnold

Ryan Garcia for Quanta Magazine

In the complex cells of humans and other organisms, two different genomes collaborate to sustainlife. The larger genome, with DNA encoding thousands of genes, resides in the cell nucleus, whilecopies 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 ofmismatches between the two. Emerging evidence shows that this “mitonuclear conflict” can drive a

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wedge between organisms, possibly turning one species into two. It’s too soon to say how frequentlymitonuclear conflict acts as a force in speciation, but researchers agree that better understanding ofthat tension may help to solve mysteries about what barricade separates some apparently similarpopulations into distinct species.

More than 1.5 billion years ago, an ancient bacterium snuggled inside a fellow simple cell. Instead ofdigesting the interloper, the larger cell let it stick around for the valuable energy that it produced. Inexchange, the invader got refuge and protection from predators, and over thousands of generationsevolved into the mitochondrion, which produces energy in the form of a molecule called ATP. Thusbegan the complex eukaryotic cell, a primordial partnership that has evolved into one of life’s mostsuccessful 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 themitochondrial genes moved into the long, linear genome in the eukaryotic cell’s nucleus, but themitochondrion 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 helpmitochondria produce ATP with building blocks from both mitochondrial and nuclear genes. Thisrequires 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 overlookedfactor in the health and survival of organisms. “And that has big implications for our concept ofspecies and natural selection,” said Geoffrey Hill, an ornithologist and evolutionary biologist atAuburn University.

Incompatible CousinsFor the past 40 years, the marine evolutionary geneticist Ron Burton has stalked tide pools along thePacific Coast, armed with an aquarium fish net in his search for a tiny crustacean named Tigriopuscalifornicus. 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. Notsurprisingly, the copepods Burton found outside his lab at the Scripps Institution of Oceanography inSan Diego were more closely related to the specimens he scooped out of tide pools in Baja Californiathan those more than 2,000 miles north on the coast of Alaska. Burton wondered what thesignificance of their genetic differences might be.

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Waldo Nell

Tiny crustaceans called copepods of the species Tigriopus californicus can be found along much of the NorthAmerican Pacific coast. But because of mitonuclear conflicts, hybrids of copepods from different regions seem to beless fit in the long run.

To find out, he and his colleagues bred copepods from populations sampled all along the coast. Theydidn’t just breed copepods from the same population; they also put together males and females ofdifferent groups. The first generation of these hybrid offspring — the F1 — appeared normal andhealthy when the lab began these experiments in the late 1980s. When Burton then bred the F1generation with itself, however, problems appeared.

That second generation, the F2, had fewer young and didn’t survive some environmental stresses aswell as non-hybrids did. Those results meant that although interbreeding between thegeographically separated copepod populations was technically possible, the evolutionary cards werestacked 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, onlymitochondrial problems could possibly explain these difficulties. His previous work had shown thatnot only did the nuclear genomes of T. californicus vary among populations, so did theirmitochondrial genomes. Since proper mitochondrial functioning required the interaction of proteinsmade by both genomes, Burton hypothesized that a mismatch between mitochondrial and nuclearDNA sat at the heart of the F2’s problems.

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Scripps Institution of Oceanography at UC San Diego

Ron Burton, a marine evolutionary geneticist at the University of California, San Diego, discovered that geneticconflicts seem to be reproductively isolating different groups of copepods.

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“The people thinking about mitochondrial function were not evolutionary biologists, andevolutionary biologists weren’t thinking about mitochondria, so no one was really putting these twoideas together,” Burton said. His copepods and his guess revealed how the forces of naturalselection 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 mitochondrialgenome in the 1960s, scientists hypothesized that the genes encoded by this DNA were so central tocellular function that they had to resist further shaping by natural selection. The forces of naturehad no room to experiment. Or so the theory went.

“I always thought this was a bad idea,” Burton admitted. Instead, evidence is emerging thatmitochondrial DNA is far more mutable than researchers thought. Because mitochondrial DNA lackscapabilities for checking DNA for errors and repairing it, in animals it mutates on average 10 timesas frequently as its nuclear counterpart does. (The difference varies considerably: In copepods, themitochondrial 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 totheir DNA sequence can create problems. Witness the severity of mitochondrial disease, caused bydefects in mitochondria, which in humans can cause seizure, stroke, developmental delays or evendeath.

To evolutionary biologists, this high mutation rate posed an interesting question: How does thenuclear 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 bothparents like its nuclear genome. This different pattern of inheritance gives mitochondrial genes adifferent evolutionary agenda than nuclear DNA does.

