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.

A Population Phylogenetic View of Mitochondrial Heteroplasmy

“…This may seem to contradict previous observations that heteroplasmies become more numerous with age (e.g., Rebolledo-Jaramillo et al, 2014; Li et al, 2016). If the effective population size of the somatic stem cells supporting mitotic somatic tissues is larger than the effective population size during embryogenesis or the maternal germ line, an accumulation of genetic drift with age would produce additional de novo somatic heteroplasmies.…”

Quasi-Mendelian Paternal Inheritance of mitochondrial DNA: A notorious artifact, or anticipated mtDNA behavior?

“…As far as the germline is concerned, the abrupt enrichment of one genotype over the other have been recognized as the mtDNA bottleneck effect since a seminal work in heteroplasmic cows (Hauswirth and Laipis, 1982). More recently, extensive population studies on human mother/offspring pairs showed a significant number of cases where a genotype that was not detectable in the mother showed up as significant heteroplasmy in the child (Rebolledo-Jaramillo et al, 2014), (Li et al, 2016). This implies that a rare genotype, perhaps a nascent mutant molecule, in some cases may enjoy a dramatic enrichment among germline mitochondria in normal humans within a one generation time frame.…”

A population phylogenetic view of mitochondrial heteroplasmy

“…In particular, for certain ontogenetic processes, we model the rate of accumulation of genetic drift and mutation with age. This is motivated by previous observations that heteroplasmic variants segregate and accumulate with time within somatic tissues (Li et al, 2015;Sondheimer et al, 2011;Rebolledo-Jaramillo et al, 2014) and within the germline (Rebolledo-Jaramillo et al, 2014;Li et al, 2016;Wachsmuth et al, 2016). Finally, in the typical population-phylogenetic model, each branch of the phylogeny represents a single period in evolutionary history and is modeled by a single parameter.…”

“…While it was long thought that the mitochondria within the human body are genetic clones, it is now recognized that variation of mitochondrial DNA (mtDNA) is common within human cells and tissues. This variation, termed mitochondrial heteroplasmy, is a normal part of healthy human biology (Rebolledo-Jaramillo et al, 2014;Li et al, 2016Li et al, , 2010, but it is also important in human health and disease, being the primary mode of inheritance of mitochondrial disease and playing a role in cancer and aging (reviewed in Stewart and Chinnery, 2015;Wallace and Chalkia, 2013).…”

“…There has been considerable debate about whether the mechanism of this bottleneck involves an actual decrease in the number of mitochondrial genome copies versus co-segregation of genetically homogeneous groups of mitochondrial DNA (e.g., Jenuth et al, 1996;Cao et al, 2007;Cree et al, 2008;Wai et al, 2008;Carling et al, 2011). Nevertheless, in order to better predict the change in heteroplasmy frequencies between generations, previous studies have sought to infer the size of the oogenic bottleneck, either through direct observation (in mice) of the number of mitochondrial DNA genome copies (Cree et al, 2008;Cao et al, 2007), or through indirect measurement, making statistical conclusions about the bottleneck size based on observed frequency changes between generations (Johnston et al, 2015;Rebolledo-Jaramillo et al, 2014;Millar et al, 2008;Hendy et al, 2009;Li et al, 2016). Recently, Johnston et al (2015) have proposed a statistical framework that combines direct observations of mtDNA copy number with genetic variance in order to make inferences about the dynamics of the oogenic bottleneck.…”