title: Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck.
abstract: Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies.
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; Fondation Mérieux, 69002 Lyon, France;
authors.forename: Mingkun
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rothwell
authors.affiliation: Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
authors.forename: Martijn
authors.initials: M
authors.lastname: Vermaat
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Manja
authors.initials: M
authors.lastname: Wachsmuth
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Roland
authors.initials: R
authors.lastname: Schröder
authors.affiliation: Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Laros
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands;
authors.forename: Mannis
authors.initials: M
authors.lastname: van Oven
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands;
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 BT, The Netherlands;
authors.forename: Jasper A
authors.initials: JA
authors.lastname: Bovenberg
authors.affiliation: Legal Pathways Institute for Health and Bio Law, Aerdenhout 2111, The Netherlands;
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands;
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands;
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands;
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands;
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
authors.affiliation: Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands;
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA; Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zöllner
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
authors.forename: Peter
authors.initials: P
authors.lastname: de Knijff
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Mark
authors.initials: M
authors.lastname: Stoneking
mesh_terms: D000483:Alleles; D004272:DNA, Mitochondrial; D005190:Family; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D009426:Netherlands; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D014427:Twins; D044465:White People / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial