Gene copy number polymorphism, a major source of genetic variation between humans
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE4981 | GEO | 2006/07/01
SECONDARY ACCESSION(S): PRJNA95485
REPOSITORIES: GEO
Similar Datasets
Project description:We have performed a genome wide analysis of gene copy number polymorphisms and report here for the first time that the human genome contains thousands of well-characterized genes at copy numbers different from one maternal and one paternal allele; and that, furthermore, the copy numbers of hundreds of well-characterized genes can vary between two normal healthy humans making this a major source of genetic variation. Groups of genes affected by CNPs include genes involved in signal transduction, oncogenesis, cell adhesion activity and several types of immune response. In contrast to SNPs, which preferentially affect non-coding regions of the genome, copy number polymorphisms of well-characterized and actively expressed genes are very likely to have important biological consequences. Experiment Overall Design: We utilized an expression microarray to analyze gene copy number variations (GCNVs).
2008-06-13 | E-GEOD-4981 | biostudies-arrayexpress
Project description:The role natural selection plays in governing the locations and early evolution of copy number mutations remains largely unexplored. Here we employ high-density full-genome tiling arrays to create a fine-scale genomic map of copy number polymorphisms (CNPs) in Drosophila melanogaster. We inferred a total of 2,658 independent CNPs, 56% of which overlap genes. These include CNPs likely to be under positive selection, most notably high frequency duplications encompassing toxin-response genes. The locations and frequencies of CNPs are strongly shaped by purifying selection with deletions under stronger purifying selection than duplications. Among duplications, those overlapping exons or introns and those falling on the X-chromosome seem to be subject to the strongest purifying selection. In order to characterize copy number polymorphisms (CNPs) in Drosophila malanogaster, we applied comparative genome hybridization (CGH) using tiling arrays covering the full euchromatic genome of Drosophila melanogaster. We inferred copy number changes with a Hidden Markov Model (HMM) that returned the posterior probabilities for copy number by comparing DNA hybridization intensities between natural isolates and the reference genome strain. Training data for copy number changes were obtained via hybridization with a line known to contain a ~200kb homozygous duplication and from a set of 52 validated homozygous deletions. The probabilities of mutation were parsed to make CNP calls. Key words: comparative genomic hybridization, CGH, copy number polymorphism, CNP, copy number variation, CNV, duplication, deletion
2008-06-06 | GSE11326 | GEO
Project description:Copy number variants (CNVs) can reach appreciable frequencies in the human population, and several of these copy number polymorphisms (CNPs) have been recently associated with human diseases including lupus, psoriasis, Crohn disease, and obesity. Despite new advances, significant biases remain in terms of CNP discovery and genotyping. Developing a novel method based on single channel intensity data and benchmarking against copy numbers determined from sequencing read-depth, we successfully obtained CNP genotypes for 1489 CNPs from 487 human DNA samples from diverse ethnic backgrounds. This customized microarray was enriched for segmental duplication-rich regions and novel insertions of sequences not represented in the reference genome assembly or on standard single nucleotide polymorphism (SNP) microarray platforms. We observe that CNPs in segmental duplications are more likely to be population differentiated than CNPs in unique regions (p = 0.015) and that bi-allelic CNPs show greater stratification when compared to frequency-matched SNPs (p = 0.0026). Although bi-allelic CNPs show a strong correlation of copy number with flanking SNP genotypes, the majority of multi-copy CNPs do not (40% with r >0.8). We selected a subset of CNPs for further characterization in 1873 additional samples from 62 populations (947 samples analyzed by microarray; 926 samples analyzed with PCR based assays); this revealed striking population-differentiated structural variants in genes of clinical significance such as the OCLN gene, a tight junction protein involved in hepatitis C viral entry. Our new microarray design allows these variants to be rapidly tested for disease association and our results suggest that CNPs (especially those that are not in linkage disequilibrium with SNPs) may have contributed disproportionately to human diversity and selection.
