Not Your Mom’s Genes: Mitochondrial DNA Can Come from Dad

The first time Taosheng Huang saw the test results, he was sure there’d been a mistake. Even after a technician repeated the diagnostic, Huang didn’t believe it. “That’s impossible,” he said.

Huang, a pediatrician and geneticist at Cincinnati Children’s Hospital Medical Center, asked the patient to come back and provide fresh samples of blood, which Huang then split among several research labs to reduce any chance of error. It was a finding that Huang knew would break a central tenet of human genetics—but time and time again, the outcome was the same.

Huang’s patient, a four-year-old boy, was carrying two different sets of mitochondrial DNA: one from his mother, as expected—and another, from his father.

This was only the beginning. Using modern DNA sequencing technology, Huang and his colleagues have conclusively verified paternally-inherited mitochondrial DNA in 17 individuals spanning three unrelated families. Their work appears today in the journal PNAS.

“This is a really groundbreaking discovery,” says Xinnan Wang, a biologist at Stanford University who studies mitochondria but was not involved in the new findings. “It could open up an entirely new field… and change how we look for the cause of [certain] diseases.”

Broadly speaking, we’re each a genetic mix of Mom and Dad. In the nucleus, which contains our chromosomes, this holds true. But the nucleus isn’t the only part of the cell that contains DNA. Cells contain power centers called mitochondria that also carry their own sets of DNA—and in nearly all known animals, mitochondrial DNA is inherited exclusively from the mother. This lopsided acquisition is so ingrained that researchers often analyze mitochondrial DNA to trace maternal lineages back in time.

Scientists still aren’t completely sure why this process has evolved to be strictly matrilineal, but a few theories have come to the forefront. For one, the mitochondria of sperm are believed to experience higher rates of mutation than those in eggs, making their input somewhat riskier. Additionally, having only one type of mitochondria makes it easier for the genomes in the nucleus and mitochondria to coordinate, as both generate the raw materials necessary for proper cellular function, explains Sophie Breton, a mitochondrial geneticist at the University of Montreal who did not participate in the study. The addition of another mitochondrial stakeholder, so the theory goes, could muddle this intimate two-way dialogue.

Whatever is driving maternal mitochondrial inheritance, it’s clear our cells have taken quite a few precautions to keep it that way. A formidable bevy of molecular machines stands at the ready to ensure that no unwanted paternal contribution slips through in the process of fertilization. Even though a sperm’s mitochondria help power its odyssey to the egg, its mitochondria aren’t meant to last. Some mitochondria are thought to be lost as sperm develop; the few that make it through the fertilization process are tagged with a chemical marker that allows the egg to easily recognize and annihilate any rogue paternal interlopers.

A handful of animals, including flies and mice, are known to occasionally “leak” paternal mitochondrial DNA into offspring alongside maternal input, but humans have historically been excluded from this club. Only a few reports of dad-derived mitochondrial DNA exist, and most have been chalked up to contamination or laboratory sample mix-ups. One case, described in 2002, received considerable attention when it was independently confirmed by another research group. But in the 16 years since, the search for another instance of this genetic anomaly has been unfruitful.

Amazingly, all three families seemed to show similar patterns of inheritance of this unusual trait. Not all members were afflicted, meaning that some individuals passed on their genes in the typical fashion, conceiving children that inherited only their mothers’ mitochondrial DNA. But it was clear that the mitochondrial genomes of several men in these families were breaking the biological rules of fatherhood. Rather than being discarded, these paternal packages of genetic information somehow kept pace with their maternal counterparts during fertilization, leaving some of their kids with mixed mitochondria.

Daughters with these mixed genomes then went on bequeath their heterogeneous heirlooms onto their own children in carbon copy. This meant their kids inherited mixtures indirectly—even though the children possessed none of their own father’s mitochondrial DNA. Such was the case with Huang’s original four-year-old patient.

Sons who acquired mixed mitochondrial genomes presented a slightly more complex picture. The ability to pass on paternal DNA seemed to be a dominant trait, or one that requires a gene from only one parent to show itself in offspring. This meant that some of the men who had inherited hybrid mitochondrial genomes were able to transfer them into their children, who displayed even more diversity as they mixed Dad’s genes with Mom’s. But not all men with mixtures retained this ability, leading to occasional dead-ends.

Exactly how paternal mitochondrial DNA infiltrates the embryo still isn’t entirely clear. It’s definitely a genetic trait—but not one, ironically, found in the mitochondrial genome itself. In fact, apart from the unusual mode of inheritance, there don’t seem to be any defects present in any of these patients’ mitochondria. Instead, whatever allows dads to deposit their mitochondrial DNA in their offspring is likely a mutation encoded in the nucleus—where things are supposed to come from both mom and dad.

Florence Marlow, a developmental biologist at the Icahn School of Medicine at Mount Sinai who was not involved in the research, theorizes that the anomaly could be at the step where the mitochondria of sperm are normally tagged for destruction. If this labeling step never occurs, she explains, the fertilized egg has no way of identifying and eliminating these paternal interlopers—meaning Dad’s mitochondria get a clear pass to proceed alongside Mom’s.

Since putting together their initial findings, Huang and his team have already identified several more candidate families with mixed mitochondrial DNA. According to his preliminary estimates, this phenomenon may be present in as many as 1 in every 5,000 people. While Wang stresses that more research by other groups is needed to confirm these numbers, the work from Huang’s team indicates that paternal transmission of mitochondria may be far more widespread than researchers once thought.

So how has this been overlooked for so long? “Most people have taken for granted that mitochondrial inheritance is strictly maternal,” Breton explains. “But sequencing techniques are so much more powerful than they were even just a few years ago.”

The possibility of paternal inheritance could also expand our options for assisted reproductive technology in the distant future. Huang’s group previously played a part in the successful conception and delivery of a “three-parent” baby in 2016. The child’s mother suffered from a mitochondrial disease, so Huang and his colleagues transferred her nuclear DNA into a donor egg, which had been stripped of its own chromosomes but could supply healthy mitochondria. This hybrid egg, containing the genetic information from two mothers, was then fertilized with the father’s sperm.

In theory, Breton says, if paternal mitochondria are viable, they could be added to—or perhaps even replace—defective maternal mitochondria, obviating the need for a third parent.

But that’s a big if, especially considering that the mitochondrial DNA of sperm is more prone to mutation. We’re far from understanding the full repercussions of inheriting bi-parental mitochondria under natural circumstances, much less through artificial medical procedures, many of which are likely to fuel continued debates on ethics.

For now, maternal inheritance of mitochondrial DNA is still the norm. But simply expanding our view of genetic inheritance opens up countless doors. “These results will change the way we describe mitochondrial inheritance,” Breton says. “I’m 100 percent sure we’ll find more cases like these in the future.”