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Site Twist: Mitochondrial DNA can come from both parents

Mitochondria (red) and the cell nucleus (blue) of two connective tissue cells derived from a mouse embryo.
Zoom / Mitochondria (red) and the cell nucleus (blue) of two connective tissue cells derived from a mouse embryo.

Institute of Molecular Medicine I, University of Düsseldorf

The vast majority of our DNA – the chromosomes in the nucleus of each cell – is what you expect: a combination of genetic material from both the mother and the father. But mitochondria are the exception. They contain a relatively small amount of DNA, and in almost all mammals and even single-celled organisms, this DNA comes strictly from the mother. We even used this fact to trace the spread of humanity throughout the world.

But in 2002, researchers in Copenhagen reported jaws. Seeking to understand why one of their patients was very tired during a workout, despite seemingly healthy in many ways, they began to study their mitochondria – the power generating power plants that live in each cell. What they found covered them: the person had mitochondrial DNA (mtDNA) that matched both his father and his mother.

Since 2002, no other cases of mtDNA inherited by the father have been found in humans, despite the fact that several research groups were actively looking for. But this week's article PNAS reports mtDNA inherited from both parents from 17 different people from three families. Such inheritance is still extremely rare and, apparently, is associated with mitochondrial disease, but reliable confirmation of this in humans is great news for biology and medicine.

Father's fathers DNA

It is not clear why mtDNA prefers to be exclusively maternal, but a higher mutation rate in paternal mtDNA may have something to do with it. Thanks to a huge set of mechanisms that various species have evolved to prevent paternal interlingual contributions, it seems that evolution holds the contribution of males to the hand. And although some species turned out to be “leaking out” of paternal DNA, including mice and sheep, the messages in humans were very limited. In addition to the case in Denmark, the review of other reports stated that all of them can be “attributed solely to contamination and sample mixing”.

Taosheng Huang and his colleagues sought to avoid such a problem, so when they found strange samples in the patient's mitochondrial DNA, they sent fresh samples to be retested. The results returned to the same thing: the four-year-old boy had both his father's and mother's mtDNA, as well as his two sisters.

Detective work has just begun. Juan and his colleagues sequenced mtDNA from 11 people in the family, find a sample of paternal contributions. When they looked at the other two families, as with a family member with suspected mitochondrial disease, they found similar results. In total, they found 17 people in three families with mixed mtDNA. In all cases there was a backup check: the entire procedure was “repeated independently in at least two different laboratories by different laboratory specialists with recently obtained blood samples,” the researchers write.

Since the researchers studied the genomes of entire families, they were able to develop a pattern of transmission across generations. Some people in families have not suffered; they just had a typical maternal mtDNA. It seemed that if the mother mixed mtDNA, she passed this mixture directly to the children – the children would inherit the same mixture as hers, essentially getting the male mtDNA from further growth in the family tree. But if his father had mixed mtDNA, he passed part of his mtDNA to his children.

All this pointed to the men in the family as the probable source of the exit hatch to the normal paternal impasse. This model suggests that there may be a gene in families that allows paternal mtDNA to cling to the egg with sperm and then continue there, and this gene is probably in the normal nuclear genome, and not in the mtDNA itself. This genetic trait can be passed down, giving every man who inherits his ability to transmit his mtDNA to his descendants.

Implications for medicine and evolution

How exactly this happens is still completely unknown. Understanding the mechanism that allows transmission by birth in these families will be a huge incentive for understanding how mitochondrial transmission works in general, and this can be useful from a medical point of view. “Children with three parents” who have mtDNA in the donor to prevent the transmission of mitochondrial disease are a recent, controversial and costly development, so if there is a way to get paternal mtDNA for survival, this may provide an alternative opportunity for therapy. However, there are many opportunities to learn: it is possible that evolution is so far removed from paternal mtDNA for a very good reason.

With human pedigrees traced through mtDNA, there are potential implications for our understanding of human evolution. However, genetic estimates of when populations diverge are based on a wide range of data, most of which are still subject to discussion and constant discovery. This discovery may trigger new and exciting work that will contribute to a bunch of research trying to refine these estimates.

As exciting as this discovery is, it is worth emphasizing the rarity of the paternal transmission. “The inheritance of motherhood remains absolutely dominant on an evolutionary scale,” write Juan and his colleagues. Cases of paternal mtDNA transmission are rare, they add and do not seem to have left fingerprints on a common human genetic record: “The central dogma of maternal inheritance of mtDNA remains in force.”

PNAS, 2018. DOI: 10.1073 / pnas.1810946115 (About DOIs).

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