scholarly journals The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marco Colnaghi ◽  
Andrew Pomiankowski ◽  
Nick Lane
Keyword(s):  
De Novo ◽  
Genetic Diseases ◽  
Primordial Germ Cells ◽  
Evolutionary Model ◽  
Mutation Rates ◽  
Human Populations ◽  
Mitochondrial Mutations ◽  
Germline Development ◽  
High Quality ◽  
Female Germline

Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.

scholarly journals The need for high-quality oocyte mitochondria at extreme ploidy dictates germline development

2020 ◽  
Author(s):  
Marco Colnaghi ◽  
Andrew Pomiankowski ◽  
Nick Lane
Keyword(s):  
De Novo ◽  
Genetic Diseases ◽  
Primordial Germ Cells ◽  
Evolutionary Model ◽  
Cell Loss ◽  
Human Populations ◽  
Mitochondrial Mutations ◽  
Germline Development ◽  
High Quality ◽  
Female Germline

ABSTRACTSelection against severe mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters, the evolutionary model accurately predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show that biogenesis of high-quality mitochondria at extreme ploidy in mature oocytes can only be achieved under realistic parameters through selective pooling of mitochondria into the Balbiani body. The principal mechanisms debated in the literature, bottlenecks and follicular atresia, fail to predict these clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive germ cell loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.

scholarly journals The Mammalian Ovary from Genesis to Revelation

2009 ◽  
Vol 30 (6) ◽  
pp. 624-712 ◽  
Author(s):  
Mark A. Edson ◽  
Ankur K. Nagaraja ◽  
Martin M. Matzuk
Keyword(s):  
Germ Cells ◽  
Ovarian Function ◽  
Primordial Germ Cells ◽  
Bioactive Molecules ◽  
Sex Characteristics ◽  
Germline Development ◽  
Peptide Growth Factors ◽  
Development And Differentiation ◽  
Common Destiny ◽  
Female Germline

Abstract Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago.

scholarly journals Mitochondrial mutations in Caenorhabditis elegans show signatures of oxidative damage and an AT-bias

2021 ◽  
Author(s):  
Gus Waneka ◽  
Joshua M. Svendsen ◽  
Justin C. Havird ◽  
Daniel B. Sloan
Keyword(s):  
Caenorhabditis Elegans ◽  
Oxidative Damage ◽  
De Novo ◽  
Mutation Spectrum ◽  
Mutation Rates ◽  
Mtdna Mutation ◽  
Mitochondrial Mutations ◽  
C Elegans ◽  
Template Strand ◽  
Mtdna Mutations

Rapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e. the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterize de novo mtDNA mutations in Caenorhabditis elegans. This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in the C. elegans mtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CGAT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Further, we found an excess of GT and CT changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations in C. elegans highlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation.

scholarly journals Mitochondrial mutations in Caenorhabditis elegans show signatures of oxidative damage and an AT-bias

Genetics ◽  
2021 ◽  
Author(s):  
Gus Waneka ◽  
Joshua M Svendsen ◽  
Justin C Havird ◽  
Daniel B Sloan
Keyword(s):  
Caenorhabditis Elegans ◽  
Oxidative Damage ◽  
De Novo ◽  
Mutation Spectrum ◽  
Mutation Rates ◽  
Mtdna Mutation ◽  
Mitochondrial Mutations ◽  
C Elegans ◽  
Template Strand ◽  
Mtdna Mutations

Abstract Rapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e. the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterize de novo mtDNA mutations in Caenorhabditis elegans. This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in the C. elegans mtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CG→AT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Further, we found an excess of G→T and C→T changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations in C. elegans highlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation.

scholarly journals Detecting de novo mitochondrial mutations in angiosperms with highly divergent evolutionary rates

