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CGH analysis of inbred mouses strains

ABSTRACT: The contribution to genetic diversity of genomic segmental copy number variations (CNVs) is less well understood than that of single-nucleotide polymorphisms (SNPs). While less frequent than SNPs, CNVs have greater potential to affect phenotype. In this study, we have performed the most comprehensive survey to date of CNVs in mice, analyzing the genomes of 42 Mouse Phenome Consortium priority strains. This microarray comparative genomic hybridization (CGH)-based analysis has identified 2094 putative CNVs, with an average of 10 Mb of DNA in 51 CNVs when individual mouse strains were compared to the reference strain C57BL/6J. This amount of variation results in gene content that can differ by hundreds of genes between strains. These genes include members of large families such as the major histocompatibility and pheromone receptor genes, but there are also many singleton genes including genes with expected phenotypic consequences from their deletion or amplification. Using a whole-genome association analysis, we demonstrate that complex multigenic phenotypes, such as food intake, can be associated with specific copy number changes. Keywords: comparative genomic hybridization

ORGANISM(S): Mus musculus

PROVIDER: GSE9186 | GEO | 2007/11/06

SECONDARY ACCESSION(S): PRJNA102755

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. Keywords: array comparative genomic hybridization (aCGH)

2006-11-21 | GSE5805 | GEO

Array comparative genomic hybridization of canine diffuse large B-cell lymphoma (cDLBCL)

Project description:The aim of this work was to identify copy number variations (CNVs) by high-resolution array comparative genomic hybridization (aCGH) on 50 dogs with newly diagnosed DLBCL.

2019-05-01 | GSE113258 | GEO

Genomic copy number variation induced by TAQing system in Saccharomyces cerevisiae.

Project description:We developed an artificial genome evolution system, which we termed ‘TAQing’, by introducing multiple genomic DNA double-strand breaks using a heat-activatable endonuclease in mitotic yeast. The heat-activated endonuclease, TaqI, induced random DSBs, which resulted in diverse types of chromosomal rearrangements including translocations. Array comparative genomic hybridization (aCGH) analysis was performed with cell-fused Saccharomyces cerevisiae strains induced genome evolution by TAQing system. Some of copy number variations (CNVs) induced by massive genome rearrangements were detected in the TAQed yeast strains.

2018-05-02 | GSE90025 | GEO

Recurrent DNA copy number variation in the laboratory mouse

Project description:We have conducted a genome-wide analysis of spontaneous copy number variation (CNV) in the laboratory mouse. We used high resolution microarrays to identify 38 CNVs between 14 colonies of the C57BL/6 strain spanning ~967 generations of inbreeding, and examined these loci in 12 additional strains. It is clear from our results that many CNVs arise through a highly non-random process: 18 of 38 were the product of recurrent mutation, and rates of change vary roughly four orders of magnitude across different loci. These recurrent CNVs are distributed throughout the genome, affect 43 genes, and fluctuate in copy number over mere hundreds of generations, observations that raise questions about their contribution to natural variation. Keywords: Representational oligonucleotide microarray analysis, comparative genomic hybridization, DNA copy number variation, structural variation, inbred mice, spontaneous mutation rate

2007-10-28 | GSE8980 | GEO

Recurrent DNA copy number variation in the laboratory mouse

Project description:We have conducted a genome-wide analysis of spontaneous copy number variation (CNV) in the laboratory mouse. We used high resolution microarrays to identify 38 CNVs between 14 colonies of the C57BL/6 strain spanning ~967 generations of inbreeding, and examined these loci in 12 additional strains. It is clear from our results that many CNVs arise through a highly non-random process: 18 of 38 were the product of recurrent mutation, and rates of change vary roughly four orders of magnitude across different loci. These recurrent CNVs are distributed throughout the genome, affect 43 genes, and fluctuate in copy number over mere hundreds of generations, observations that raise questions about their contribution to natural variation. Keywords: comparative genomic hybridization, DNA copy number variation, structural variation, inbred mice, spontaneous mutation rate

2007-10-28 | GSE8885 | GEO

Mouse Segmental Duplication and Copy-Number Variation

Project description:Detailed analyses of the clone-based genome assembly reveal that the recent duplication content of mouse (4.94%) is now comparable to that of human (5.5%), in contrast to previous estimates from the whole-genome shotgun sequence assembly. The architecture of mouse and human genomes differ dramatically; most mouse duplications are organized into discrete clusters of tandem duplications that are depleted for genes/transcripts and enriched for LINE1 and LTR retroposons. We assessed copy-number variation of the C57BL/6J duplicated regions within 15 mouse strains used for genetic association studies, sequencing, and the mouse phenome project. We determined that over 60% of these basepairs are polymorphic between the strains (on average 20 Mbp of copy-number variable DNA between different mouse strains). Our data suggest that different mouse strains show comparable, if not greater, copy-number polymorphism when compared to human; however, such variation is more locally restricted. We show large and complex patterns of inter-strain copy-number variation restricted to large gene families associated with spermatogenesis, pregnancy, viviparity, phermone signaling, and immune response. Keywords: comparative genomic hybridization

2008-05-10 | GSE11369 | 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

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

The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells

Project description:The extent to which differences in germ line DNA copy number contribute to natural phenotypic variation is unknown. We analyzed the copy number content of the mouse genome to a sub-10 kb resolution. We identified over 1,300 copy number variant regions (CNVRs), most of which are < 10 kb in length, are found in more than one strain, and, in total, span 3.2% (85 Mb) of the genome. To assess the potential functional impact of copy number variation, we mapped expression profiles of purified hematopoietic stem and progenitor cells, adipose tissue and hypothalamus to CNVRs in cis. Of the more than 600 significant associations between CNVRs and expression profiles, most map to CNVRs outside of the transcribed regions of genes. In hematopoietic stem/progenitor cells, up to 28% of strain-dependent expression variation is associated with copy number variation, supporting the role of germ line CNVs as major contributors to natural phenotypic variation in the laboratory mouse. To map the CNV content of the mouse genome, we selected 17 Tier 1-3 Mouse Phenome Project strains and three additional strains of biomedical interest, representing all major inbred lineages. We performed comparative genomic hybridization using a long-oligonucleotide array containing 2,149,887 probes evenly spaced across the reference genome with a median inter-probe spacing of 1,015 bases. Labeling, hybridization, washing and array imaging were performed as previously described (PMID:16075461). We performed segmentation using wuHMM, a Hidden Markov Model algorithm that utilizes sequence-level information and can detect CNVs less than 5 kb in length (fewer than five probes) at a low false positive rate (PMID:18334530). To estimate the overall impact of CNV on gene expression in vivo, we performed expression profiling of hematopoietic stem/progenitors cells using the Illumina Mouse Beadchip-6v1 platform. See manuscript for further details.

2009-03-08 | E-GEOD-10656 | biostudies-arrayexpress

CGH analysis of chemical induced pluripotent stem cells

Project description:Comparative genomic hybridization (CGH) analysis of CiPSCs (clone CiPS-57 and CiPS-58) and OSKM-iPSCs. C57BL/6 mouse embryonic fibroblasts (MEFs) genome DNA as a reference. No consistent copy number variations (CNVs) among CiPSCs and OSKM-iPSCs.

2013-07-22 | GSE48231 | GEO

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