Mutation rates and the evolution of germline structure

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2016, Volume and Issue: 371(1699), P. 20150137 - 20150137

Published: June 21, 2016

Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities our understanding human germline mutation. In particular, the mutation rate observed modern is substantially lower than that estimated from calibration against fossil record, and paternal age effect transmitted to offspring much weaker expected long-standing model spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes life-history parameters such as generation time puberty, a contribution undetected post-zygotic early embryo development, cellular processes at different stages germline. suggest revised stem-cell state transitions during spermatogenesis, which ‘dark’ gonial stem cells play more active role hitherto envisaged, with long cycle experimental observations. More generally, argue its evolution depend intimately on structure other primates. This article part themed issue ‘Dating species divergences using rocks clocks'.

Language: Английский

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On the origin of sperm epigenetic heterogeneity

Reproduction, Journal Year: 2016, Volume and Issue: 151(5), P. R71 - R78

Published: Feb. 17, 2016

The influence of epigenetic modifications on reproduction and the function male germ cells has been thoroughly demonstrated. In particular, aberrant DNA methylation levels in sperm have associated with abnormal parameters, lower fertilization rates impaired embryo development. Recent reports indicated that human might be epigenetically heterogeneous found infertile men could due to presence populations different quality. However, origin contribution cell types this suspected heterogeneity remain unclear. review, we focus epigenetics at level its importance reproduction. We take into account latest developments hypotheses concerning functional significance coming from field stem cancer biology discuss potential consequences for reproduction, (in)fertility assisted reproductive technologies (ART). Based current information, propose a model which spermatogonial variability, either intrinsic or external factors (such as endocrine action environmental stimuli), can lead heterogeneity, epimutations infertility. elucidation precise causes epimutations, conception adequate therapeutic options development selection based quality should regarded crucial improvement ART outcome near future.

Language: Английский

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Clonal inactivation of TERT impairs stem cell competition

Nature, Journal Year: 2024, Volume and Issue: 632(8023), P. 201 - 208

Published: July 17, 2024

Abstract Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres—nucleoprotein caps that protect chromosome ends 1 . Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation in a telomere-independent manner 2–8 , but so far, loss-of-function studies have provided no evidence TERT has direct role cell function. In many tissues, homeostasis shaped by competition, process which compete on basis inherent fitness. Here we show conditional deletion Tert spermatogonial (SSC)-containing population mice markedly impairs competitive clone formation. Using lineage tracing from locus, find TERT-expressing SSCs yield long-lived clones, clonal inactivation promotes differentiation genome-wide reduction open chromatin. This for formation occurs independently both its activity canonical complex. Inactivation causes reduced MYC oncogene, transgenic expression TERT-deleted pool efficiently rescues Together, these data reveal catalytic-activity-independent requirement enhancing uncover genetic connection between suggest selective advantage high levels contributes to telomere elongation male germline during ageing.

Language: Английский

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Reconstructing Lineage Hierarchies of Mouse Uterus Epithelial Development Using Single-Cell Analysis

Stem Cell Reports, Journal Year: 2017, Volume and Issue: 9(1), P. 381 - 396

Published: June 15, 2017

Highlights•Single-cell transcriptome of mouse uterine epithelial development is provided•Epithelial progenitors during early epithelia identified•Molecular cascades orchestrating are dissected•Cellular hierarchical map reconstructedSummaryThe endometrial layer comprises luminal and glandular that both develop from the same simple fetal epithelium. Mechanisms progenitor self-renewal differentiation unclear. This study aims to systematically analyze molecular cellular mechanisms by single-cell analysis. An integrated set transcriptomic data their differentiated progenies provided. Additionally unique signatures these cells, characterized sequential upregulation specific epigenetic metabolic activities, activation signaling pathways transcription factors, were also investigated. Finally a subpopulation progenitor, as well lineages, identified. A complex hierarchy was thus delineated. Our therefore decoded markers program sheds light on developmental biology.Graphical abstract

Language: Английский

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Single-cell gene expression analysis reveals diversity among human spermatogonia

Molecular Human Reproduction, Journal Year: 2017, Volume and Issue: unknown

Published: Jan. 15, 2017

Is the molecular profile of human spermatogonia homogeneous or heterogeneous when analysed at single-cell level? Heterogeneous expression profiles may be a key characteristic spermatogonia, supporting existence stem cell population. Despite fact that many studies have sought to identify specific markers for fingerprint these cells remains hitherto unknown. Testicular tissues from patients with spermatogonial arrest (arrest, n = 1) and qualitatively normal spermatogenesis (normal, 7) were selected pool 179 consecutively obtained biopsies. Gene analyses populations single-cells (n 105) performed. Two OCT4-positive individual global transcriptional capture using shallow RNA-seq. Finally, four candidate was assessed by immunohistochemistry. Histological analysis blood hormone measurements LH, FSH testosterone performed prior testicular sample selection. Following enzymatic digestion tissues, differential plating subsequent micromanipulation employed enrich isolate respectively. Endpoint qPCR cells, RNA-seq immunohistochemical analyses. Unexpectedly, data patient (20 cells) showed profiles. Also, spermatogenesis, patterns undifferentiated (OCT4, UTF1 MAGE A4) differentiated marker genes (BOLL PRM2) within each cluster (13 clusters 85 cells). Shallow validated, spermatogonia-specific protein (DDX5, TSPY1, EEF1A1 NGN3) demonstrated. The heterogeneity RNA levels is snapshot. To further assess functional meaning this dynamics populations, approaches need developed facilitate repeated cells. Our suggest model Future will in fertile infertile patients. published GEO database: GSE91063. This work supported Max Planck Society Deutsche Forschungsgemeinschaft DFG-Research Unit FOR 1041 Germ Cell Potential (grant numbers SCHO 340/7-1, SCHL394/11–2). authors declare there no conflict interest.

Language: Английский

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