scholarly journals Lineage tracing of human embryonic development and foetal haematopoiesis through somatic mutations

2020 ◽  
Author(s):  
Michael Spencer Chapman ◽  
Anna Maria Ranzoni ◽  
Brynelle Myers ◽  
Nick Williams ◽  
Tim Coorens ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Somatic Mutations ◽  
Lineage Tracing ◽  
Whole Genome ◽  
Healthy Human ◽  
Foetal Development ◽  
Embryonic Tissues ◽  
Embryonic Origin ◽  
Haematopoietic System ◽  
Human Foetuses

AbstractTo date, ontogeny of the human haematopoietic system during foetal development has been characterized mainly through careful microscopic observations. Here we used whole-genome sequencing (WGS) of 511 single-cell derived haematopoietic colonies from healthy human foetuses of 8 and 18 post-conception weeks (pcw) coupled with deep targeted sequencing of tissues of known embryonic origin to reconstruct a phylogenetic tree of blood development. We found that in healthy foetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 pcw. Using these mutations as barcodes, we timed the divergence of embryonic and extra-embryonic tissues during development and estimated the number of blood antecedents at different stages of embryonic development. Our analysis has shown that ectoderm originates from a smaller set of blood antecedents compared to endoderm and mesoderm. Finally, our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.

scholarly journals Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Irene Franco ◽  
Hafdis T. Helgadottir ◽  
Aldo Moggio ◽  
Malin Larsson ◽  
Peter Vrtačnik ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Adult Life ◽  
Cell Types ◽  
Human Cells ◽  
Specific Cell ◽  
Whole Genome ◽  
Cell Type ◽  
Healthy Human

Abstract Background The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.

scholarly journals Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges

2021 ◽  
Author(s):  
Marketa Kaucka ◽  
Bara Szarowska ◽  
Michaela Kavkova ◽  
Maria Eleni Kastriti ◽  
Polina Kameneva ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Inner Ear ◽  
Gene Knockout ◽  
Hair Follicles ◽  
Lineage Tracing ◽  
Pigment Cells ◽  
Hearing Function ◽  
Embryonic Origin ◽  
Schwann Cell Precursors ◽  
Evolutionary Aspects

AbstractMelanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.

scholarly journals Whole genome resequencing and custom genotyping unveil clonal lineages in ‘Malbec’ grapevines (Vitis vinifera L.)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luciano Calderón ◽  
Nuria Mauri ◽  
Claudio Muñoz ◽  
Pablo Carbonell-Bejerano ◽  
Laura Bree ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Somatic Mutations ◽  
Clonal Propagation ◽  
Variant Calling ◽  
Vitis Vinifera L ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Genome Resequencing ◽  
Diversity Pattern ◽  
Whole Genome Resequencing

AbstractGrapevine cultivars are clonally propagated to preserve their varietal attributes. However, genetic variations accumulate due to the occurrence of somatic mutations. This process is anthropically influenced through plant transportation, clonal propagation and selection. Malbec is a cultivar that is well-appreciated for the elaboration of red wine. It originated in Southwestern France and was introduced in Argentina during the 1850s. In order to study the clonal genetic diversity of Malbec grapevines, we generated whole-genome resequencing data for four accessions with different clonal propagation records. A stringent variant calling procedure was established to identify reliable polymorphisms among the analyzed accessions. The latter procedure retrieved 941 single nucleotide variants (SNVs). A reduced set of the detected SNVs was corroborated through Sanger sequencing, and employed to custom-design a genotyping experiment. We successfully genotyped 214 Malbec accessions using 41 SNVs, and identified 14 genotypes that clustered in two genetically divergent clonal lineages. These lineages were associated with the time span of clonal propagation of the analyzed accessions in Argentina and Europe. Our results show the usefulness of this approach for the study of the scarce intra-cultivar genetic diversity in grapevines. We also provide evidence on how human actions might have driven the accumulation of different somatic mutations, ultimately shaping the Malbec genetic diversity pattern.

scholarly journals Dynamics of Structural Barriers and Innate Immune Components during Incubation of the Avian Egg: Critical Interplay between Autonomous Embryonic Development and Maternal Anticipation

2018 ◽  
Vol 11 (2) ◽  
pp. 111-124 ◽  
Author(s):  
Maxwell T. Hincke ◽  
Mylène Da Silva ◽  
Nicolas Guyot ◽  
Joël Gautron ◽  
Marc D. McKee ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Innate Immune ◽  
Vitelline Membrane ◽  
Structural Barriers ◽  
Embryonic Tissues ◽  
Egg Incubation ◽  
Evolutionary Success ◽  
Protective Structures ◽  
Amniotic Membranes ◽  
Autonomous Development

The integrated innate immune features of the calcareous egg and its contents are a critical underpinning of the remarkable evolutionary success of the Aves clade. Beginning at the time of laying, the initial protective structures of the egg, i.e., the biomineralized eggshell, egg-white antimicrobial peptides, and vitelline membrane, are rapidly and dramatically altered during embryonic development. The embryo-generated extra-embryonic tissues (chorioallantoic/amniotic membranes, yolk sac, and associated chambers) are all critical to counteract degradation of primary egg defenses during development. With a focus on the chick embryo (Gallus gallus domesticus), this review describes the progressive transformation of egg innate immunity by embryo-generated structures and mechanisms over the 21-day course of egg incubation, and also discusses the critical interplay between autonomous development and maternal anticipation.

scholarly journals Evolution of the hypoxia-sensitive cells involved in amniote respiratory reflexes