2020 ◽  
Author(s):  
Amanda K. Broz ◽  
Gus Waneka ◽  
Zhiqiang Wu ◽  
Daniel B. Sloan
Keyword(s):  
De Novo ◽  
Sequence Divergence ◽  
Mutation Rates ◽  
High Fidelity ◽  
Sequence Evolution ◽  
Mitochondrial Mutations ◽  
Mitochondrial Mutation ◽  
Mitochondrial Sequence ◽  
Sequencing Technologies ◽  
Close Relatives

ABSTRACTAlthough plant mitochondrial genomes typically show low rates of sequence evolution, the levels of sequence divergence in certain angiosperm lineages suggest anomalously high mitochondrial mutation rates. However, de novo mutations have never been directly analyzed in such lineages. Recent advances in high-fidelity DNA sequencing technologies have enabled detection of mitochondrial mutations when still present at low heteroplasmic frequencies. To date, these approaches have only been performed on a single plant species (Arabidopsis thaliana). Here, we apply a high-fidelity technique (Duplex Sequencing) to Silene, an angiosperm genus that exhibits extreme heterogeneity in rates of mitochondrial sequence evolution among close relatives. Consistent with phylogenetic evidence, we found that S. latifolia maintains low mitochondrial variant frequencies that are comparable to previous measurements in Arabidopsis. Silene noctiflora also exhibited low variant frequencies despite high levels of historical sequence divergence, which supports other lines of evidence that this species has reverted to lower mitochondrial mutation rates after a past episode of acceleration. In contrast, S. conica shows much higher variant frequencies, indicating an ongoing bout of elevated mutation rates. Moreover, we found an altered mutational spectrum in S. conica with a heavy bias towards AT→GC transitions (and to a lesser extent AT→CG transversions). We also observed an unusually low number of mitochondrial genome copies per cell in S. conica, potentially pointing to reduced opportunities for homologous recombination to accurately repair mismatches in this species. Overall, these results indicate that historical fluctuations in mutation rates are driving extreme variation in rates of plant mitochondrial sequence evolution.

scholarly journals Detecting de novo mitochondrial mutations in angiosperms with highly divergent evolutionary rates

Genetics ◽  
2021 ◽  
Author(s):  
Amanda K Broz ◽  
Gus Waneka ◽  
Zhiqiang Wu ◽  
Matheus Fernandes Gyorfy ◽  
Daniel B Sloan
Keyword(s):  
De Novo ◽  
Sequence Divergence ◽  
Plastid Dna ◽  
Mutation Rates ◽  
High Fidelity ◽  
Sequence Evolution ◽  
De Novo Mutations ◽  
Mitochondrial Mutations ◽  
Mitochondrial Mutation ◽  
Mitochondrial Sequence

Abstract Although plant mitochondrial genomes typically show low rates of sequence evolution, levels of divergence in certain angiosperm lineages suggest anomalously high mitochondrial mutation rates. However, de novo mutations have never been directly analyzed in such lineages. Recent advances in high-fidelity DNA sequencing technologies have enabled detection of mitochondrial mutations when still present at low heteroplasmic frequencies. To date, these approaches have only been performed on a single plant species (Arabidopsis thaliana). Here, we apply a high-fidelity technique (Duplex Sequencing) to multiple angiosperms from the genus Silene, which exhibits extreme heterogeneity in rates of mitochondrial sequence evolution among close relatives. Consistent with phylogenetic evidence, we found that S. latifolia maintains low mitochondrial variant frequencies that are comparable to previous measurements in Arabidopsis. Silene noctiflora also exhibited low variant frequencies despite high levels of historical sequence divergence, which supports other lines of evidence that this species has reverted to lower mitochondrial mutation rates after a past episode of acceleration. In contrast, S. conica showed much higher variant frequencies in mitochondrial (but not in plastid) DNA, consistent with an ongoing bout of elevated mitochondrial mutation rates. Moreover, we found an altered mutational spectrum in S. conica heavily biased towards AT→GC transitions. We also observed an unusually low number of mitochondrial genome copies per cell in S. conica, potentially pointing to reduced opportunities for homologous recombination to accurately repair mismatches in this species. Overall, these results suggest that historical fluctuations in mutation rates are driving extreme variation in rates of plant mitochondrial sequence evolution.

