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The influence of segmental copy number variation on tissue transcriptomes through development

ABSTRACT: A preliminary understanding of the phenotypic effect of copy number variation (CNV) of DNA segments is emerging. These rearrangements were demonstrated to influence, in a somewhat dose-dependent manner, the expression of genes mapping within. They were shown to also affect the expression of genes located on their flanks, sometimes at great distance. Here, we show by monitoring these effects at multiple life stages, that these controls over expression are effective throughout mouse development. Similarly, we observe that the more specific spatial expression patterns of CNV genes are maintained throughout life. However, we find that some brain-expressed genes appear to be under compensatory loops only at specific time-points, indicating that the influence of CNVs on these genes is modulated through development. We also observe that CNV genes are significantly enriched upon transcripts that show variable time-course of expression in different strains. Thus modifying the number of copy of a gene not only potentially alters its expression level, but possibly also its time of expression. Keywords: comparative genomic

ORGANISM(S): Mus musculus

PROVIDER: GSE16675 | GEO | 2010/11/17

SECONDARY ACCESSION(S): PRJNA117393

REPOSITORIES: GEO

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The influence of segmental copy number variation on tissue transcriptomes through development

Project description:A preliminary understanding of the phenotypic effect of copy number variation (CNV) of DNA segments is emerging. These rearrangements were demonstrated to influence, in a somewhat dose-dependent manner, the expression of genes mapping within. They were shown to also affect the expression of genes located on their flanks, sometimes at great distance. Here, we show by monitoring these effects at multiple life stages, that these controls over expression are effective throughout mouse development. Similarly, we observe that the more specific spatial expression patterns of CNV genes are maintained throughout life. However, we find that some brain-expressed genes appear to be under compensatory loops only at specific time-points, indicating that the influence of CNVs on these genes is modulated through development. We also observe that CNV genes are significantly enriched upon transcripts that show variable time-course of expression in different strains. Thus modifying the number of copy of a gene not only potentially alters its expression level, but possibly also its time of expression. Keywords: comparative genomic Expression from brain and liver tissues from C57BL/6J, DBA2/J and 129S2 mouse strains at different developmental time points.

2010-11-17 | E-GEOD-16675 | biostudies-arrayexpress

Genome-wide maps of chromatin state in Williams-Beuren (WBS), Williams-Beuren Region duplication (WBRdupS), Smith-Magenis (DGS), DiGeorge (DGS) lymphoblastoid cell lines

Project description:Copy number variants (CNV) influence the expression of genes that map not only within, but also on their flanks. To assess the possible mechanism(s) underlying this “neighboring effect”, we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. We detected alteration of intrachromosomal interactions (chromosomal looping) between the loci of affected genes and the rearranged interval using chromosome conformation capture (4C-seq). These results are consistent with the observed gene expression alterations. We also pinpointed concomitant changes in histone modifications between samples. Modified genes were often looping together, possibly forming an interacting cluster. We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thus possibly modulating expression globally and modifying the phenotype. For example, we observe that the chromatin conformation, histone marks and relative expression levels of the AUTS2 gene, mutations of which are associated with autism and intellectual disabilities, are modified in Williams-Beuren syndrome patients cell lines. Examination of 2 different histone modifications in genomic disorders patients' cell lines.

2013-11-16 | E-GEOD-33784 | biostudies-arrayexpress

Genome-wide maps of chromatin state in Williams-Beuren (WBS), Williams-Beuren Region duplication (WBRdupS), Smith-Magenis (DGS), DiGeorge (DGS) lymphoblastoid cell lines

2013-11-16 | GSE33784 | GEO

Post-transcriptional mechanisms modulate the consequences of adaptive copy number variation

Project description:Copy-number variants (CNVs) are large-scale amplifications or deletions of DNA that can drive rapid adaptive evolution and result in large-scale changes in gene expression. Whereas alterations in the copy number of one or more genes within a CNV can confer a selective advantage, other genes within a CNV can decrease fitness when their dosage is changed. Dosage compensation - in which the gene expression output from multiple gene copies is less than expected - is one means by which an organism can mitigate the fitness costs of deleterious gene amplification. Previous research has shown evidence for dosage compensation at both the transcriptional level and at the level of protein expression; however, the extent of compensation differs substantially between genes, strains, and studies. Here, we investigated sources of dosage compensation at multiple levels of gene expression regulation by defining the transcriptome, translatome and proteome of experimentally evolved yeast (Saccharomyces cerevisiae) strains containing adaptive CNVs.

2023-11-01 | PXD046587 | Pride

Copy Number Variation across 12 tribes of African cichlid species

Project description:This study examines genomic copy-number variation among African cichlids spanning multiple tribes and radiations. We map CNVs and hotspots throughout the Oreochromis niloticus reference genome, categorize gene ontology enrichment within CNV regions, and compare results with sequence-based cichlid phylogenies.

