Extraordinary claims require extraordinary evidence in asserted mtDNA biparental inheritance

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• The central dogma of human mitochondrial DNA (mtDNA) inheritance posits exclusive maternal transmission.
• A recent study by Luo et al. in PNAS proposed biparental mtDNA inheritance, challenging this established principle.

Purpose of the Study:

• To critically re-evaluate the data and methodology presented by Luo et al.
• To investigate potential methodological issues, such as nuclear mitochondrial DNA (NUMTs) and DNA rearrangements, that could lead to misinterpretations.
• To assess the validity of claims challenging the maternal inheritance of mtDNA.

Main Methods:

• Re-analysis of original FASTQ files and reported results from Luo et al.
• Statistical evaluation of the probability of the reported findings.
• Analysis of sequencing replicates for variant aberrations.
• Application of reductio ad absurdum to evaluate proposed nuclear factors.

Main Results:

• The probability of the findings reported by Luo et al. is extremely low (likely < 10^-37).
• Sequencing replicates showed aberrant variants, suggesting potential methodological artifacts or external contributions.
• The proposed nuclear factor mechanism is biologically implausible due to its required complexity and precision.

Conclusions:

• The data presented by Luo et al. contain significant methodological and analytical issues.
• These issues must be addressed before challenging the paradigm of maternal mtDNA inheritance.
• Alternate explanations, including in-vitro fertilization and therapeutic mtDNA replacement, can account for similar observations.