Inhibition of DMRTA2 impairs human female germline development in xeno-grafted ovaries

2014 ◽  
Author(s):  
Marine Poulain ◽  
Sophie Tourpin ◽  
Vincent Muczynski ◽  
Sebastien Messiaen ◽  
Delphine Moison ◽  
...  
Keyword(s):  
Human Female ◽  
Germline Development ◽  
Female Germline

Genetic Engineering of AAV Capsid Gene for Gene Therapy Application

2020 ◽  
Vol 20 (5) ◽  
pp. 321-332
Author(s):  
Yunbo Liu ◽  
Xu Zhang ◽  
Lin Yang
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Human Subjects ◽  
Genetic Diseases ◽  
Capsid Gene ◽  
Human Populations ◽  
Stable Gene ◽  
Efficient Gene ◽  
Gene Therapy Application

Adeno-associated virus (AAV) is a promising vector for in vivo gene therapy because of its excellent safety profile and ability to mediate stable gene expression in human subjects. However, there are still numerous challenges that need to be resolved before this gene delivery vehicle is used in clinical applications, such as the inability of AAV to effectively target specific tissues, preexisting neutralizing antibodies in human populations, and a limited AAV packaging capacity. Over the past two decades, much genetic modification work has been performed with the AAV capsid gene, resulting in a large number of variants with modified characteristics, rendering AAV a versatile vector for more efficient gene therapy applications for different genetic diseases.

scholarly journals A study of transposable element-associated structural variations (TASVs) using a de novo-assembled Korean genome

2021 ◽  
Author(s):  
Seyoung Mun ◽  
Songmi Kim ◽  
Wooseok Lee ◽  
Keunsoo Kang ◽  
Thomas J. Meyer ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Genome Assembly ◽  
De Novo ◽  
Personal Genome ◽  
Human Populations ◽  
Whole Genome ◽  
Structural Variations ◽  
Insert Size ◽  
Human Genomes ◽  
Next Generation Sequencing Ngs

AbstractAdvances in next-generation sequencing (NGS) technology have made personal genome sequencing possible, and indeed, many individual human genomes have now been sequenced. Comparisons of these individual genomes have revealed substantial genomic differences between human populations as well as between individuals from closely related ethnic groups. Transposable elements (TEs) are known to be one of the major sources of these variations and act through various mechanisms, including de novo insertion, insertion-mediated deletion, and TE–TE recombination-mediated deletion. In this study, we carried out de novo whole-genome sequencing of one Korean individual (KPGP9) via multiple insert-size libraries. The de novo whole-genome assembly resulted in 31,305 scaffolds with a scaffold N50 size of 13.23 Mb. Furthermore, through computational data analysis and experimental verification, we revealed that 182 TE-associated structural variation (TASV) insertions and 89 TASV deletions contributed 64,232 bp in sequence gain and 82,772 bp in sequence loss, respectively, in the KPGP9 genome relative to the hg19 reference genome. We also verified structural differences associated with TASVs by comparative analysis with TASVs in recent genomes (AK1 and TCGA genomes) and reported their details. Here, we constructed a new Korean de novo whole-genome assembly and provide the first study, to our knowledge, focused on the identification of TASVs in an individual Korean genome. Our findings again highlight the role of TEs as a major driver of structural variations in human individual genomes.

scholarly journals De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families

2021 ◽  
Author(s):  
Jonathan R. Belyeu ◽  
Harrison Brand ◽  
Harold Wang ◽  
Xuefang Zhao ◽  
Brent S. Pedersen ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
De Novo ◽  
Mutation Rates ◽  
Structural Mutation
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