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

Kateryna Makova, Department of Biology, Penn State University, USA (kdm16@psu.edu)

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 pre-dicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious het-eroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a dis-ease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy trans-mission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one het-eroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele fre-quency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and esti-mated the effective size of the germ-line mtDNA bottleneck at only ∼30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10(-8) (in-terquartile range from 4.2 × 10(-9) to 4.1 × 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 heteroplas-mies 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 evolution-ary dynamics of the mitochondrial genome.

Recent Publications:
Rebolledo-Jaramillo B, Su MS, Stoler N, McElhoe JA, Dickins B, Blankenberg D, Korneliussen T, Nielsen R, Holland MM, Paul IM, Nekrutenko A, Makova KD. (2014) Maternal Age Effect and Severe Germline Bottle-neck in the Inheritance of Human Mitochondrial DNA. PNAS 2014 111 (43) 15474-15479
Kuruppumullage Don P, Ananda G, Chiaromonte F, Makova KD. 2013. Segmenting the human genome based on states of neutral genetic divergence. Proceedings of the National Academy of Sciences USA 110
(36): 14699-14704

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