Modulation of global expression by aneuploids and CNV of dosage sensitive regulatory genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE180089 | GEO | 2021/10/27
REPOSITORIES: GEO
Similar Datasets
Project description:Modulation of global expression by aneuploids and CNV of dosage sensitive regulatory genes
| PRJNA746500 | ENA
Project description:Genomic disorders are the clinical conditions manifested by submicroscopic genomic rearrangements including copy number variants (CNVs). The CNVs can be identified by array-based comparative genomic hybridization (aCGH), the most commonly used technology for molecular diagnostics of genomic disorders. However, clinical aCGH only informs CNVs in the probe-interrogated regions. Neither orientational information nor the resulting genomic rearrangement structure is provided, which is a key to uncovering mutational and pathogenic mechanisms underlying genomic disorders. Long-range polymerase chain reaction (PCR) is a traditional approach to obtain CNV breakpoint junction, but this method is inefficient when challenged by structural complexity such as often found at the PLP1 locus in association with Pelizaeus-Merzbacher disease (PMD). Here we introduced 'capture and single-molecule real-time sequencing' (cap-SMRT-seq) and newly developed 'asymmetry linker-mediated nested PCR walking' (ALN-walking) for CNV breakpoint sequencing in 49 subjects with PMD-associated CNVs. Remarkably, 29 (94%) of the 31 CNV breakpoint junctions unobtainable by conventional long-range PCR were resolved by cap-SMRT-seq and ALN-walking. Notably, unexpected CNV complexities, including inter-chromosomal rearrangements that cannot be resolved by aCGH, were revealed by efficient breakpoint sequencing. These sequence-based structures of PMD-associated CNVs further support the role of DNA replicative mechanisms in CNV mutagenesis, and facilitate genotype-phenotype correlation studies. Intriguingly, the lengths of gained segments by CNVs are strongly correlated with clinical severity in PMD, potentially reflecting the functional contribution of other dosage-sensitive genes besides PLP1. Our study provides new efficient experimental approaches (especially ALN-walking) for CNV breakpoint sequencing and highlights their importance in uncovering CNV mutagenesis and pathogenesis in genomic disorders.
| S-EPMC6075079 | biostudies-literature
Project description:Genomic imbalance caused by varying the dosage of individual chromosomes or chromosomal segments (aneuploidy) has more detrimental effects than altering the dosage of complete chromosome sets (ploidy). Previous analysis on RNA-sequencing data of varied dosage of various chromosomal regions in maize (Zea mays) revealed global modulation of gene expression both on the varied chromosome (cis) and the remainder of the genome (trans). Dysregulation of microRNA (miRNA) dosage has been reported to have profound deleterious effects in many species. miRNAs are preferentially retained as duplicates following whole-genome duplication in grass species and are postulated to be dosage-sensitive. However, little is known regarding the role of miRNAs under genomic imbalance. We examined the impact of increased and/or decreased dosage of 1 interstitial and 19 distal chromosomal regions in concert with a whole-genome ploidy series of haploid, diploid, triploid, and tetraploid via small RNA-sequencing of diploid and haploid maize mature leaf tissue to investigate the impact of aneuploidy and polyploidy on expression of miRNAs. In general, cis miRNAs in aneuploids present a predominant gene-dosage effect, whereas trans miRNAs trend toward the inverse level, although other types of responses including dosage compensation, increased effect, and decreased effect also occur. Significant correlations between expression levels of miRNAs and their targets were identified in aneuploids, indicating the regulatory role of miRNAs on gene expression triggered by genomic imbalance. The findings provide novel insights into understanding of gene balance from the aspect of the function of miRNAs.
