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: London Nature Publishing Group UK 08.04.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 631/208/2156; 631/208/726/2129; 631/208/726/649; Cell Nucleus - genetics; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; Family; Female; Genomes; Haplotypes; Haplotypes - genetics; Heteroplasmy; Humanities and Social Sciences; Humans; Male; Mitochondrial DNA; Models, Genetic; multidisciplinary; Nucleotide sequence; Offspring; Paternal Inheritance - genetics; Pedigree; Reproducibility of Results; Science; Science (multidisciplinary); 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. Recent evidence has questioned the dogma of strict maternal transmission of mitochondrial DNA (mtDNA) in humans. Wei et al. saw no evidence of paternal transmission of mtDNA in 11,035 human trios, and show that nuclear-mitochondrial segments (NUMTs) can give the impression of paternal mtDNA transmission, but are actually inherited through the nuclear genome.