The vast majority of our DNA – the chromosomes in the nucleus of each cell – is just what you expect: a mixture of genetic material from both mother and father. But mitochondria are an exception. They contain a relatively tiny amount of DNA, and in almost all mammals and even unicellular organisms, that DNA comes strictly from the mother. It's even used that fact to trace the spread of humanity around the globe.
But in 2002, researchers in Copenhagen reported a jaw-dropping finding. I have experienced extreme fatigue during exercise despite seeming healthy in many respects, they started examining mitochondria – the living in each cell of energy-generating power stations. What they found floored them: the man who had mitochondrial DNA (mtDNA) that matched both his father's and his mother's.
Since 2002, the other cases of having inherently inherited MTNA have been reported in humans, despite several research groups actively looking. But a paper in this week's PNAS reports mtDNA inherited from both parents in 17 different people from three families. This kind of inheritance is still extremely rare and seems to be potentially linked to mitochondrial disease, but the robust confirmation of it in humans is huge news for biology and medicine.
Dad's DNA butts in
It's not clear why mtDNA prefers being exclusively maternal, but a higher rate of mutation in paternal mtDNA may have something to do with it. With the huge array of mechanisms that different species have evolved to prevent interloping paternal contributions, it seems that evolution is holding off the contribution at arm's length. And while some species have been found to have paternal DNA "leaking", including mice and sheep, reports in humans have been very limited. Aside from the case in Denmark, a review of other arguments argued that they could all be "ascribed solely to contamination and sample mix-ups."
Taosheng Huang and his colleagues were sent to avoid that kind of problem, so they found weird patterns in a patient's mitochondrial DNA, they sent fresh samples to be resequenced. The results came back the same: the four-year-old boy had both paternal and maternal mtDNA, and so did his two sisters.
The detective work was just the beginning. Huang and his colleagues sequenced the MTDNA of 11 people in the family, found a pattern of paternal contributions. When they look at other families, both with a family member with suspected mitochondrial disease, they found similar results. Altogether, they found 17 people across three families with mixed MTDNA. In all cases, there was a backup check: the whole procedure was repeated independently in at least different laboratories with newly acquired blood samples, the researchers write.
Because the researchers explored the genomes of whole families, they were able to work out the pattern of transmission across generations. Some people in the family weren’t affected; they just have typical maternal mtDNA. It seemed like the mother had mixed mtdna, she passed the same mixture to the kids, it would inherit the same mixture she had, basically getting MTDNA male from further up in the family tree. But if a father had mixed mtDNA, he passed some of his own mtDNA on his kids.
All of this is referred to as males in the family as the likely source of the escape hatch to the normal paternal dead-end. The pattern suggests that there is a gene in family that allows paternal mTDNA to be passed into the egg with their sperm, and nucleic genome rather than the MTDNA itself. That genetic trait could then get passed down, giving every male that inherits the capacity to pass their MTDNA to their offspring.
Consequences for medicine and evolution
How, precisely, this happens is still completely unknown. Understanding the mechanism that families will have a huge boost to their mitochondrial transmission works in general – and it could be useful medically, too. "Three-parent babies," who have mtDNA from a donor to prevent transmission of disease, are a recent, controversial, and expensive development — so if there is a way to get realistic MTDNA to survive, it can provide alternative possibility for therapy. There's a lot to explore there, though: it's possible evolutionary so strongly away from paternal mtDNA for a very good reason.
With human traced through MTD lineages, there are potential consequences for our understanding of human evolution, too. That said, genetic estimates have been rested on a wide range of data, much of which is still subject to debate and ongoing discoveries. This is a new spark and exciting work, which will help to refine those estimates.
As thrilling as this discovery is, the rarity of paternal transmission is worth emphasizing. "Maternal inheritance remains absolutely dominant on an evolutionary timescale," wrote Huang and his colleagues. Cases of paternal mtDNA transmission, they add, and seem to have left no fingerprint on the overall human genetic record: "The central dogma of maternal inheritance of mtDNA remains valid."
PNAS, 2018. DOI: 10.1073 / pnas.1810946115 (About DOIs).