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A high resolution map of segmental DNA copy number variation in the mouse genome

ABSTRACT: Submicroscopic (< 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study twenty-one well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays (oligo-aCGH) to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21-2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits. Keywords: array comparative genomic hybridization (aCGH)

ORGANISM(S): Mus musculus

PROVIDER: GSE5805 | GEO | 2006/11/21

SECONDARY ACCESSION(S): PRJNA97179

REPOSITORIES: GEO

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A high resolution map of segmental DNA copy number variation in the mouse genome

Project description:Submicroscopic (< 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study twenty-one well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays (oligo-aCGH) to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21-2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits. 21 strains of mouse were assayed for copy number changes. Seven strains were assayed at least twice. DNA was extracted from tail for all strains. For two strains spleen DNA was also assayed on separate chips. C57BL/6 was used as the reference sample in all experiments.

2006-11-20 | E-GEOD-5805 | biostudies-arrayexpress

Genome-Wide Detection of CNVs and Their Association with Complex Traits in Holsteins

Project description:Copy number variation (CNV) is an important type of genetic variation contributing to phenotypic differences among mammals. Up to now, GWAS analysis using CNV called by array CGH is lacking in livestock like Holstein cattle. The objectives of this work are to identify CNVs using high-density aCGH data and explore functional CNVs which are associated with complex traits by GWAS method in Holstein cattle. In this study, we reported a systematic CNV association analysis of CNVs and 39 complex production traits in Holsteins. This research identified 1043 CNV regions (CNVRs) by array CGH data in 47 Holstein bulls. Using a genome-wide association analysis (GWAS) approach, we identified 79 significant CNVRs associated with at least one complex traits after false discovery rate (FDR) correction. Notably, 24 CNVRs were markedly related to daughter pregnancy rate (DPR). This study observed the pleiotropy phenomenon of 39 CNV loci which can simultaneously regulate at least 2 complex traits. In summary, the significant CNVs identified in this research could be utilized additional molecular markers for genetic improvement programs in Holsteins.

2019-02-16 | GSE122478 | GEO

CNV Identification: Prostate Cancer (PCa) vs Benign Prostatic Hyperplasia (BPH) Human DNA Samples

Project description:Copy number variations (CNVs) in the human genome have been linked to various carcinomas including prostate cancer (PCa). This study was conducted to identify CNVs in high grade PCa. We performed a pilot genome-wide CNV analysis in 36 subjects (18 high grade PCa and 18 benign prostatic hyperplasia) using array comparative genomic hybridization (aCGH) technique. Array results were validated using PCR-based copy number counting method. A total of 339 CNV regions were found to be unique to PCa subjects in this cohort (P < 0.05). Data segregation and filtering revealed six putative CNV loci associated with susceptibility to PCa. Of these, four were rare (1q21.3, 15q15, 3q27.2 and 7p12.1) and one was a novel copy number gain (12q23.1), harbouring genes such as the ARNT, THBS1, SLC5A8 and DDC which are crucial in the p53 and cancer pathways. Another CNV was a loss at 8p11.21 which contains the SFRP1 gene from the Wnt signalling pathway, known for its interaction with androgen receptors as reported for urological malignancy. Cross comparison analysis with genes already known to be associated with PCa revealed significant CNVs involved in crucial biological processes that elicit cancer pathogenesis via cytokine production, disease progression through endothelial cell proliferation and xenobiotic metabolism. In conclusion, these findings suggest that the CNV regions identified could provide an insight into the development of high grade PCa.

2018-12-18 | GSE79402 | GEO

Copy number variation of individual cattle genomes using next-generation sequencing.

Project description:Copy number variations (CNVs) affect a wide range of phenotypic traits; however, CNVs in or near segmental duplication regions are often intractable. Using a read depth approach based on next-generation sequencing, we examined genome-wide copy number differences among five taurine (three Angus, one Holstein and one Hereford) and one indicine (Nelore) cattle. Within mapped chromosomal sequence, we identified 1,265 CNV regions comprising ~55.6 Mbp sequence-476 of which (~38%) have not previously been reported. We validated this sequence-based CNV call set with aCGH, qPCR and FISH, achieving a validation rate of 82% and a false positive rate of 8%. We further estimated absolute copy numbers for genomic segments and annotated genes in each individual. Surveys of the top 25 most variable genes revealed that the Nelore individual had the lowest copy numbers in 13 cases (~52%, chi squared test; p value <0.05). In contrast, genes related to pathogen- and parasite-resistance, such as CATHL4 and ULBP17, were highly duplicated in the Nelore individual relative to the taurine cattle, while genes involved in lipid transport and metabolism, including APOL3 and FABP2, were highly duplicated in the beef breeds. These CNV regions also harbor genes like BPIFA2A (BSP30A) and WC1, suggesting that some CNVs may be associated with breed-specific differences in adaptation, health, and production traits. By providing the first individualized cattle CNV and segmental duplication maps and genome-wide gene copy number estimates, we enable future CNV studies into highly duplicated regions in the cattle genome. 5 NimbleGen Bos Taurus UMD3 custom 2.1M whole genome high density aCGH

