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

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Rebolledo-Jaramillo, B., Su, M.S.-W., Stoler, N., McElhoe, J.A., Dickins, B. ORCID: 0000-0002-0866-6232, Blankenberg, D., Korneliussen, T.S., Chiaromonte, F., Nielsen, R., Holland, M.M., Paul, I.M., Nekrutenko, A. and Makova, K.D., 2014. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proceedings of the National Academy of Sciences of the United States of America, 111 (43), pp. 15474-15479. ISSN 1091-6490

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Official URL: http://dx.doi.org/10.1073/pnas.1409328111

Abstract

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–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× 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 ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile 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 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.

Item Type:

Journal article

Publication Title:

Proceedings of the National Academy of Sciences of the United States of America

Creators:

Rebolledo-Jaramillo, B., Su, M.S.-W., Stoler, N., McElhoe, J.A., Dickins, B., Blankenberg, D., Korneliussen, T.S., Chiaromonte, F., Nielsen, R., Holland, M.M., Paul, I.M., Nekrutenko, A. and Makova, K.D.

Publisher:

National Academy of Sciences of the United States of America

Date:

2014

Volume:

111

Number:

ISSN:

1091-6490

Identifiers: