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 ∼20,000× 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.
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Boris
authors.initials: B
authors.lastname: Rebolledo-Jaramillo
authors.affiliation: Biology, and.
authors.forename: Marcia Shu-Wei
authors.initials: MS
authors.lastname: Su
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stoler
authors.affiliation: Forensic Science Program, Pennsylvania State University, University Park, PA 16802;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: McElhoe
authors.affiliation: School of Science and Technology, Nottingham Trent University, Nottingham NG1 4BU, United Kingdom;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dickins
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blankenberg
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, CA 94720; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, DK-1350 Copenhagen, Denmark; and.
authors.forename: Thorfinn S
authors.identifier: http://orcid.org/0000-0001-7576-5380
authors.initials: TS
authors.lastname: Korneliussen
authors.affiliation: Statistics.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiaromonte
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, CA 94720;
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Forensic Science Program, Pennsylvania State University, University Park, PA 16802;
authors.forename: Mitchell M
authors.initials: MM
authors.lastname: Holland
authors.affiliation: Department of Pediatrics, College of Medicine, Pennsylvania State University, Hershey, PA 17033.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Paul
authors.affiliation: Departments of Biochemistry and Molecular Biology, anton@bx.psu.edu kdm16@psu.edu.
authors.forename: Anton
authors.initials: A
authors.lastname: Nekrutenko
authors.affiliation: Biology, and anton@bx.psu.edu kdm16@psu.edu.
authors.forename: Kateryna D
authors.initials: KD
authors.lastname: Makova
mesh_terms: D000367:Age Factors; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics*; D004194:Disease / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D040582:Inheritance Patterns / Q000235:genetics*; D008423:Maternal Age; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial
keywords: heteroplasmy; mitochondria