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A Pushback on Paternal Mitochondrial DNA Inheritance

In November 2018, a study appearing in PNAS challenged some foundational knowledge of basic biology when it reported that mitochondrial DNA can in rare instances be paternally inherited in humans. Researchers led by Cincinnati Children's Hospital Medical Center's Taosheng Huang and the Mayo Clinic Hospital's Paldeep Atwal reported that they found biparental mtDNA inheritance in three families, and said they confirmed their findings at independent labs with different methodologies.

Now, however, a group of European researchers is throwing some cold water on that study, claiming that a comprehensive analysis of the data reveals "a number of issues that must be carefully addressed."

The analysis, which was posted on the preprint server BioRxiv yesterday, asserts that such extraordinary claims as the ones presented in the PNAS study require similarly extraordinary evidence. "Unfortunately, the methods section lacks any description of sample management, validation of their results in independent laboratories was deficient, and the reported findings have been observed at a frequency at complete variance with established evidence," the European team writes. "Moreover, the remarkably high (and unusually homogeneous) levels of heteroplasmy reported can be readily detected using classical techniques for DNA sequencing. By reassessing the raw sequencing data with an alternative computational pipeline, we report strong correlation to the NextGENe results provided by the authors on a per sample base. However, 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."

They also say that they've demonstrated that the nuclear factor shown in the original study would need to be "extraordinarily complex and precise" in order to preclude linear accumulation of mtDNA lineages across generations, and present alternate scenarios that could explain the findings.

For example, they write, the simplest explanation is that blood samples, DNA samples, PCR amplicons, or other samples were accidentally mixed or extracted from different donors on the bench. Another explanation is that the long-range PCR covering the complete mitochondrial genome could be too unspecific, leading to an mtDNA-to-nDNA ratio in high levels. The European team also presents the possibilities that bone marrow transplantation or other types of transplant might have given rise to chimerisms that mimic a pattern of biparental inheritance, or that mitochondrial genome editing in vivo made to correct pathogenic mtDNA variation could also mimic scenarios of seeming biparental inheritance. 

"That mtDNA is transmitted from the mother to the offspring constitutes a central tenet of biology for decades. Therefore, claims of biparental inheritance of the mtDNA require exceptional evidence, and such evidence should come from fully independent laboratories, not just those involved in the original publication," they conclude. "Aiming to facilitate such independent validation, we were unsuccessful in obtaining key biological samples from the authors of Luo et al. (2018), because they denied our request for blood samples. Therefore, serious open questions remain in the reported work of Luo et al. (2018) that need to be clarified before accepting these results as evidence of biparental inheritance."