2012-01-25 | E-GEOD-31018 | biostudies-arrayexpress

Copy number variation: the balance between gene dosage and expression in Drosophila melanogaster

Project description:Copy number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. While previous CNV studies focused on heterogeneous strains, here we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand, relaxed purifying selection might account for the higher number of protein-protein interactions in dosage insensitive CNVs than in dosage-sensitive CNVs. Dosage-sensitive CNVs that are up-regulated and down-regulated coincide with copy number increases and decreases. Our results help clarify the relation between CNV dosage and gene expression in the D. melanogaster genome.

2011-03-03 | GSE27632 | GEO

wuHMM: a robust algorithm to detect DNA copy number variation using long oligonucleotide microarray data

Project description:Copy number variants (CNVs) are currently defined as genomic sequences that are polymorphic in copy number and range in length from 1,000 to several million base pairs. Among current array-based CNV detection platforms, long-oligonucleotide arrays promise the highest resolution. However, the performance of currently available analytical tools suffers when applied to these data because of the lower signal:noise ratio inherent in oligonucleotide-based hybridization assays. We have developed wuHMM, an algorithm for mapping CNVs from array comparative genomic hybridization (aCGH) platforms comprised of 385,000 to more than 3 million probes. wuHMM is unique in that it can utilize sequence divergence information to reduce the false positive rate (FPR). We apply wuHMM to 385K-aCGH, 2.1M-aCGH, and 3.1M-aCGH experiments comparing the 129X1/SvJ and C57BL/6J inbred mouse genomes. We assess wuHMM’s performance on the 385K platform by comparison to the higher resolution platforms and we independently validate 10 CNVs. The method requires no training data and is robust with respect to changes in algorithm parameters. At a FPR of less than 10%, the algorithm can detect CNVs with five probes on the 385K platform and three on the 2.1M and 3.1M platforms, resulting in effective resolutions of 24 kb, 2-5 kb, and 1 kb, respectively. Keywords: CNV detection algorithm development and assessment

2008-03-12 | GSE10511 | GEO

Identification of global copy number variations among diverse pig breeds by a CGH array

Project description:A CNV map in pigs could facilitate the identification of chromosomal regions that segregate for important economic and disease phenotypes. The goal of this study was to identify CNV regions (CNVRs) in pigs based on a custom array comparative genome hybridization (aCGH). We carried out a custom-made array comparative genome hybridization (aCGH) experiment in order to identify copy number variations (CNVs) in the pig genome analysing animals of diverse pig breeds (White Duroc, Yangxin, Erhualian, Tongcheng, Large White, Pietrain, Landrace and Chinese new pig line DIV ) using a tiling oligonucleotide array with ~720,000 probes designed on the pig genome (Sus scrofa genome version 9.0).

2013-08-09 | GSE41488 | GEO

Analysis of CNVs in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies

Project description:Copy number variants (CNVs) are heritable gains and losses of genomic DNA in normal individuals. While copy number variation is widely studied in humans, our knowledge of CNVs in other mammalian species is more limited. We have designed a custom array-based comparative genomic hybridization (aCGH) platform with 385,000 oligonucleotide probes based on the reference genome sequence of the rhesus macaque (Macaca mulatta), the most widely studied non-human primate in biomedical research. We used this platform to identify 123 CNVs among 10 unrelated macaque individuals, with 24% of the CNVs observed in multiple individuals. We found that segmental duplications were significantly enriched at macaque CNV loci. We also observed significant overlap between rhesus macaque and human CNVs, suggesting that certain genomic regions are prone to recurrent CNV formation and instability, even across a total of ~50 million years of primate evolution (~25 million years in each lineage). Furthermore, for 8 of the CNVs that were observed in both humans and macaques, previous human studies have reported a relationship between copy number and gene expression or disease susceptibility. Therefore, the rhesus macaque offers an intriguing, non-human primate model organism for which hypotheses concerning the specific functions of phenotypically-relevant human CNVs can be tested. Keywords: array-based comparative genomic hybridization, oligonucleotide probes

2008-01-15 | GSE9220 | 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 of individual cattle genomes using next-generation sequencing.

2012-01-25 | GSE31018 | GEO

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