Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans

• Published in: Nature communications Vol. 11; no. 1; p. 1740
• Main Authors: Wei, Wei, Pagnamenta, Alistair T, Gleadall, Nicholas, Sanchis-Juan, Alba, Stephens, Jonathan, Broxholme, John, Tuna, Salih, Odhams, Christopher A, Fratter, Carl, Turro, Ernest, Caulfield, Mark J, Taylor, Jenny C, Rahman, Shamima, Chinnery, Patrick F
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 08.04.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Cell Nucleus - genetics; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; Family; Female; Genomes; Haplotypes; Haplotypes - genetics; Heteroplasmy; Humans; Male; Mitochondrial DNA; Models, Genetic; Nucleotide sequence; Offspring; Paternal Inheritance - genetics; Pedigree; Reproducibility of Results; Segments
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15336-3

Several 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.