Evolutionary impact of copy number variation rates.
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ABSTRACT:
SUBMITTER: Rodrigo G
PROVIDER: S-EPMC5553737 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of ?30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of ? = 1.2 × 10(-2) CNVs per genome per transmission (? = 6.5 × 10(-3) for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 × 10(-3)) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.
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Project description:Genomic structural variations are an important source of genetic diversity. Copy number variations (CNVs), gains and losses of large regions of genomic sequence between individuals of a species, have been associated with a wide variety of phenotypic traits. However, in cattle, as well as many other species, relatively little is understood about CNV, including frequency of CNVs in the genome, sizes, and locations, chromosomal properties, and evolutionary processes acting to shape CNV. In this work, we focused on copy number variation in the bovine genome, with the aim to detect CNVs in Bos taurus coding sequence and explore potential evolutionary mechanisms shaping these CNV. We identified and characterized CNV regions by utilizing exome sequence from 175 influential sires used in the Germplasm Evaluation project, representing 10 breeds. We examined various evolutionary and functional aspects of these CNVs, including selective constraint on CNV-overlapped genes, centrality of CNV genes in protein-protein interaction networks, and tissue-specific expression of CNV genes. Patterns of CNV in the Bos taurus genome reveal that reduced functional constraint and mutational bias may play a prominent role in shaping this type of structural variation.
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Project description:Recent years have witnessed a flurry of important technological and methodological developments in the discovery and analysis of copy number variations (CNVs), which are increasingly enabling the systematic evaluation of their impact on a broad range of phenotypes from molecular-level (intermediate) traits to higher-order clinical phenotypes. Like single nucleotide variants in the human genome, CNVs have been linked to complex traits in humans, including disease and drug response. These recent developments underscore the importance of incorporating complex forms of genetic variation into disease mapping studies and promise to transform our understanding of genome function and the genetic basis of disease. Here we review some of the findings that have emerged from transcriptome studies of CNVs facilitated by the rapid advances in -omics technologies and corresponding methodologies.
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Project description:BACKGROUND:Chromosomal deletions and duplications, which result in halving or doubling of copy number in a block of genes, are an important source of variation between individuals. Phenotypic effects of copy number variation are commonly observed, but effects on sensitivity to volatile anesthetics have not been assessed in any organism. METHODS:The potency with which halothane depresses the righting reflex of fruit flies was measured in congenic Drosophila strains, each of which was heterozygous for a deletion of average size 400 kb. Over 200 strains were examined, thereby scanning approximately half of the fly genome. RESULTS:Although the vast majority of deletion heterozygotes were indistinguishable from the control, eight had significantly altered sensitivity to halothane. Genetic tests supported the hypothesis that the change in anesthetic sensitivity was the result of reduction in copy number and not adventitious mutations in the strains. Among the eight outliers, the difference in halothane potency ranged from a 25% increase to a 15% decrease. Changes of similar magnitude but distinctive patterns were found when these lines were tested with enflurane, isoflurane, and sevoflurane. CONCLUSIONS:Variation in gene copy number has a significant impact on anesthetic sensitivity in Drosophila melanogaster. The level of transcription of a few genes must thus be limiting for a normal response to volatiles. Coupling between gene copy and gene expression is universal, and the components of the fly's nervous system are highly conserved; therefore, this work provides a rationale for investigating the clinical impact of copy number variation.
