Published in

Cold Spring Harbor Laboratory Press, Genome Research, 4(26), p. 417-426, 2016

DOI: 10.1101/gr.203216.115

Links

Tools

Export citation

Search in Google Scholar

Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck

Journal article published in 2016 by Mingkun K. Li, Martijn Vermaat, Gert Jan B. Van Ommen, Gonneke Willemsen, Manja Wachsmuth, Bruce Wolffenbuttel, Rebecca Rothwell, Mannis van Oven, Kai Ye, Paul I. W. de Bakker, Barbera D. C. Van Schaik, Roland Schröder, Cornelia M. van Duijn, Jeroen F. J. Laros, Anton J. M. De Craen and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Green circle
Preprint: archiving allowed
Red circle
Postprint: archiving forbidden
Orange circle
Published version: archiving restricted
Data provided by SHERPA/RoMEO

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.