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 S. Korneliussen, Francesca Chiaromonte, Rasmus Nielsen, Mitchell M. Holland, Ian M. Paul, Anton Nekrutenko, Kateryna D. Makova

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)15474-15479
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number43
DOIs
StatePublished - Oct 28 2014

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Maternal Age
Mitochondrial DNA
Germ Cells
Mothers
Mitochondrial Diseases
Oogenesis
Mitochondrial Genome
Germ-Line Mutation
Cheek
Mutation Rate
Fertilization
Gene Frequency
Oocytes
Maternal Inheritance
Alleles
Polymerase Chain Reaction
Mutation
DNA

All Science Journal Classification (ASJC) codes

  • General

Cite this

Rebolledo-Jaramillo, Boris ; Su, Marcia Shu Wei ; Stoler, Nicholas ; McElhoe, Jennifer A. ; Dickins, Benjamin ; Blankenberg, Daniel ; Korneliussen, Thorfinn S. ; Chiaromonte, Francesca ; Nielsen, Rasmus ; Holland, Mitchell M. ; Paul, Ian M. ; Nekrutenko, Anton ; Makova, Kateryna D. / Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 43. pp. 15474-15479.
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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.",
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Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. / Rebolledo-Jaramillo, Boris; Su, Marcia Shu Wei; Stoler, Nicholas; McElhoe, Jennifer A.; Dickins, Benjamin; Blankenberg, Daniel; Korneliussen, Thorfinn S.; Chiaromonte, Francesca; Nielsen, Rasmus; Holland, Mitchell M.; Paul, Ian M.; Nekrutenko, Anton; Makova, Kateryna D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 43, 28.10.2014, p. 15474-15479.

Research output: Contribution to journalArticle

TY - JOUR

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 S.

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.

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