Abstract
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.
Highlights
Several strands of evidence question the dogma that human mitochondrial DNA is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a ‘heteroplasmic haplotype’ consistent with biparental transmission
We show that rare inherited nuclear-encoded mitochondrial segments (NUMTs) can create the impression of heteroplasmy resembling the signature of paternally transmitted mitochondrial DNA (mtDNA)
To increase the specificity we increased the threshold for the allele fraction (AF) to 5% in this analysis (Methods)
Summary
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. The second sibling did not inherit any of these NUMTs, so the mixed haplotypes were observed in the father, mother and first sibling, but not in the second sibling IGV Screenshots from all aligned reads corresponding to the rare NUMTs on the nuclear DNA are shown in Supplementary Fig. 3.
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