“What’s good for one genome might not be good for the other,” said Elina Immonen, an evolutionarygeneticist and researcher at Uppsala University. “Males and females also might have differentevolutionary interests.”

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Lucy Reading-Ikkanda/Quanta Magazine

The mismatch of evolutionary forces on mitochondrial and nuclear genomes could be seen inBurton’s F2 copepods. He extracted mitochondria from their cells and measured theirmitochondria’s energy output in the form of ATP. The F2 hybrids produced significantly less ATPthan their nonhybrid counterparts did, a clear indication of mitochondrial dysfunction.

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Confirmation of the mitonuclear conflict occurred when the researchers bred F2 males with femalesfrom the original maternal populations. This “backcross” again paired the right nuclear genes withtheir historically right mitochondrial genes, and it rescued the resulting F3 generation: Thoseoffspring did not suffer the shortened lives and reduced fertility of their F2 fathers. (Becausemitochondria 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 conflictin wild animals. Other work in the fruit fly Drosophila melanogaster revealed another aspect tomitonuclear conflict. Jonci Wolff at Monash University in Australia and colleagues irradiated maleflies to generate large numbers of DNA mutations, and then mated these flies with females that hadidentical nuclear genomes but one of six different mitochondrial genomes. As the researchersdescribed in a paper published in April on bioRxiv, the percentage of each female’s eggs thathatched varied by which mitochondrial genome she carried.

That result showed that the mitochondrial genome normally plays a major role in the DNA repairpathway, but also that mutations in the mitochondrial DNA can affect how well it interacts with thenuclear DNA. “There’s a huge contrast between the small size of its genome and how important themitochondrion is,” Wolff said.

Neither of these studies was sufficient to show that this force could divide a group of organisms intotwo separate species. That evidence lay along the eastern coast of Australia.

A Mitonuclear Wedge Between PopulationsWhen 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 isin the United States, the Eastern Yellow is a common backyard bird from Melbourne to Brisbane, itsbright yellow belly providing a flash of color against a blue-gray head and back. Around two millionyears ago, the common backyard bird began splitting into a southern group that lives in the moretemperate climes of Victoria and New South Wales, and a northern group that lives in more tropicalQueensland. The sheer size of their territory keeps most of the northern and southern robinsseparate.

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Patrick Kavanagh

Coastal and inland populations of the Eastern Yellow Robin in Australia show a number of genetic changes andadaptations to their environment. Those include mutations in their mitochondrial DNA, which might isolate thegroups.

When the evolutionary biologist Hernán Morales was a graduate student at Monash, he sequencedthe 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 hotterand 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 theenergy-producing electron transport chain. He became curious about the interactions betweenmitochondrial 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 arenuclear genes with mitochondrial function that also have this geographic distribution,” said MaulikPatel, 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 inlandbirds. Many of these differences cluster on a chromosomal region that encodes for nuclear genesthat interacted with mitochondrial genes. Natural selection had weeded out variability around thesegenes, which suggested that the coastal and inland birds had hit upon a narrow combination ofcompatible nuclear and mitochondrial genes. Because this combination is so specific, hybrids withthe wrong combinations are likely selected out, which keeps the coastal and inland populations ofrobins largely separate. To call these coastal and inland birds different species would be a reach, but

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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 adescription of this work on bioRxiv in June. Because that paper is under review with a scientificjournal, Morales was unable to speak to Quanta about his work.)

“The mitochondrial and nuclear genomes are going down different pathways, which selects againsthybrids and could create the reproductive isolation needed for a new species,” said Darren Irwin, anevolutionary biologist at the University of British Columbia.

Auburn University Photo Services

Geoffrey Hill, an evolutionary biologist at Auburn University, has proposed a species concept based on mitonuclearconflicts.

To Geoffrey Hill of Auburn, Morales’s study points to the importance of mitonuclear co-adaptation asa major evolutionary force. In an April article in The Auk, Hill outlined what he called themitonuclear species concept, which states that a species is a group of organisms with co-adaptedmitochondrial 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 powerfulevolutionary forces, even ones that assist with the formation of new species. But he cautions that notenough 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 otherexperiments to say with any confidence how common mitonuclear conflict really is.

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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 providefundamental new insights on how species evolve. “Scientists know how important the mitochondrionis,” Patel said, “but this work would show its importance in evolution.”

This article was reprinted on Wired.com.