Mitochondrial DNA Heteroplasmy and Purifying Selection in the Mammalian Female Germ Line

The rate of chromosome segregation errors that emerge during meiosis I in the mammalian female germ line are known to increase with maternal age; however, little is known about the underlying molecular mechanism. The objective of this study was to analyze meiotic progression of mouse oocytes in relation to maternal age. Using the mouse as a model system, we analyzed the timing of nuclear envelope breakdown and the morphology of the nuclear lamina of oocytes obtained from young (2 months old) and aged females (12 months old). Oocytes obtained from older females display a significantly faster progression through meiosis I compared to the ones obtained from younger females. Furthermore, in oocytes from aged females, lamin A/C structures exhibit rapid phosphorylation and dissociation. Additionally, we also found an increased abundance of MPF components and increased translation of factors controlling translational activity in the oocytes of aged females. In conclusion, the elevated MPF activity observed in aged female oocytes affects precocious meiotic processes that can multifactorially contribute to chromosomal errors in meiosis I.

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Germline selection shapes human mitochondrial DNA diversity

Science ◽

10.1126/science.aau6520 ◽

2019 ◽

Vol 364 (6442) ◽

pp. eaau6520 ◽

Cited By ~ 62

Author(s):

Wei Wei ◽

Salih Tuna ◽

Michael J. Keogh ◽

Katherine R. Smith ◽

Timothy J. Aitman ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Genome ◽

Germ Line ◽

Population Level ◽

Maternal Transmission ◽

Human Mitochondrial Dna ◽

Genetic Lineages ◽

Selective Forces ◽

Female Germ Line ◽

Genomic Regions

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.

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Mitochondrial DNA Replacement in Primate Female Germ Line.

Biology of Reproduction ◽

10.1093/biolreprod/85.s1.239 ◽

2011 ◽

Vol 85 (Suppl_1) ◽

pp. 239-239 ◽

Cited By ~ 1

Author(s):

Hyo-Sang Lee ◽

Hong Ma ◽

Maidina Tuohetahuntila ◽

Masahito Tachibana ◽

Michelle Sparman ◽

...

Keyword(s):

Mitochondrial Dna ◽

Germ Line ◽

Female Germ Line

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Dicer in the mammalian female germ line

Nature Reviews Genetics ◽

10.1038/nrg2120 ◽

2007 ◽

Vol 8 (5) ◽

pp. 327-327

Author(s):

Carrie Patis

Keyword(s):

Germ Line ◽

Female Germ Line ◽

Mammalian Female

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Energy, ageing, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0263 ◽

2013 ◽

Vol 368 (1622) ◽

pp. 20120263 ◽

Cited By ~ 31

Author(s):

Wilson B. M. de Paula ◽

Cathy H. Lucas ◽

Ahmed-Noor A. Agip ◽

Gema Vizcay-Barrena ◽

John F. Allen

Keyword(s):

Mitochondrial Dna ◽

Free Radicals ◽

Electron Transport ◽

Oxidative Phosphorylation ◽

Germ Line ◽

Atp Synthesis ◽

Mitochondrial Morphology ◽

Male Gametes ◽

Female Germ Line ◽

Respiratory Electron Transport

Oxidative phosphorylation couples ATP synthesis to respiratory electron transport. In eukaryotes, this coupling occurs in mitochondria, which carry DNA. Respiratory electron transport in the presence of molecular oxygen generates free radicals, reactive oxygen species (ROS), which are mutagenic. In animals, mutational damage to mitochondrial DNA therefore accumulates within the lifespan of the individual. Fertilization generally requires motility of one gamete, and motility requires ATP. It has been proposed that oxidative phosphorylation is nevertheless absent in the special case of quiescent, template mitochondria, that these remain sequestered in oocytes and female germ lines and that oocyte mitochondrial DNA is thus protected from damage, but evidence to support that view has hitherto been lacking. Here we show that female gametes of Aurelia aurita , the common jellyfish, do not transcribe mitochondrial DNA, lack electron transport, and produce no free radicals. In contrast, male gametes actively transcribe mitochondrial genes for respiratory chain components and produce ROS. Electron microscopy shows that this functional division of labour between sperm and egg is accompanied by contrasting mitochondrial morphology. We suggest that mitochondrial anisogamy underlies division of any animal species into two sexes with complementary roles in sexual reproduction. We predict that quiescent oocyte mitochondria contain DNA as an unexpressed template that avoids mutational accumulation by being transmitted through the female germ line. The active descendants of oocyte mitochondria perform oxidative phosphorylation in somatic cells and in male gametes of each new generation, and the mutations that they accumulated are not inherited. We propose that the avoidance of ROS-dependent mutation is the evolutionary pressure underlying maternal mitochondrial inheritance and the developmental origin of the female germ line.

