Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA


The frequency of intraindividual mitochondrial DNA (mtDNA) polymorphisms extemdashheteroplasmies extemdashcan change dramatically from mother to child owing to the mitochondrial bottleneck at oogenesis. For deleterious heteroplasmies such a change may transform alleles that are benign at low frequency in a mother into disease-causing alleles when at a high frequency in her child. Our study estimates the mtDNA germ-line bottleneck to be small (30 extendash35) and documents a positive association between the number of child heteroplasmies and maternal age at fertilization, enabling prediction of transmission of disease-causing variants and informing mtDNA evolution.The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother extendashchild pairs of European ancestry (a total of 156 samples, each sequenced at ̃20,000 exttimes per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency >=1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ~30 extendash35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 exttimes 10-8 (interquartile range from 4.2 exttimes 10-9 to 4.1 exttimes 10-8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.

Proceedings of the National Academy of Sciences