The first time Taosheng Huang saw the test results, he was convinced that there had been a mistake. Even after a technician repeated the diagnosis, Huang did not believe it. "It's impossible," he said.
Huang, pediatrician and geneticist at the Cincinnati Children's Hospital Medical Center, asked the patient to come back and provide him with new blood samples, which he then spread to several research labs in order to reduce the risk of error. Huang knew that this was a statement that would violate a fundamental principle of human genetics – but on many occasions the result was the same.
Huang's patient, a four-year-old boy, wore two different sets of mitochondrial DNA: one from his mother, as expected, and the other from his father.
It was only the beginning. With the help of modern DNA sequencing technology, Huang and his colleagues have conclusively verified the mitochondrial DNA inherited from the paternity of 17 people belonging to three unrelated families. Their work appears today in the newspaper PNAS.
"This is a truly groundbreaking discovery," says Xinnan Wang, a biologist at Stanford University, who studies mitochondria but is not involved in new discoveries. "This could open up a whole new field … and change the way we look for the cause of the [certain] diseases. "
Basically, we are each a genetic mix of mom and dad. In the nucleus, which contains our chromosomes, this is true. But the nucleus is not the only part of the cell containing DNA. The cells contain power centers called mitochondria that also carry their own sets of DNA – and in almost all known animals, mitochondrial DNA is inherited exclusively from the mother. This unbalanced acquisition is so entrenched that researchers often analyze mitochondrial DNA to trace maternal lineages over time.
Scientists still unsure Why this process has evolved to become strictly matrilineal, but some theories have come to the fore. On the one hand, sperm mitochondria are thought to have higher mutation rates than ova, making their intake somewhat more risky. In addition, having only one type of mitochondria facilitates the coordination of the nucleus and mitochondrial genomes, because they generate all the raw materials necessary for cell function, explains Sophie Breton, a geneticist. mitochondrial from the University of Montreal who did not participate. in the study. According to the theory, the addition of another mitochondrial intervener could blur this two-way, intimate dialogue.
Whatever the engine of maternal mitochondrial inheritance, it is clear that our cells took a lot of precautions to preserve it. A considerable set of molecular machines is ready to ensure that no unwanted paternal contribution is lost during the fertilization process. Although sperm mitochondria help her odyssey to turn into an egg, her mitochondria are not meant to last. Some mitochondria are thought to be lost as spermatozoa develop; the few who manage to cross the fertilization process carry a chemical marker that allows the egg to easily recognize and annihilate dishonest paternal intruders.
A handful of animals, including flies and mice, is sometimes known to "scare" paternal mitochondrial DNA into offspring with maternal intake, but humans have always been excluded from this club. There are only a few cases of dna-derived mitochondrial DNA, and most have been attributed to contamination or errors in laboratory samples. One case, described in 2002, received considerable attention when it was independently confirmed by another research group. But for 16 years, the search for another example of this genetic anomaly has been unsuccessful.
So, even after Huang was convinced that his remarkable four-year-old patient had inherited mitochondrial DNA from both parents, he knew that the job was far from over. When the researchers then traced this strange genetic signature in the boy's family tree, they found that over three generations, 10 people in the patient's family appeared to have mixed mitochondrial DNA. Now that researchers knew where to look – and what to look for – as they expanded their search. Shortly thereafter, seven other people from two other unrelated families were confirmed as having the same disease.
Surprisingly, the three families seemed to present inheritance patterns similar to this unusual trait. Not all members were affected, which meant that some individuals transmitted their genes in the typical way, designing children who inherited only their mother's mitochondrial DNA. But it was clear that the mitochondrial genomes of several men in these families were violating the biological rules of fatherhood. Rather than being rejected, these packages of paternal genetic information have kept pace with their maternal counterparts during fertilization, leaving some of their children with mixed mitochondria.
The girls with these mixed genomes then left their heterogeneous heritage to their own children in carbon copy. This meant that their children had inherited the mixtures indirectly – even if the children did not have the mitochondrial DNA of their own father. Such was the case of the original patient of Huang, four years old.
The sons who acquired mixed mitochondrial genomes presented a slightly more complex picture. The ability to transmit paternal DNA seemed to be a dominant trait or gene requiring the gene of a single parent to manifest in offspring. This meant that some of the men who had inherited hybrid mitochondrial genomes were able to transfer them to their children, who displayed even greater diversity by mixing daddy's genes with those of mom. But not all men with blends have retained this ability, leading to occasional stalemates.
Exactly How The paternal mitochondrial DNA infiltrating the embryo is not yet entirely clear. This is a genetic trait, but not, ironically, the mitochondrial genome itself. In fact, apart from the unusual mode of transmission, there do not appear to be defects in the mitochondria of these patients. Instead, all that allows dads to drop their mitochondrial DNA into their offspring is probably a coded mutation in the nucleus – where things are happening. Assumed come from mom and dad.
Florence Marlow, a developmental biologist at Mt. Sinai Medical School Icahn who did not participate in the research, hypothesized that this anomaly could be at the stage where sperm mitochondria are normally labeled to be destroyed. . If this labeling step never happens, she says, the fertilized egg has no way of identifying and eliminating these paternal intruders, which means dad's mitochondria get a pass to go along with mom's.
Since the compilation of their first results, Huang and his team have already identified several other candidate families with mixed mitochondrial DNA. According to his preliminary estimates, this phenomenon could affect up to 1 in 5,000 people. While Wang points out that more research by other groups is needed to confirm these numbers, the team's work from Huang indicate that paternal transmission of mitochondria could be much more widespread than researchers thought.
So how was this neglected for so long? "Most people have taken for granted that the mitochondrial inheritance is strictly maternal," says Breton. "But the sequencing techniques are so much more powerful than they were a few years ago."
The possibility of a father inheritance could also expand our options for assisted reproductive technology in the distant future. Huang's group had already played a role in the conception and successful delivery of a "three-parent" baby in 2016. The child's mother was suffering from a mitochondrial disease . Huang and his colleagues then transferred his nuclear DNA to a donor egg, which had been stripped. of its own chromosomes, but could provide healthy mitochondria. This hybrid egg, containing the genetic information of two mothers, was then fertilized with the father's sperm.
In theory, says Breton, if the paternal mitochondria are viable, they could be added, or even replaced, to defective maternal mitochondria, thus avoiding the use of a third parent.
But it's a big one, especially since the mitochondrial DNA of sperm is more subject to mutation. We are far from fully understanding the full impact of biparental mitochondrial inheritance in natural circumstances, let alone through artificial medical procedures, many of which are likely to fuel ongoing debates about ethics.
For now, the maternal inheritance of mitochondrial DNA is still the norm. But simply expanding our vision of genetic heritage opens countless doors. "These results will change the way we describe the mitochondrial inheritance," Breton says. "I am 100% sure that we will find more cases like this in the future."