A novel, wave-shaped profile of germline selection of pathogenic mtDNA mutations is discovered by bypassing a classical statistical bias.

The shift of the level of disease-causing mtDNA mutations (heteroplasmy) from mother to child is typically negatively correlated with the mother ′ s heteroplasmy (Hm). In other words, mothers with low Hm tend to have children with a higher mutation level (Hch) than their own. In contrast, mothers with high Hm typically see a decrease in heteroplasmy in their children. This peculiar trend has been commonly interpreted as a result of a descending germline selection profile, i.e., positive selection at low Hm, gradually turning negative at high Hm. Here we demonstrate, however, that the negative correlation is mostly driven by RTM, or ′ Regression To the Mean ′, a classical statistical bias. We further show that RTM can be nullified by using the average between the mother ′ s and child ′ s heteroplasmy, as a new variable, instead of the commonly used mother ′ s heteroplasmy in blood. Additionally, we demonstrate that mother/child average is a better proxy of the actual germline heteroplasmy. Moreover, the elimination of RTM revealed a previously hidden wave-shaped HS-profile (positive mother-to-child shift at intermediate average mother/child heteroplasmy, decreasing towards high and low average heteroplasmy). In confirmation of this finding, we show that simulations that involve both wave-shaped HS-profile and RTM, reproduce the observed patterns of inheritance of mtDNA mutations in unprecedented detail. From the health care perspective, the uncovering of the wave-shaped HS-profile (and the removal of the RTM bias) are crucial for millions of families affected by mtDNA disease. From the fundamental perspective, the wave-shaped profile offers a novel understanding of the germline dynamics of mtDNA and a novel potential mechanism that prevents the spread of detrimental mtDNA mutations in the population. ### Competing Interest Statement The authors have declared no competing interest.