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Dorit Hockman ◽  
Alan J Burns ◽  
Gerhard Schlosser ◽  
Keith P Gates ◽  
Benjamin Jevans ◽  
...  
Keyword(s):  
Neural Crest ◽  
Blood Vessels ◽  
Carotid Body ◽  
Lineage Tracing ◽  
Neuroendocrine Cells ◽  
Genetic Lineage ◽  
Glomus Cells ◽  
Evolutionary Origins ◽  
Embryonic Origin ◽  
Respiratory Reflexes

The evolutionary origins of the hypoxia-sensitive cells that trigger amniote respiratory reflexes – carotid body glomus cells, and ‘pulmonary neuroendocrine cells’ (PNECs) - are obscure. Homology has been proposed between glomus cells, which are neural crest-derived, and the hypoxia-sensitive ‘neuroepithelial cells’ (NECs) of fish gills, whose embryonic origin is unknown. NECs have also been likened to PNECs, which differentiate in situ within lung airway epithelia. Using genetic lineage-tracing and neural crest-deficient mutants in zebrafish, and physical fate-mapping in frog and lamprey, we find that NECs are not neural crest-derived, but endoderm-derived, like PNECs, whose endodermal origin we confirm. We discover neural crest-derived catecholaminergic cells associated with zebrafish pharyngeal arch blood vessels, and propose a new model for amniote hypoxia-sensitive cell evolution: endoderm-derived NECs were retained as PNECs, while the carotid body evolved via the aggregation of neural crest-derived catecholaminergic (chromaffin) cells already associated with blood vessels in anamniote pharyngeal arches.

scholarly journals Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Nature ◽  
2019 ◽  
Vol 566 (7742) ◽  
pp. E1-E1 ◽  
Author(s):  
Serena Nik-Zainal ◽  
Helen Davies ◽  
Johan Staaf ◽  
Manasa Ramakrishna ◽  
Dominik Glodzik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Whole Genome ◽  
Genome Sequences

scholarly journals Quantifying the influence of mutation detection on tumour subclonal reconstruction

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lydia Y. Liu ◽  
Vinayak Bhandari ◽  
Adriana Salcedo ◽  
Shadrielle M. G. Espiritu ◽  
Quaid D. Morris ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Cancer Cells ◽  
Clinical Outcomes ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Somatic Mutations ◽  
Mutation Detection ◽  
Cell Populations ◽  
Whole Genome ◽  
Prostate Cancers

AbstractWhole-genome sequencing can be used to estimate subclonal populations in tumours and this intra-tumoural heterogeneity is linked to clinical outcomes. Many algorithms have been developed for subclonal reconstruction, but their variabilities and consistencies are largely unknown. We evaluate sixteen pipelines for reconstructing the evolutionary histories of 293 localized prostate cancers from single samples, and eighteen pipelines for the reconstruction of 10 tumours with multi-region sampling. We show that predictions of subclonal architecture and timing of somatic mutations vary extensively across pipelines. Pipelines show consistent types of biases, with those incorporating SomaticSniper and Battenberg preferentially predicting homogenous cancer cell populations and those using MuTect tending to predict multiple populations of cancer cells. Subclonal reconstructions using multi-region sampling confirm that single-sample reconstructions systematically underestimate intra-tumoural heterogeneity, predicting on average fewer than half of the cancer cell populations identified by multi-region sequencing. Overall, these biases suggest caution in interpreting specific architectures and subclonal variants.

scholarly journals Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms

2019 ◽  
Vol 28 (R2) ◽  
pp. R197-R206 ◽  
Author(s):  
Michael A Lodato ◽  
Christopher A Walsh
Keyword(s):  
Human Brain ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Late Onset ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Age Related ◽  
The Brain ◽  
Over Time

AbstractAging is a mysterious process, not only controlled genetically but also subject to random damage that can accumulate over time. While DNA damage and subsequent mutation in somatic cells were first proposed as drivers of aging more than 60 years ago, whether and to what degree these processes shape the neuronal genome in the human brain could not be tested until recent technological breakthroughs related to single-cell whole-genome sequencing. Indeed, somatic single-nucleotide variants (SNVs) increase with age in the human brain, in a somewhat stochastic process that may nonetheless be controlled by underlying genetic programs. Evidence from the literature suggests that in addition to demonstrated increases in somatic SNVs during aging in normal brains, somatic mutation may also play a role in late-onset, sporadic neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. In this review, we will discuss somatic mutation in the human brain, mechanisms by which somatic mutations occur and can be controlled, and how this process can impact human health.

Mechanics of Embryonic Head Fold Morphogenesis

2008 ◽  
Author(s):  
Victor D. Varner ◽  
Dmitry A. Voronov ◽  
Larry A. Taber
Keyword(s):  
Embryonic Development ◽  
Incubation Period ◽  
Neural Plate ◽  
Vitelline Membrane ◽  
Heart Tube ◽  
Germ Layers ◽  
Embryonic Tissues ◽  
Anterior Extent ◽  
Insight Into ◽  
Embryonic Head

Head fold morphogenesis constitutes the first discernible epithelial folding event in the embryonic development of the chick. It arises at Hamburger and Hamilton (HH) stage 6 (approximately 24 hours into a 21-day incubation period) and establishes the anterior extent of the embryo [1]. At this stage, the embryonic blastoderm is composed of three germ layers (endoderm, mesoderm, and ectoderm), which are organized into a flat layered sheet that overlies the fibrous vitelline membrane (VM). Within this blastodermal sheet, a crescent-shaped head fold develops just anterior to the elongating notochord, spanning across the embryonic midline at the rostral end of neural plate. At the crest of this fold, the bilateral precardiac plates fuse in a cranial to caudal direction and give rise to the primitive heart tube and foregut [2, 3]. An understanding of head fold morphogenesis may thus offer insight into how embryonic tissues are arranged to make ready for proper cardiac formation.

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