2022-05-12 | GSE189317 | GEO
Project description:Copy number changes in protein-coding genes are detrimental if the consequent changes in protein concentrations disrupt essential cellular functions. The dosage sensitivity of transcription factor (TF) genes is particularly interesting because their products are essential in regulating the expression of genetic information. From four recently curated data sets of dosage-sensitive genes (genes with conserved copy numbers across mammals, ohnologs, and two data sets of haploinsufficient genes), we compiled a data set of the most reliable dosage-sensitive (MRDS) genes and a data set of the most reliable dosage-insensitive (MRDIS) genes. The MRDS genes were those present in all four data sets, while the MRDIS genes were those absent from any one of the four data sets and with the probability of being loss of function-intolerant (pLI) values < 0.5 in both of the haploinsufficient gene data sets. Enrichment analysis of TF genes among the MRDS and MRDIS gene data sets showed that TF genes are more likely to be dosage-sensitive than other genes in the human genome. The nuclear receptor family was the most enriched TF family among the dosage-sensitive genes. TF families with very few members were also deemed more likely to be dosage-sensitive than TF families with more members. In addition, we found a certain number of dosage-insensitive TFs. The most typical were the Krüppel-associated box domain-containing zinc-finger proteins (KZFPs). Gene ontology (GO) enrichment analysis showed that the MRDS TFs were enriched for many more terms than the MRDIS TFs; however, the proteins interacting with these two groups of TFs did not show such sharp differences. Furthermore, we found that the MRDIS KZFPs were not significantly enriched for any GO terms, whereas their interacting proteins were significantly enriched for thousands of GO terms. Further characterizations revealed significant differences between MRDS TFs and MRDIS TFs in the lengths and nucleotide compositions of DNA-binding sites as well as in expression level, protein size, and selective force.
| S-EPMC6904359 | biostudies-literature
Project description:In many diploid species, sex determination is linked to a pair of sex chromosomes that evolved from a pair of autosomes. In these organisms, the degeneration of the sex-limited Y or W chromosome causes a reduction in gene dose in the heterogametic sex for X- or Z-linked genes. Variations in gene dose are detrimental for large chromosomal regions when they span dosage-sensitive genes, and many organisms were thought to evolve complete mechanisms of dosage compensation to mitigate this. However, the recent realization that a wide variety of organisms lack complete mechanisms of sex chromosome dosage compensation has presented a perplexing question: How do organisms with incomplete dosage compensation avoid deleterious effects of gene dose differences between the sexes? Here we use expression data from the chicken (Gallus gallus) to show that ohnologs, duplicated genes known to be dosage-sensitive, are preferentially dosage-compensated on the chicken Z chromosome. Our results indicate that even in the absence of a complete and chromosome wide dosage compensation mechanism, dosage-sensitive genes are effectively dosage compensated on the Z chromosome.
| S-EPMC4860703 | biostudies-literature
Project description:How and why female somatic X-chromosome inactivation (XCI) evolved in mammals remains poorly understood. It has been proposed that XCI is a dosage-compensation mechanism that evolved to equalize expression levels of X-linked genes in females (2X) and males (1X), with a prior twofold increase in expression of X-linked genes in both sexes ("Ohno's hypothesis"). Whereas the parity of X chromosome expression between the sexes has been clearly demonstrated, tests for the doubling of expression levels globally along the X chromosome have returned contradictory results. However, changes in gene dosage during sex-chromosome evolution are not expected to impact on all genes equally, and should have greater consequences for dosage-sensitive genes. We show that, for genes encoding components of large protein complexes (? 7 members)--a class of genes that is expected to be dosage-sensitive--expression of X-linked genes is similar to that of autosomal genes within the complex. These data support Ohno's hypothesis that XCI acts as a dosage-compensation mechanism, and allow us to refine Ohno's model of XCI evolution. We also explore the contribution of dosage-sensitive genes to X aneuploidy phenotypes in humans, such as Turner (X0) and Klinefelter (XXY) syndromes. X aneuploidy in humans is common and is known to have mild effects because most of the supernumerary X genes are inactivated and not affected by aneuploidy. Only genes escaping XCI experience dosage changes in X-aneuploidy patients. We combined data on dosage sensitivity and XCI to compute a list of candidate genes for X-aneuploidy syndromes.