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Exploring Corneal Neovascularization: An Integrated Approach Using Transcriptomics and Proteomics in an Alkali Burn Mouse Model

Project description:Purpose Corneal neovascularization (CNV) impairs corneal transparency and visual acuity. The study aims to deepen our understanding of the molecules involved in CNV induced by alkali burns, facilitate a better grasp of CNV mechanisms, and uncover potential therapeutic targets. Methods Mice were selected for establishing CNV models via alkali burns. On days 3, 7, and 14 after the burns, corneal observations and histological investigations were conducted. An integrated analysis of RNA sequencing (RNA-seq)-based transcriptomics and label-free quantitative proteomics was performed in both normal and burned corneas. Bioinformatics approaches, encompassing GO and KEGG analysis, were applied to discern differentially expressed genes (DEGs) and crucial signaling pathways. Four potentially CNV-related genes were validated using qRT-PCR and Western blot. Results Significant CNV was observed on the seventh day. Forty-one genes were differentially expressed in neovascularized corneas, with 15 upregulated and 26 downregulated at both mRNA and protein levels. Bioinformatics analysis revealed that these DEGs participated in diverse biological processes, encompassing retinol and retinoic acid metabolism, neutrophil chemotaxis, and actin filament assembly, along with significant enrichment pathways like cytochrome P450, tyrosine, and phenylalanine metabolism. The upregulation of lymphocyte cytosolic protein 1 (LCP1) and cysteine and glycine-rich protein 2 (CSRP2) genes and the downregulation of transglutaminase 2 (TGM2) and transforming growth factor-beta-induced (TGFBI) genes were confirmed. Conclusions We analyzed gene expression differences in mouse corneas seven days after alkali burns, finding 41 genes with altered expression. The exact role of these genes in CNV is not fully understood, but exploring angiogenesis-related molecules offers potential for CNV treatment or prevention.

2024-01-26 | PXD047367 | Pride

Copy number variation and gene expression in the mouse

Project description:Copy number variation (CNV) of DNA segments has recently been identified as a major source of genetic diversity, but a more comprehensive understanding of the extent and phenotypic effect of this type of variation is only beginning to emerge. In this study we generated genome-wide expression data from 6 mouse tissues to investigate how CNVs influence gene expression. Keywords: genetic background, gene expression profiling

2009-02-28 | GSE10744 | GEO

Cerebral organoids model neocortical development disrupted by 16p11.2 CNV in autism

Project description:The 16p11.2 is the most common copy number variant (CNV) associated with Autism Spectrum Disorder (ASD). We used patient-derived cerebral organoids to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. To investigate molecular dysregulation in DEL and DUP organoids, we carried out RNA sequencing and Tandem Mass Tag mass spectrometry (TMT-MS) on 1-month and 3-month organoids from the same samples. In proteomic analyses, we quantified a total of 6126 proteins in 1-month and 5481 proteins in 3-month organoids, with 13 and 11 proteins from within 16p11.2 CNV, respectively. Transcriptomic and proteomic profiling of organoids identifies the key drivers of functional effect by 16p11.2 CNV during neocortical development.

2019-12-19 | MSV000084727 | MassIVE

Genomic copy number variation correlates with survival outcomes in glioblastoma patients

Project description:Allele-specific copy number analysis of tumors (ASCAT) assesses copy number variations (CNV) while accounting for aberrant cell fraction (ACF) and tumor ploidy. Here, we evaluate if ASCAT-assessed CNV are associated with survival outcomes in patients with WHO grade IV gliomas. Methods: We identified 56 patients with WHO grade IV gliomas. Tumor data analyzed by Affymetrix OncoScan FFPE Assay yielded the log ratio (R) and B-allele frequency (BAF). Input into ASCAT quantified CNV using the segmentation function to measure copy number inflection points throughout the genome. Actuarial overall survival (OS) and progression-free survival (PFS) assessed with Kaplan-Meier method and subgroups compared by the log-rank test. Results were validated on The Cancer Genome Atlas (TCGA) glioblastoma dataset. Results: Our cohort’s median age was 60.4 years (range: 26.1-86.3). Tumors were hyper-methylated at MGMT in 25 (44.6%) with IDH1 mutations in 6 (10.7%). Median follow-up time was 36.4 months, and median PFS and OS were 8 and 14.7 months, respectively. PFS was longer for higher log R and BAF segment counts with hazard ratios (HR) of 0.32 and 0.49 respectively (p<0.001 and p=0.022). Patients with higher log R segment counts had significantly longer 12-month OS (81% vs 46.3%, p=0.0088). In the TCGA validation cohort, higher BAF segment counts had longer 12-month OS with a trend for log R (62.3% vs. 51.9%, p=0.0129 and 63.6% vs. 55.2%, p=0.0696 respectively). Conclusions: Our analysis demonstrated a longer PFS and OS for patients with increased genomic CNV. This may provide a novel method for assessing glioblastoma outcomes.

2019-01-18 | GSE125255 | GEO

Transcriptome Profiling of patients with 16p11.2 rearrangements

Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies.

2015-05-10 | GSE57802 | GEO

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