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Team Describes 'Ongoing' Mitochondrial DNA Insertions in Human Genome

NEW YORK – A research team based at the University of Cambridge, Genomics England, and Queen Mary University of London has demonstrated that the insertion of mitochondrial DNA (mtDNA) sequences into the nuclear genome, known as nuclear-mitochondrial segments (NUMTs), is a process that is not restricted to the past but continues today.

"NUMTs were considered ancient remnants of previous mtDNA translocation events that were often shared between related species," senior and corresponding author Patrick Chinnery, a University of Cambridge clinical neuroscience and mitochondrial biology researcher, and his colleagues wrote in Nature on Wednesday, calling NUMT "an ongoing process."

Starting with genome sequences from almost 68,400 Genomics England Rare Disease Project participants and 26,488 tumor genome sequences generated for the Genomics England Cancer Project, the researchers searched for inserted mtDNA sequences in more than 12,500 individuals with cancer and almost 53,600 without.

In the process, the team identified 1,637 distinct NUMTs, which together turned up in more than 99 percent of the individuals analyzed. Despite their scarcity in the broader population, meanwhile, ultra-rare NUMTs turned up in genome sequences from one in every eight participants.

The researchers noted that the vast majority of the NUMTs appear to have entered the human genome since the split between the lineages leading to humans and apes, arguing against the notion that these insertions were found only in our deep evolutionary past.

Rather, they estimated that new NUMT events with lasting germline effects turn up in one person per 4,000 births, while mtDNA insertions tend to be somewhat more abundant in human cancers.

"Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA," the authors reported.

Rather than bolstering the size of the nuclear genome, for example, the team saw signs that increasingly large NUMTs are found at decreasing frequency in the population considered, consistent with the notion that the mtDNA insertions are subject to selection that maintains a steady genome size.

Moreover, the researchers explained, information on the NUMTs identified in the study suggest that noncoding mtDNA is more apt to become inserted into the human genome than coding sequences in the mitochondrial genome. Those insertions also appeared to be overrepresented at PRDM9 binding sites implicated in double-strand DNA break repair and recombination hotspots that are active in meiosis.

"In this way, NUMTs can acts as 'temporary fixes' resembling a sticking-plaster, repairing [double-strand breaks] until they are removed during meiosis," the authors speculated, adding that the "higher burden and distribution of NUMTs in cancers probably reflects a heightened state of genome instability in the absence of selection over short time periods."