2011-02-01 | GSE26450 | GEO
Project description:Deletions and amplifications of the human genomic sequence (Copy Number Polymorphisms, or 'CNPs') are the cause for numerous diseases and a potential cause of phenotypic variation in the normal population. Comparative Genomic Hybridization (CGH) has been developed as a useful tool for detecting alterations in DNA copy number that involve blocks of DNA several kilobases or greater in size. We have developed High-Resolution CGH (HR-CGH) to detect accurately and with relatively little bias the presence and extent of chromosomal aberrations in human DNA. Maskless array synthesis was used to construct arrays containing 393,000 oligonucleotides with isothermal probes of 45-85 bp in length; arrays tiling the β-globin locus and chromosome 22q were prepared. Arrays with 9 bp tiling path were used to map a 622 bp heterozygous deletion in the β-globin locus. Arrays with an 85 bp tiling path were used to analyze DNA from patients with copy number changes in the pericentromeric region of chromosome 22. Heterozygous deletions and duplications as well as partial triploidies and partial tetraploidies of portions of chromosome 22q were mapped with high resolution in each patient, and the precise breakpoint of two deletions was confirmed by DNA sequencing. Additional peaks potentially corresponding to known and novel additional CNPs were also observed. Our results demonstrate that HR-CGH allows the detection of copy-number changes in any given region of the human genome comprehensively and at an unprecedented level of resolution. Keywords: high resolution comparative genome hybridization (HR-CGH)
2006-02-16 | GSE4240 | GEO
Project description:Thomas Hunt Morgan and colleagues identified variation in gene copy number in Drosophila in the 1920s and 1930s and linked such variation to phenotypic differences [Bridges, C. B. (1936) Science 83, 210]. Yet the extent of variation in the number of chromosomes, chromosomal regions, or gene copies, and the importance of this variation within species, remain poorly understood. Here, we focus on copy-number variation in Drosophila melanogaster. We characterize copy-number polymorphism (CNP) across genomic regions, and we contrast patterns to infer the evolutionary processes acting on this variation. Copy-number variation in D. melanogaster is non-randomly distributed, presumably due to a mutational bias produced by tandem repeats or other mechanisms. Comparisons of coding and noncoding CNPs, however, reveal a strong effect of purifying selection in the removal of structural variation from functionally constrained regions. Most patterns of CNP in D. melanogaster suggest that negative selection and mutational biases are the primary agents responsible for shaping structural variation. Keywords: comparative genomic hybridization
2008-03-20 | GSE9639 | GEO
Project description:Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately one percent of the general population. Most genetic studies so far focused on disease association with common genetic variation such as single nucleotide polymorphisms, but recently it has become apparent that large-scale genomic copy number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrixâ GeneChip 250K SNP arrays. Keywords: genomic hybridisation We hybridized genomic DNA of 54 patients with deficit schizophrenia to Affymetrix' GeneChip 250K SNP (Nsp) arrays, and identified genome-wide CNV using the Copy Number Analyzer for Affymetrix GeneChip (CNAG v2.0) software, which uses a Hidden Markov Model (HMM) algorithm to calculate copy numbers.
2010-05-18 | E-GEOD-12714 | biostudies-arrayexpress
Project description:Goal: To identify copy number variation in normal individuals using high density, non-polymorphic oligonucleotide probes Background DNA sequence diversity within the human genome may be more greatly affected by copy number variations (CNVs) than single nucleotide polymorphisms (SNPs). Although the importance of CNVs in genome wide association studies (GWAS) is becoming widely accepted, the optimal methods for identifying these variants are still under evaluation. We have previously reported a comprehensive view of CNVs in the HapMap DNA collection using high density 500K EA (Early Access) SNP genotyping arrays which revealed greater than 1,000 CNVs ranging in size from 1kb to over 3Mb. Although the arrays used most commonly for GWAS predominantly interrogate SNPs, CNV identification and detection does not necessarily require the use of DNA probes centered on polymorphic nucleotides and may even be hindered by the dependence on a successful SNP genotyping assay. Results In this study, we have designed and evaluated a high density array predicated on the use of non-polymorphic oligonucleotide probes for CNV detection. This approach effectively uncouples copy number detection from SNP genotyping and thus has the potential to significantly improve probe coverage for genome-wide CNV identification. This array, in conjunction with PCR-based, complexity-reduced DNA target, queries over 1.3M independent NspI restriction enzyme fragments in the 200bp to 1100bp size range, which is a several fold increase in marker density as compared to the 500K EA array. In addition, a novel algorithm was developed and validated to extract CNV regions and boundaries. Conclusions Using a well-characterized pair of DNA samples, close to 200 CNVs were identified, of which nearly 50% appear novel yet were independently validated using quantitative PCR. The results indicate that non-polymorphic probes provide a robust approach for CNV identification, and the increasing precision of CNV boundary delineation should allow a more complete analysis of their genomic organization. A set of five genomic DNA samples containing different numbers of X chromosomes (1X to 5X sample set, including NA15510 and NA10851) were hybridized to Nsp copy number (CN) arrays in triplicate to evaluate detection of copy number variation using high density, non-polymorphic oligonucleotide probes. 6 Hapmap samples were hybridized to Nsp CN arrays to evaluate Mendelian inheritance of CNVs.
2008-04-24 | E-GEOD-9053 | biostudies-arrayexpress
Project description:In this study, we present a clear genotype for the P. falciparum SB1-A6 acridone-resistant clonal parasite strain and, through a combination of targeted and whole-cell methods, establish that the mechanism of resistance to both cytochrome bc1 and DHODH inhibitors results from the contribution of multiple genetic polymorphisms. We find that P. falciparum SB1-A6 accumulates both a copy number variation and a specific mutation in PfDHODH, and both of these genetic polymorphisms contribute to the panresistant phenotype. This study uncovers a mechanism of cross-resistance between PfDHODH and mtETC inhibitors and serves as a cautionary note to future antimalarial combination therapy formulations containing such drugs.
2021-01-17 | ST001652 | MetabolomicsWorkbench
Project description:The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs) in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant eQTL. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to increased copies of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites. Keywords: Segregation patterns of gene expression levels.
2008-11-20 | GSE12515 | GEO
Project description:Identify copy number variation in the MCF7 genome Keywords: Copy number variation detection
2008-02-08 | GSE8508 | GEO