LONDON – A study of thousands of whole genome sequences of people in the U.K. has provided the first direct evidence of cross talk between the nuclear DNA inherited from both parents and mitochondrial DNA inherited solely from the mother.

The finding raises questions over the safety of mitochondrial donation to prevent the inheritance of serious mitochondrial diseases.

"This discovery shows us that there's a subtle relationship between the mitochondria and nuclei in our cells that we're only just starting to understand," said Patrick Chinnery, head of the Department of Clinical Neurosciences at Cambridge University. "What this suggests to us is that swapping mitochondria might not be as straightforward as just changing the batteries in a device."

The research, published in Science on May 24, 2019, confirms the significance of earlier in vitro studies in which 15% of human embryonic stem cell lines that had mutant mitochondria replaced with normal copies reverted back to the original pathogenic genotype.

It also mirrors studies in fruit flies and mice, where a mismatch between the mitochondrial and nuclear DNA haplotypes affected how long the organisms lived and caused cardiovascular and metabolic complications later in life.

The aim of the study was to get a precise reading of how common mitochondrial DNA mutations are in humans and to increase understanding of the origins of mitochondrial disease. "What we found was that there is some kind of selection taking place when mitochondrial DNA is transmitted down a generation, allowing some mutations to be passed on and others to be blocked," said first author Wei Wei from the Medical Research Council Mitochondrial Biology Unit in Cambridge.

The researchers looked at DNA sequences of more than 1,500 mother-child pairs in the U.K.'s 100,000 Genomes database and found 45% of individuals within those pairs had mutations affecting at least 1% of their mitochondrial DNA.

Common, previously observed genetic variants in mitochondrial DNA were more likely to be passed on than completely new ones. Mutations in the D-loop region – which controls how mitochondrial DNA replicates – were more likely to be transmitted, while mutations in other parts of mitochondrial DNA, such as regions coding for how mitochondria produce their own proteins, were more likely to be suppressed.

The researchers said that implies there is a selection pressure from the nuclear genome that filters the mitochondrial DNA when it is being passed down from mother to child.

It raises the possibility of reversion, in which mutant mitochondrial DNA with a selective advantage on a particular nuclear DNA background could be preferentially amplified at the expense of the non-mutant donor mitochondrial DNA. That could happen if a small amount of the mother's mitochondrial DNA was carried over to the donor egg with the nuclear DNA.

Chinnery previously worked with the team at Newcastle University which is pioneering the use of mitochondrial donation, in which a would-be mother's nuclear DNA is transplanted into a donor egg while retaining the donor's mitochondria. The technique is licensed in the U.K. to prevent transmission of serious mitochondrial diseases.

The evidence that mitochondrial DNA is in some way controlled by nuclear DNA "raises questions for the future," said Chinnery. "I must emphasize our study has not revealed any health implications at all – for example, for mitochondrial transfer. But it clearly suggests we need to keep a careful eye on this, and further work will be needed to be sure that this is not causing any adverse consequences long term."

Peter Braude, professor of obstetrics and gynecology at King's College London, said the possible risk was taken into account when mitochondrial transfer was legally approved, by a recommendation that where possible, the haplotype of the donor should be matched with that of the recipient.

"Whilst it was already understood from the work on embryonic stem cell lines that there could be a risk of an abnormal mutation increasing, rather than being eliminated or suppressed as anticipated, this risk would likely be small," said Braude. There would still be a substantial reduction of risk compared to the certain transmission of the disease-causing mutation to the child without mitochondrial transfer.

"These new results support the recommendation for prenatal diagnosis where feasible, and for mandatory long-term follow-up of any children resulting from mitochondrial donation, until the true risk is established," Braude said.

The research is the first major population study based on data collected as part of the 100,000 Genomes Project, which is sequencing the whole genomes of patients receiving treatment in the National Health Service, with the aim of systematically translating advances in genomics through to clinical care.

"It is a great pleasure that 100,000 Genomes has been able to facilitate these insights into the mitochondrial genome," said Mark Caulfield, chief executive of Genomics England, which oversees the project. "I think the key thing is that the U.K. now has fantastic assets to contribute to global understanding of biology, and that then, this paves the way to new insights into disease."

It is the responsibility of Genomics England to take health care implications of new findings arising from the 100,000 genomes collection and transform them into health care.

"This research is a first step, and this is exactly what we hoped would happen; that we would have an ecosystem where we are bringing direct benefits to patients and that we were also fueling new biology," Caulfield said.