| S-EPMC3325647 | biostudies-literature
Project description:Current techniques for identifying mutations that convey a small increased cancer risk or those that modify cancer risk in carriers of highly penetrant mutations are limited by the statistical power of epidemiologic studies, which require screening of large populations and candidate genes. To identify dosage-sensitive genes that mediate genomic stability, we performed a genomewide screen in Saccharomyces cerevisiae for heterozygous mutations that increase chromosome instability in a checkpoint-deficient diploid strain. We used two genome stability assays sensitive enough to detect the impact of heterozygous mutations and identified 172 heterozygous gene disruptions that affected chromosome fragment (CF) loss, 45% of which also conferred modest but statistically significant instability of endogenous chromosomes. Analysis of heterozygous deletion of 65 of these genes demonstrated that the majority increased genomic instability in both checkpoint-deficient and wild-type backgrounds. Strains heterozygous for COMA kinetochore complex genes were particularly unstable. Over 50% of the genes identified in this screen have putative human homologs, including CHEK2, ERCC4, and TOPBP1, which are already associated with inherited cancer susceptibility. These findings encourage the incorporation of this orthologous gene list into cancer epidemiology studies and suggest further analysis of heterozygous phenotypes in yeast as models of human disease resulting from haplo-insufficiency.
| S-EPMC2278055 | biostudies-literature
Project description:Dosage effect is one of the common mechanisms of somatic copy number alteration in the development of colorectal cancer, yet the roles of dosage-sensitive genes (DSGs) in colorectal cancer (CRC) remain to be characterized more deeply. In this study, we developed a five-step pipeline to identify DSGs and analyzed their characterization in CRC. Results showed that our pipeline performed better than existing methods, and the result was significantly overlapped between solid tumor and cell line. We also found that the top five DSGs (PSMF1, RAF1, PTPRA, MKRN2, and ELP3) were associated with the progression of CRC. By analyzing the characterization, DSGs were enriched in driver genes and they drove sub-pathways of CRC. In addition, immune-related DSGs are associated with CRC progression. Our results also showed that the CRC samples affected by high microsatellites have fewer DSGs, but a higher overlap with DSGs in microsatellite low instability and microsatellite stable samples. In addition, we applied DSGs to identify potential drug targets, with the results showing that 22 amplified DSGs were more sensitive to four drugs. In conclusion, DSGs play an important role in CRC, and our pipeline is effective to identify them.
| S-EPMC7390836 | biostudies-literature
Project description:Sex chromosomes are subject to unique evolutionary forces that cause suppression of recombination, leading to sequence degeneration and the formation of heteromorphic chromosome pairs (i.e., XY or ZW). Although progress has been made in characterizing the outcomes of these evolutionary processes on vertebrate sex chromosomes, it is still unclear how recombination suppression and sequence divergence typically occur and how gene dosage imbalances are resolved in the heterogametic sex. The threespine stickleback fish (Gasterosteus aculeatus) is a powerful model system to explore vertebrate sex chromosome evolution, as it possesses an XY sex chromosome pair at relatively early stages of differentiation. Using a combination of whole-genome and transcriptome sequencing, we characterized sequence evolution and gene expression across the sex chromosomes. We uncovered two distinct evolutionary strata that correspond with known structural rearrangements on the Y chromosome. In the oldest stratum, only a handful of genes remain, and these genes are under strong purifying selection. By comparing sex-linked gene expression with expression of autosomal orthologs in an outgroup, we show that dosage compensation has not evolved in threespine sticklebacks through upregulation of the X chromosome in males. Instead, in the oldest stratum, the genes that still possess a Y chromosome allele are enriched for genes predicted to be dosage sensitive in mammals and yeast. Our results suggest that dosage imbalances may have been avoided at haploinsufficient genes by retaining function of the Y chromosome allele through strong purifying selection.
| S-EPMC4635650 | biostudies-literature
Project description:The massive genomic data from The Cancer Genome Atlas (TCGA), including proteomics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC), provides a unique opportunity to study cancer systematically. While most observations are made from a single type of genomics data, we apply big data analytics and systems biology approaches by simultaneously analyzing DNA amplification, mRNA and protein abundance. Using multiple genomic profiles, we have discovered widespread dosage compensation for the extensive aneuploidy observed in TCGA breast cancer samples. We do identify 11 genes that show strong correlation across all features (DNA/mRNA/protein) analogous to that of the well-known oncogene HER2 (ERBB2). These genes are generally less well-characterized regarding their role in cancer and we advocate their further study. We also discover that shRNA knockdown of these genes has an impact on cancer cell growth, suggesting a vulnerability that could be used for cancer therapy. Our study shows the advantages of systematic big data methodologies and also provides future research directions.
| S-EPMC6336338 | biostudies-literature