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Project description:The aim of the present study was to detect copy number variations (CNVs) related to tumour progression and metastasis of urothelial carcinoma through whole-genome scanning. A total of 30 bladder cancer samples staged from pTa to pT4 were included in the study. DNA was extracted from freshly frozen tissue via standard phenol-chloroform extraction and CNV analysis was performed on two alternative platforms (CytoChip Oligo aCGH, 4x44K and Infinium OncoArray-500K BeadChip; Illumina, Inc.). Data were analysed with BlueFuse Multi software and Karyostudio, respectively. The results highlight the role of genomic imbalances in regions containing genes with metastatic and proliferative potential for tumour invasion. A high level of genomic instability in uroepithelial tumours was observed and a total of 524 aberrations, including 175 losses and 349 gains, were identified. The most prevalent genetic imbalances affected the following regions: 1p, 1q, 2q, 4p, 4q, 5p, 5q, 6p, 6q, 7q, 8q, 9p, 9q, 10p, 10q, 11q, 13q and 17q. High-grade tumours more frequently harboured genomic imbalances (n=227) than low-grade tumours (n=103). A total of 36 CNVs in high-grade bladder tumours were detected in chromosomes 1-5, 8-11, 14, 17, 19 and 20. Furthermore, five loss of heterozygosity variants containing 176 genes were observed in high-grade bladder cancer and may be used as potential targets for precision therapy. Revealing specific chromosomal regions related to the metastatic potential of uroepithelial tumours may lay a foundation for implementing molecular CNV profiling of bladder tumours as part of a routine progression risk estimation strategy, thus expanding the personalized therapeutic approach.
| S-EPMC8243332 | biostudies-literature
Project description:Next-generation sequencing (NGS) technologies offer new opportunities for precise and accurate identification of genomic aberrations, including copy number variations (CNVs). For high-throughput NGS data, using depth of coverage has become a major approach to identify CNVs, especially for whole exome sequencing (WES) data. Due to the high level of noise and biases of read-count data and complexity of the WES data, existing CNV detection tools identify many false CNV segments. Besides, NGS generates a huge amount of data, requiring to use effective and efficient methods. In this work, we propose a novel segmentation algorithm based on the total variation approach to detect CNVs more precisely and efficiently using WES data. The proposed method also filters out outlier read-counts and identifies significant change points to reduce false positives. We used real and simulated data to evaluate the performance of the proposed method and compare its performance with those of other commonly used CNV detection methods. Using simulated and real data, we show that the proposed method outperforms the existing CNV detection methods in terms of accuracy and false discovery rate and has a faster runtime compared to the circular binary segmentation method.
| S-EPMC7278034 | biostudies-literature
Project description:Extensive studies are currently being performed to associate disease susceptibility with one form of genetic variation, namely, single-nucleotide polymorphisms (SNPs). In recent years, another type of common genetic variation has been characterized, namely, structural variation, including copy number variants (CNVs). To determine the overall contribution of CNVs to complex phenotypes, we have performed association analyses of expression levels of 14,925 transcripts with SNPs and CNVs in individuals who are part of the International HapMap project. SNPs and CNVs captured 83.6% and 17.7% of the total detected genetic variation in gene expression, respectively, but the signals from the two types of variation had little overlap. Interrogation of the genome for both types of variants may be an effective way to elucidate the causes of complex phenotypes and disease in humans.
| S-EPMC2665772 | biostudies-literature
Project description:Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.
| S-EPMC3330748 | biostudies-literature
Project description:The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
| S-EPMC3021798 | biostudies-literature
Project description:Integration of various genome-scale measures of molecular alterations is of great interest to researchers aiming to better define disease processes or identify novel targets with clinical utility. Particularly important in cancer are measures of gene copy number DNA methylation. However, copy number variation may bias the measurement of DNA methylation. To investigate possible bias, we analyzed integrated data obtained from 19 head and neck squamous cell carcinoma (HNSCC) tumors and 23 mesothelioma tumors.Statistical analysis of observational data produced results consistent with those anticipated from theoretical mathematical properties. Average beta value reported by Illumina GoldenGate (a bead-array platform) was significantly smaller than a similar measure constructed from the ratio of average dye intensities. Among CpGs that had only small variations in measured methylation across tumors (filtering out clearly biological methylation signatures), there were no systematic copy number effects on methylation for three and more than four copies; however, one copy led to small systematic negative effects, and no copies led to substantial significant negative effects.Since mathematical considerations suggest little bias in methylation assayed using bead-arrays, the consistency of observational data with anticipated properties suggests little bias. However, further analysis of systematic copy number effects across CpGs suggest that though there may be little bias when there are copy number gains, small biases may result when one allele is lost, and substantial biases when both alleles are lost. These results suggest that further integration of these measures can be useful for characterizing the biological relationships between these somatic events.
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