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

Boris Rebolledo-Jaramillo; Marcia Shu-Wei Su; Nicholas Stoler; Jennifer A. McElhoe; Benjamin Dickins; Daniel Blankenberg; Thorfinn Sand Korneliussen; Francesca Chiaromonte; Rasmus Nielsen; Mitchell M. Holland; Ian M. Paul; Anton Nekrutenko; Kateryna D. Makova

doi:10.1073/pnas.1409328111

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

Boris Rebolledo-Jaramillo, Marcia Shu-Wei Su, Nicholas Stoler, Jennifer A. McElhoe, Benjamin Dickins, Daniel Blankenberg, Thorfinn Sand Korneliussen, Francesca Chiaromonte, Rasmus Nielsen, Mitchell M. Holland, Ian M. Paul, Anton Nekrutenko, Kateryna D. Makova

110 Citationer (Scopus)

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 ∼20,000x 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 germline 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 andmaternal 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 novomutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	111
Udgave nummer	43
Sider (fra-til)	15474-15479
Antal sider	6
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1409328111
Status	Udgivet - 28 okt. 2014

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10.1073/pnas.1409328111

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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., & 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), 15474-15479. https://doi.org/10.1073/pnas.1409328111

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. / Rebolledo-Jaramillo, Boris; Su, Marcia Shu-Wei; Stoler, Nicholas et al.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 111, Nr. 43, 28.10.2014, s. 15474-15479.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Rebolledo-Jaramillo, B, Su, MS-W, Stoler, N, McElhoe, JA, Dickins, B, Blankenberg, D, Korneliussen, TS, Chiaromonte, F, Nielsen, R, Holland, MM, Paul, IM, Nekrutenko, A & Makova, KD 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, bind 111, nr. 43, s. 15474-15479. https://doi.org/10.1073/pnas.1409328111

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

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 ∼20,000x 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 germline 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 andmaternal 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 novomutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.",

author = "Boris Rebolledo-Jaramillo and Su, {Marcia Shu-Wei} and Nicholas Stoler and McElhoe, {Jennifer A.} and Benjamin Dickins and Daniel Blankenberg and Korneliussen, {Thorfinn Sand} and Francesca Chiaromonte and Rasmus Nielsen and Holland, {Mitchell M.} and Paul, {Ian M.} and Anton Nekrutenko and Makova, {Kateryna D.}",

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doi = "10.1073/pnas.1409328111",

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T1 - Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

AU - Rebolledo-Jaramillo, Boris

AU - Su, Marcia Shu-Wei

AU - Stoler, Nicholas

AU - McElhoe, Jennifer A.

AU - Dickins, Benjamin

AU - Blankenberg, Daniel

AU - Korneliussen, Thorfinn Sand

AU - Chiaromonte, Francesca

AU - Nielsen, Rasmus

AU - Holland, Mitchell M.

AU - Paul, Ian M.

AU - Nekrutenko, Anton

AU - Makova, Kateryna D.

PY - 2014/10/28

Y1 - 2014/10/28

N2 - 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 ∼20,000x 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 germline 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 andmaternal 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 novomutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.

AB - 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 ∼20,000x 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 germline 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 andmaternal 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 novomutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.

U2 - 10.1073/pnas.1409328111

DO - 10.1073/pnas.1409328111

M3 - Journal article

C2 - 25313049

SN - 0027-8424

VL - 111

SP - 15474

EP - 15479

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

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

IS - 43

ER -

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

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