Natural selection of mitochondria during somatic lifetime promotes healthy aging (original) (raw)
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Mitochondrial DNA: more than an evolutionary bystander
Functional Ecology, 2014
1. The vast majority of studies employing mtDNA in evolutionary biology and ecology have used it as a means to infer demographic and historical patterns without pondering the underlying functional implications. In contrast, the biochemical and medical communities often aim to understand the influence of specific mtDNA mutations on mitochondrial functions, but rarely consider the evolutionary and ecological implications.
BioEssays, 2000
In this article we develop a model for the organization and maintenance of mitochondrial DNA (mtDNA) in mammalian somatic cells, based on the idea that the unit of genetic function comprises a group of mtDNA molecules that are semi-permanently associated as a mitochondrial nucleoid. Different mtDNA molecules within a nucleoid need not be genetically identical. We propose that nucleoids replicate faithfully via a kind of mitochondrial mitosis, generating daughter nucleoids that are identical copies of each other, but which can themselves segregate freely. This model can account for the very slow rates of mitotic segregation observed in cultured, heteroplasmic cell-lines, and also for the apparently poor complementation observed between different mutant mtDNAs co-introduced into q 0 cells (cells that lack endogenous mtDNA). It also provides a potential system for maintaining the mitochondrial genetic fitness of stem cells in the face of a presumed high somatic mutation rate of mtDNA and many rounds of cell division in the absence of phenotypic selection.
ABSTRACTMitochondrial DNA (mtDNA) is a cytoplasmic genome that is essential for respiratory metabolism. While uniparental mtDNA inheritance is most common in animals and plants, distinct mtDNA haplotypes can coexist in a state of heteroplasmy, either because of paternal leakage or de novo mutations. MtDNA integrity and the resolution of heteroplasmy have important implications, notably for mitochondrial genetic disorders, speciation and genome evolution in hybrids. However, the impact of genetic variation on the transition to homoplasmy from initially heteroplasmic backgrounds remains largely unknown. Here, we useSaccharomycesyeasts, fungi with constitutive biparental mtDNA inheritance, to investigate the resolution of mtDNA heteroplasmy in a variety of hybrid genotypes. We previously designed 11 crosses along a gradient of parental evolutionary divergence using undomesticated isolates ofSaccharomyces paradoxusandSaccharomyces cerevisiae. Each cross was independently replicated 48 t...
Nature Genetics, 2012
A genetic bottleneck explains the marked changes in mitochondrial DNA (mtDNA) heteroplasmy observed during the transmission of pathogenic mutations, but the precise timing remains controversial, and it is not clear whether selection plays a role. These issues are critically important for the genetic counseling of prospective mothers, and developing treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single base-pair deletion in the mitochondrial tRNA Met gene, we show that mammalian mtDNA heteroplasmy levels are principally determined prenatally within the developing female germ line. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentage levels of the tRNA Met mutation were linked to a compensatory increase in overall mitochondrial RNAs, ameliorating the biochemical phenotype, and explaining why fecundity is not compromised.
Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA
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 germline 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 andmaternal 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 novomutation.Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.
Mitochondrial behaviors prime the selective inheritance against harmful mitochondrial DNA mutations
2019
Although mitochondrial DNA (mtDNA) is prone to mutation and few mtDNA repair mechanisms exist, deleterious mutations are exceedingly rare. How the transmission of detrimental mtDNA mutations are restricted through the maternal lineage is debated. Here, we use Drosophila to dissect the mechanisms of mtDNA selective inheritance and understand their molecular underpinnings. Our observations support a purifying selection at the organelle level based on a series of developmentally-orchestrated mitochondrial behaviors. We demonstrate that mitochondrial fission, together with the lack of mtDNA replication in proliferating germ cells, effectively segregates mtDNA into individual organelles. After mtDNA segregation, mtDNA expression begins, which leads to the activation of respiration in each organelle. The expression of mtDNA allows the functional manifestation of different mitochondrial genotypes in heteroplasmic cells, and hence functions as a stress test for each individual genome and se...
Germline selection shapes human mitochondrial DNA diversity
Science
Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother–offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.