Extraordinary claims require extraordinary evidence in asserted mtDNA biparental inheritance

Abstract

A breakthrough article published in PNAS by Luo et al. challenges a central dogma in biology which states that the mitochondrial DNA (mtDNA) in humans is inherited exclusively from the mother. We re-analyzed original FASTQ files and results reported by Luo et al. to investigate methodological issues (e.g. nuclear mitochondrial DNA or NUMTs, DNA rearrangements) that could lead to biological misinterpretations. A comprehensive analysis of their data reveals several methodological and analytical issues that must be carefully addressed before challenging the current paradigm. We first show that the probability of the findings described by the authors is extremely small (most likely below 10^-37). The sequencing replicates from the same donors show aberrations in the variants detected that need further investigation to exclude contributions from other sources or methodological artifacts. Applying the principle of reductio ad absurdum, we demonstrate that the nuclear factor invoked by the authors to explain the phenomenon would need to be extraordinarily complex and precise to preclude linear accumulation of mtDNA lineages across generations, which would make the appearance of mixed haplotypes a much more frequent event in the population. We discuss alternate scenarios that explain findings of the same nature as reported by Luo et al., in the context of in-vitro fertilization and therapeutic mtDNA replacement ooplasmic transplantation.

Keywords: Biparental mtDNA inheritance; In-vitro fertilization; Mixtures; Next-generation sequencing; Paternal transmission; Therapeutic mtDNA replacement ooplasmic transplantation.