Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA287443 | ENA |
REPOSITORIES: ENA
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Project description:Single-cell genetic analysis using automated microfluidics to resolve somatic mosaicism
| PRJNA287813 | ENA
Project description:Human development relies on the correct replication, maintenance and segregation of our genetic blueprints. How these processes are monitored across embryonic lineages, and why genomic mosaicism varies during development remain unknown. Using pluripotent stem cells, we identify that several patterning signals –including WNT, BMP and FGF– converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls chromosome segregation fidelity in mitosis. We show that the WNT and BMP signals protect from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks in pluripotency. Cell signalling control of chromosome segregation declines during lineage specification into the three germ layers, but re-emerges in neural progenitors. In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation during the onset of neurogenesis, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight roles for morphogens and cellular identity in genome maintenance that contribute to somatic mosaicism during mammalian development.
2024-07-31 | PXD054388 | Pride
Project description:Genetic variation is responsible for the generation of phenotypic diversity, including susceptibility to disease. Two major types of variation are known: single nucleotide polymorphisms (SNPs) and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. Variation caused by CNVs has exceeded the amount of SNP-based differences expected to exist between two unrelated humans. Furthermore, many CNVs have been associated with disease predisposition. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. Here we show that CNVs are frequent in healthy somatic cells of adult humans. We tested 34 tissue samples from three subjects and, having analyzed for each tissue <10-6 of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82-176 kb, often encompassing known genes, potentially affecting gene function. Our results point to a paradigm shift in the genetics of somatic cells and indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. A considerable number of phenotypes and diseases affecting humans are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues in order to better address mosaicism in the studies of somatic disorders. Furthermore, forensic medicine laboratories should be sensitized to the issue of underestimated frequency of somatic CNV mosaicism. Keywords: copy number variation (CNV), phenotype diversity, somatic cells 31 experiments; each experiment consists of two hybridizations, i.e. regular and dye-swap (62 hybridizations in total); cerebellum from corresponding subject was used as a reference; additionally 12 control self-self hybridizations are included (cerrebellum vs self)
2008-09-16 | E-GEOD-9598 | biostudies-arrayexpress
Project description:Genetic variation is responsible for the generation of phenotypic diversity, including susceptibility to disease. Two major types of variation are known: single nucleotide polymorphisms (SNPs) and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. Variation caused by CNVs has exceeded the amount of SNP-based differences expected to exist between two unrelated humans. Furthermore, many CNVs have been associated with disease predisposition. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. Here we show that CNVs are frequent in healthy somatic cells of adult humans. We tested 34 tissue samples from three subjects and, having analyzed for each tissue <10-6 of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82-176 kb, often encompassing known genes, potentially affecting gene function. Our results point to a paradigm shift in the genetics of somatic cells and indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. A considerable number of phenotypes and diseases affecting humans are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues in order to better address mosaicism in the studies of somatic disorders. Furthermore, forensic medicine laboratories should be sensitized to the issue of underestimated frequency of somatic CNV mosaicism. Keywords: copy number variation (CNV), phenotype diversity, somatic cells
2008-09-16 | GSE9598 | GEO
Project description:Digital-scRRBS: A cost-effective, highly sensitive and automated single-cell methylome analysis platform via digital microfluidics
| PRJNA883959 | ENA
Project description:Somatic mosaic variants are a major cause of human disease, including cancer and focal epilepsies, but can be challenging to study due to their mosaicism in bulk tissue biopsies. Coupling single-cell genotype and transcriptomic data has potential to provide insight into the role somatic variants play in disease etiology, such as by determining what cell types are affected or how the mutations affect gene expression. Here, we asked whether commonly used single-cell 3’- or 5’-RNA-sequencing assays can be used to derive single-cell genotype data for a priori known variants that are located near to either end of a transcript. To that end, we compared performance of commercially available single-cell 3’- and 5’- gene expression kits using resected brain samples from three pediatric patients with focal epilepsy. We quantified the ability to detect genetic variants in single-cell datasets depending on distance from the transcript end. Finally, we demonstrated the ability to identify affected cell types in a patient with a RHEB somatic variant causing an epilepsy-associated cortical malformation. Our results demonstrate that native single-cell 3’ or 5’-RNA-sequencing data can be used successfully to genotype single-cells for somatic variants that are expressed within proximity to a transcript end.
2023-01-09 | GSE210670 | GEO
Project description:Genetic mosaicism and somatic mutation rate in tropical trees
| PRJDB14538 | ENA
Project description:Genetic mosaicism and somatic mutation rate in tropical trees
| PRJDB15012 | ENA
Project description:<p>Genetic mutations causing human disease are conventionally thought to be inherited from one's parents and present in all somatic (body) cells. Increasingly however, somatic mutations are implicated in neurological diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases, even when present at low levels of mosaicism.</p> <p>In this study we use whole genome sequencing of single neurons and bulk tissue to identify somatic mutations in control, and some disease, brains to: 1) identify and catalogue the mutations which shape the somatic neuronal genome; 2) perform a cell lineage analysis of the adult human brain using clonal somatic mutations in cortical neurons; 3) determine patterns of somatic mutations at different ages and in aging related disease phenotypes; and 4) relate cell lineage patterns to cell phenotype in the human brain by separating neuronal, glial, and other cell types.</p>
| phs001485 | dbGaP
Project description:Massively parallel single-cell RNA sequencing can precisely resolve cellular diversity in a high-throughput manner at low cost, but unbiased isolation of intact single cells from complex tissues, such as adult mammalian brains, is challenging. Here, we integrate sucrose-gradient assisted nuclei purification with droplet microfluidics to develop a highly scalable single-nucleus RNA-Seq approach (sNucDrop-Seq), which is free of enzymatic dissociation and nuclei sorting. By profiling ~18,000 nuclei isolated from cortical tissues of adult mice, we demonstrate that sNucDrop-Seq not only accurately reveals neuronal and non-neuronal subtype composition with high sensitivity, but also enables in-depth analysis of transient transcriptional states driven by neuronal activity, at single-cell resolution, in vivo.
2017-12-07 | GSE106678 | GEO