• Wei Wei, Alistair T Pagnamenta, Nicholas Gleadall, Alba Sanchis-Juan, Jonathan Stephens, John Broxholme, Salih Tuna, Christopher A Odhams, Genomics England Research Consortium, NIHR BioResource, Carl Fratter, Ernest Turro, Mark J Caulfield, Jenny C Taylor, Shamima Rahman, and Patrick F Chinnery.
• Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
• Nat Commun. 2020 Apr 8; 11 (1): 1740.

AbstractSeveral strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.

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