Typically, humans inherit mitochondria and mitochondrial DNA from their mothers only. But using sequencing data from the mitochondrial genomes of members from three unrelated families, researchers have identified 17 individuals who inherited mtDNA from both parents. The results were published last week (November 26) in PNAS.
“This is a very interesting study, bringing compelling evidence that bi-parental inheritance of mitochondrial DNA happens in human,” Sophie Breton, an evolutionary geneticist who studies mitochondrial genome inheritance at the University of Montreal and who was not involved in the work, writes in an email to The Scientist. “The [sequencing] technique used to demonstrate these results is simple but very powerful.”
Taosheng Huang, a pediatrician and medical geneticist who heads the Mitochondrial Diseases Program at the Cincinnati Children’s Hospital Medical Center, stumbled upon the first individual with mtDNA from both his parents by accident. The patient, a four-year-old boy who had some symptoms of a mitochondrial disorder, including fatigue and exercise intolerance, had come to be evaluated by Huang. The doctor sent his blood sample to the hospital’s diagnostic lab for mtDNA sequencing. The results showed that the boy appeared to have two populations of mitochondrial genomes, both at a relatively high level.
“My first instinct was that this was a mistake—even though I’ve never, in six years, seen our diagnostics lab make a mistake like this,” says Huang. He asked the patient to come back, drew a fresh blood sample himself, then sent the blood to the diagnostics lab, an in-house research lab, and an independent laboratory for sequencing. “We saw the same result come back from all three labs. That’s when I said, ‘Ok, this must be real.’”
Family members submitted samples for sequencing, and the mitochondrial genomes of the boy’s siblings, parents, and grandparents revealed that both the patient’s mother and maternal grandfather had a similar bi-parental inheritance pattern of their mtDNA. Huang and his colleagues then went back to their patient database and identified another family that exhibited the same phenomenon, and finally a third family who was evaluated at the Mayo Clinic and whose samples were then sequenced at the Baylor College of Medicine in Texas.
Some children who had mixed mitochondrial genomes appeared to have inherited the mix from their mothers, having none of their father’s mtDNA. For example, the four-year-old boy didn’t have both parents’ mtDNA, but his mother’s mtDNA and a paternal ancestor’s.
In the men with mixed genomes the ability to pass on their mtDNA appeared to be a dominant trait, as they could give their mitochondrial genes to their children. Still, not all of the males with mixed genomes could pass these onto their kids and, according to Huang, men with two populations of bi-parentally inherited mtDNA may just transfer one population onto their offspring.
The authors present their findings not as challenging that mitochondrial genomes are maternally inherited in humans, but rather that these families likely have a defect in the process of actively eliminating paternal DNA—Patric O'Farrell, University of California, San Francisco
Aside from the initially identified patients who had signs of a mitochondrial disease, the family members analyzed by the researchers who harbored a mix of maternally and paternally inherited mtDNA were seemingly healthy.
“This is very convincing evidence of paternal transmission in humans,” says Patrick O’Farrell who studies mitochondrial genome inheritance in fruit flies at the University of California, San Francisco.
Besides a single case study of an individual with evidence of paternally inherited mitochondrial DNA, the current work is the first to study this phenomenon in human families.
“It’s not clear how frequent this is because mitochondrial DNA sequencing is only done when a mitochondrial disease is suspected,” says Huang.
There are exceptions to strict maternal inheritance throughout evolution. “Biparental inheritance exists in mushrooms and yeasts, and strict paternal inheritance exists in some plants and marine alga,” writes Breton. But the animal kingdom is dominated by maternal inheritance aside from some instances in mice and fruit flies in which there is some minor paternal mtDNA that ends up in the embryo. The clear animal exceptions, according to Breton, are bivalve mollusks in which the males pass on paternal mtDNA to their male offspring but only in the gonads.
In animals, paternal mtDNA is actively eliminated from either the sperm or the fertilized embryo. In fruit flies, researchers recently identified an enzyme that degrades paternal mtDNA in the sperm and in Caenorhabditis elegans, paternal mtDNA is eliminated immediately following fertilization.
The study authors propose that the paternal mtDNA transmission they identified in these families is the result of a mutation in a nuclear gene that functions in paternal mitochondrial elimination. The team has now identified additional families with biparental inheritance and is searching for the putative nuclear gene.
“What stands out for me about this paper on paternal mitochondrial inheritance is that the authors present their findings not as challenging that mitochondrial genomes are maternally inherited in humans, but rather that these families likely have a defect in the process of actively eliminating paternal DNA,” says O’Farrell.
For Huang, who was part of the team that facilitated the mitochondrial replacement therapy (MRT) and subsequent successful live birth of three-parent baby in 2016, identifying a mechanism by which an embryo could inherit a father’s mtDNA could mean bypassing MRT altogether. “We could just dilute the mother’s disease-encoding mitochondrial genome with the father’s.”
First, however, “we need to clearly verify if biparental inheritance is a more widespread phenomenon and if the presence of both maternal and paternal mtDNAs in a person is associated with pathogenicity, including mitochondrial dysfunction,” writes Breton.
Another question for Breton is whether the mitochondrial genome might play a role in mtDNA inheritance. “For example, recent studies suggest that we have underestimated the mitochondrial functional repertoire and that this genome does [more than we thought it did],” she writes.
S. Luo et al., “Biparental inheritance of mitochondrial DNA in humans,” PNAS, https://doi.org/10.1073/pnas.1810946115, 2018.
Correction notice (December 5): The 5th paragraph erroneously stated the patient's grandmother had bi-paternal inheritance of mtDNA, when it was his maternal grandfather. The Scientist regrets the error.