Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck
- Mingkun Li1,2,
- Rebecca Rothwell3,
- Martijn Vermaat4,
- Manja Wachsmuth1,
- Roland Schröder1,
- Jeroen F.J. Laros4,
- Mannis van Oven5,
- Paul I.W. de Bakker6,7,
- Jasper A. Bovenberg8,
- Cornelia M. van Duijn9,
- Gert-Jan B. van Ommen10,
- P. Eline Slagboom11,
- Morris A. Swertz12,13,
- Cisca Wijmenga12,13,
- Genome of the Netherlands Consortium16,
- Manfred Kayser5,
- Dorret I. Boomsma14,
- Sebastian Zöllner3,15,
- Peter de Knijff11 and
- Mark Stoneking1
- 1Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
- 2Fondation Mérieux, 69002 Lyon, France;
- 3Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 4Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
- 5Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands;
- 6Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands;
- 7Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands;
- 8Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 BT, The Netherlands;
- 9Legal Pathways Institute for Health and Bio Law, Aerdenhout 2111, The Netherlands;
- 10Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands;
- 11Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
- 12Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
- 13Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands;
- 14Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands;
- 15Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109, USA
- Corresponding authors: P.de_Knijff{at}lumc.nl, stoneking{at}eva.mpg.de
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.
Footnotes
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↵16 Membership of the Genome of the Netherlands Consortium is provided at the end of this paper.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.203216.115.
- Received December 11, 2015.
- Accepted January 21, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