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MUTAGENESIS IN OOCYTES OF DROSOPHILA MELANOGASTER. I. SCHEDULED SYNTHESIS OF NUCLEAR AND MITOCHONDRIAL DNA AND UNSCHEDULED DNA SYNTHESIS

Genetics ◽

10.1093/genetics/104.2.279 ◽

1983 ◽

Vol 104 (2) ◽

pp. 279-299

Author(s):

Mark R Kelley ◽

William R Lee

Keyword(s):

Dna Repair ◽

Mitochondrial Dna ◽

Drosophila Melanogaster ◽

Dna Synthesis ◽

Nuclear Dna ◽

Germ Line ◽

Mutation Induction ◽

Time Interval ◽

Unscheduled Dna Synthesis ◽

Female Germ Line

ABSTRACT As a model system for studying mutagenesis, the oocyte of Drosophila melanogaster has exhibited considerable complexity. Very few experiments have been conducted on the effect of exposing oocytes to chemical mutagens, presumably due to their lower mutational response relative to sperm and spermatids. This lower response may be due either to a change in probability of mutation induction per adduct due to a change in the type of DNA repair or to a lower dose of the mutagen to the female germ line. To study molecular dosimetry and DNA repair in the oocyte, the large number of intracellular constituents (mtDNA, RNA, nucleic acid precursors and large quantities of proteins and lipids) must be separated from nuclear DNA. In this paper we present results showing reliable separation of such molecules enabling us to detect scheduled nuclear and mitochondrial DNA synthesis. We also, by understanding the precise timing of such events, can detect unscheduled DNA synthesis (UDS) as a measure of DNA repair. Furthermore, by comparing the UDS results in a repair competent (Ore-R) vs. a repair deficient (mei-9L1) strain, we have shown the oocyte capable of DNA repair after treatment with ethyl methanesulfonate (EMS). We conclude that the important determinant of mutation induction in oocytes after treatment with EMS is the time interval between DNA alkylation and DNA synthesis after fertilization, i.e., the interruption of continuous DNA repair.

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pitkinD, a Novel Gain-of-Function Enhancer of Position-Effect Variegation, Affects Chromatin Regulation During Oogenesis and Early Embryogenesis in Drosophila

Genetics ◽

10.1093/genetics/157.3.1227 ◽

2001 ◽

Vol 157 (3) ◽

pp. 1227-1244 ◽

Cited By ~ 1

Author(s):

Steffi Kuhfittig ◽

János Szabad ◽

Gunnar Schotta ◽

Jan Hoffmann ◽

Endre Máthé ◽

...

Keyword(s):

Germ Line ◽

Position Effect ◽

Early Embryogenesis ◽

Position Effect Variegation ◽

Chromatin Regulation ◽

Gain Of Function ◽

Position Effects ◽

Dominant Female ◽

Effect Variegation ◽

Female Germ Line

Abstract The vast majority of the >100 modifier genes of position-effect variegation (PEV) in Drosophila have been identified genetically as haplo-insufficient loci. Here, we describe pitkinDominant (ptnD), a gain-of-function enhancer mutation of PEV. Its exceptionally strong enhancer effect is evident as elevated spreading of heterochromatin-induced gene silencing along euchromatic regions in variegating rearrangements. The ptnD mutation causes ectopic binding of the SU(VAR)3-9 heterochromatin protein at many euchromatic sites and, unlike other modifiers of PEV, it also affects stable position effects. Specifically, it induces silencing of white+ transgenes inserted at a wide variety of euchromatic sites. ptnD is associated with dominant female sterility. +/+ embryos produced by ptnD/+ females mated with wild-type males die at the end of embryogenesis, whereas the ptnD/+ sibling embryos arrest development at cleavage cycle 1-3, due to a combined effect of maternally provided mutant product and an early zygotic lethal effect of ptnD. This is the earliest zygotic effect of a mutation so far reported in Drosophila. Germ-line mosaics show that ptn+ function is required for normal development in the female germ line. These results, together with effects on PEV and white+ transgenes, are consistent with the hypothesis that the ptn gene plays an important role in chromatin regulation during development of the female germ line and in early embryogenesis.

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Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01117-z ◽

2021 ◽

Author(s):

George B. Stefano ◽

Richard M. Kream

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Function ◽

Neurological Disorders ◽

Nuclear Dna ◽

Mitochondrial Dynamics ◽

Cell Types ◽

Tissue Specific ◽

Copy Numbers ◽

The Central Nervous System ◽

Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

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