Widespread endogenous retrotransposition generates somatic genetic mosaicism during human development
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REPOSITORIES: ENA
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Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. Here we show Human SNP 6.0 Array experiments on DNAs from four colorectal cancer patients (1BV, 2BV, 3BV, and 4BV) with polyps and metastases. Here we characterize the samples for CNVs and compare the samples' CNV status to their respective somatic L1 retrotransposition profile.
2015-08-10 | E-GEOD-63601 | biostudies-arrayexpress
Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. We assessed the impact of somatic L1 insertions on the expression of the corresponding protein-coding genes by comparing protein abundance in the polyp with the highest number of somatic L1 insertions with that of its paired normal colon using mass spectrometry analysis. Of the 10 validated somatic insertions that were in protein coding regions in the polyp, two proteins – KIAA1217 and WARS2 – were downregulated in the adenoma >90% and >70%, respectively.
2015-08-11 | PXD001626 | Pride
Project description:L1 retrotransposons are active elements in the genome, capable of mobilization in neuronal progenitor cells. Previously, we showed that chromatin remodeling during neuronal differentiation allows for a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can impact gene expression and neuronal function. Here we show that L1 neuronal retrotransposition in rodents is increased in the absence of MeCP2, a protein involved in global methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that Rett syndrome patients, with MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition, thereby increasing brain-specific genetic mosaicism.
2010-11-11 | GSE21037 | GEO
Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth.
2015-08-10 | GSE63601 | GEO
Project description:L1 retrotransposons are active elements in the genome, capable of mobilization in neuronal progenitor cells. Previously, we showed that chromatin remodeling during neuronal differentiation allows for a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can impact gene expression and neuronal function. Here we show that L1 neuronal retrotransposition in rodents is increased in the absence of MeCP2, a protein involved in global methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that Rett syndrome patients, with MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition, thereby increasing brain-specific genetic mosaicism. Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, or iPSCs) by over-expression of specific genes has been accomplished for fibroblasts derived from controls and Rett syndrome patients. Different clones from each were compared to respective original fibroblasts and a human embryonic stem cell line. Gene expression profiles measured using human genome Affymetrix Gene Chip arrays were grouped by hierarchical clustering, and correlation coefficients were computed for all pair-wise comparisons.
2010-11-11 | E-GEOD-21037 | biostudies-arrayexpress
Project description:Somatic L1 Retrotransposition of Colorectal Tumors
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Project description:Reprogramming human somatic cells into induced pluripotent stem cells (iPSC) has been suspected of causing de novo copy number variations (CNVs). To explore this issue, we performed a whole-genome and transcriptome analysis of 20 human iPSC lines derived from primary skin fibroblasts of 7 individuals using next-generation sequencing. We find that, on average, an iPSC line manifests two CNVs not apparent in the fibroblasts from which the iPSC was derived. Using qPCR, PCR, and digital droplet PCR (ddPCR) to amplify across the CNVs' breakpoints, we show that at least 50% of those CNVs are present as low frequency somatic genomic variants in parental fibroblasts and are manifested in iPSC colonies due to their clonal origin. Hence, reprogramming does not necessarily lead to de novo CNVs in iPSC, since most of line-manifested CNVs reflect somatic mosaicism in the human skin. Moreover, our findings demonstrate that clonal expansion, and iPSC lines in particular, can be used as a discovery tool to reliably detect low frequency CNVs in the tissue of origin. Overall, we estimate that approximately 30% of the fibroblast cells have somatic CNVs, suggesting widespread somatic mosaicism in the human body. Our study paves the way to understanding the fundamental question of the extent to which cells of the human body normally acquire structural alterations in their DNA post-zygotically. We have generated and characterized hiPSC lines derived from skin fibroblasts collected from seven members of two families, which were competent to be differentiated into neuronal progenitors and neurons
2012-10-31 | E-GEOD-41716 | biostudies-arrayexpress
Project description:Reprogramming human somatic cells into induced pluripotent stem cells (iPSC) has been suspected of causing de novo copy number variations (CNVs). To explore this issue, we performed a whole-genome and transcriptome analysis of 20 human iPSC lines derived from primary skin fibroblasts of 7 individuals using next-generation sequencing. We find that, on average, an iPSC line manifests two CNVs not apparent in the fibroblasts from which the iPSC was derived. Using qPCR, PCR, and digital droplet PCR (ddPCR) to amplify across the CNVs' breakpoints, we show that at least 50% of those CNVs are present as low frequency somatic genomic variants in parental fibroblasts and are manifested in iPSC colonies due to their clonal origin. Hence, reprogramming does not necessarily lead to de novo CNVs in iPSC, since most of line-manifested CNVs reflect somatic mosaicism in the human skin. Moreover, our findings demonstrate that clonal expansion, and iPSC lines in particular, can be used as a discovery tool to reliably detect low frequency CNVs in the tissue of origin. Overall, we estimate that approximately 30% of the fibroblast cells have somatic CNVs, suggesting widespread somatic mosaicism in the human body. Our study paves the way to understanding the fundamental question of the extent to which cells of the human body normally acquire structural alterations in their DNA post-zygotically.
2012-10-31 | GSE41716 | GEO
Project description: Not available
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