Mitochondrial DNA Occasionally Inserts into Human Genome

Researchers at the University of Cambridge and Queen Mary University of London report new insights into the role of mitochondria in human evolution and found evidence that mitochondrial DNA may help repair damage to our genetic code.

Mitochondria are organelles that provide energy in the form of the molecule ATP. Each mitochondrion has its own DNA that is distinct to the rest of the human genome, which is comprised of nuclear DNA. Mitochondrial DNA is passed down the maternal line, although a PNAS study in 2018 from researchers at the Cincinnati Children’s Hospital Medical Center reported evidence that some mitochondrial DNA had been passed down the paternal line.

To investigate this claim, the Cambridge team looked searched for patterns that looked like paternal inheritance in the DNA of over 11,000 families recruited to Genomics England’s 100,000 Genomes Project. They found mitochondrial DNA inserts in the nuclear DNA of some children that were not present in that of their parents. They claim the US team had not observed paternally-inherited mitochondrial DNA, but rather these inserts.

After extending the study to over 66,000 people, the team showed that the new inserts happen somewhat frequently, suggesting a new route for our genome to evolve. “Billions of years ago, a primitive animal cell took in a bacterium that became what we now call mitochondria. These supply energy to the cell to allow it to function normally, while removing oxygen, which is toxic at high levels. Over time, bits of these primitive mitochondria have passed into the cell nucleus, allowing their genomes to talk to each other,” says Professor Patrick Chinnery, from the Medical Research Council Mitochondrial Biology Unit and Department of Clinical Neurosciences at the University of Cambridge. “This was all thought to have happened a very long time ago, mostly before we had even formed as a species, but what we've discovered is that that’s not true. We can see this happening right now, with bits of our mitochondrial genetic code transferring into the nuclear genome in a measurable way.”

The authors report in the journal Nature that in one in every 4,000 births, some of the genetic code from mitochondria inserts itself into the person’s DNA. If that individual has children of their own, they will pass these inserts on; the team found that most of us carry five of the new inserts, and one in seven of us (14%) carry very recent ones.  It isn’t clear exactly how the mitochondrial DNA inserts itself—whether it does so directly or via an intermediary, such as RNA—but Chinnery says it is likely to occur within the mother’s egg cells.

Once in place, the inserts can occasionally lead to very rare diseases, including a rare genetic form of cancer. When the team looked at sequences taken from 12,500 tumor samples, they found that mitochondrial DNA was even more common in tumor DNA, arising in around one in 1,000 cancers, and in some cases, the mitochondrial DNA inserts caused the cancer.

“Our nuclear genetic code is breaking and being repaired all the time,” Chinnery says. “Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumors.”

More than half (58%) of the insertions were in regions of the genome that code for proteins. In the majority of cases, the body recognizes the invading mitochondrial DNA and silences it in a process known as methylation, whereby a molecule attaches itself to the insert and switches it off. A similar process occurs when viruses manage to insert themselves into our DNA. However, this method of silencing is not perfect, as some of the mitochondrial DNA inserts go on to be copied and move around the nucleus itself.

The team looked for evidence that the reverse might happen—that mitochondrial DNA absorbs parts of our nuclear DNA—but found none. There are likely to be several reasons why this should be the case. For one, cells only have two copies of nuclear DNA, but thousands of copies of mitochondrial DNA, so the chances of mitochondrial DNA being broken and passing into the nucleus are much greater than the other way around.

Also, the DNA in mitochondria is packaged inside two membranes and there are no holes in the membrane, so it would be difficult for nuclear DNA to get in. By contrast, if mitochondrial DNA manages to get out, holes in the membrane surrounding nuclear DNA would allow it pass through with relative ease.

Professor Sir Mark Caulfield, Vice Principal for Health at Queen Mary University of London, said: “I am so delighted that the 100,000 Genomes Project has unlocked the dynamic interplay between mitochondrial DNA and our genome in the cell’s nucleus. This defines a new role in DNA repair, but also one that could occasionally trigger rare disease, or even malignancy.”