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PubMed2001

The role of comparative genomic hybridisation in prenatal diagnosis.

The aims of this study were to assess the feasibility of using comparative genomic hybridisation instead of conventional cytogenetics in prenatal diagnosis and to determine the size of DNA loss that can be detected. Using comparative genomic hybridisation, six cases with standard aneuploidies were diagnosed correctly. This technique clearly identified a partial duplication of the long arm of chromosome 1 but was not capable of detecting the associated inversion. A small interstitial deletion on short arm of chromosome 10 also was detected precisely. Although the current comparative genomic hybridisation resolution is similar to the sensitivity of the highest resolution G banding, the latter is not a routine strategy in prenatal diagnosis. Comparative genomic hybridisation can allow full chromosome assessment equal to the highest resolution cytogenetic studies without the need for cell culture.

Cytogenetic Analysis↗

PubMed2006

How to become a uropathogen: comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains.

Uropathogenic Escherichia coli (UPEC) strain 536 (O6:K15:H31) is one of the model organisms of extraintestinal pathogenic E. coli (ExPEC). To analyze this strain's genetic basis of urovirulence, we sequenced the entire genome and compared the data with the genome sequence of UPEC strain CFT073 (O6:K2:H1) and to the available genomes of nonpathogenic E. coli strain MG1655 (K-12) and enterohemorrhagic E. coli. The genome of strain 536 is approximately 292 kb smaller than that of strain CFT073. Genomic differences between both UPEC are mainly restricted to large pathogenicity islands, parts of which are unique to strain 536 or CFT073. Genome comparison underlines that repeated insertions and deletions in certain parts of the genome contribute to genome evolution. Furthermore, 427 and 432 genes are only present in strain 536 or in both UPEC, respectively. The majority of the latter genes is encoded within smaller horizontally acquired DNA regions scattered all over the genome. Several of these genes are involved in increasing the pathogens' fitness and adaptability. Analysis of virulence-associated traits expressed in the two UPEC O6 strains, together with genome comparison, demonstrate the marked genetic and phenotypic variability among UPEC. The ability to accumulate and express a variety of virulence-associated genes distinguishes ExPEC from many commensals and forms the basis for the individual virulence potential of ExPEC. Accordingly, instead of a common virulence mechanism, different ways exist among ExPEC to cause disease.

Biological Evolution↗

PubMed2005

Comparative genomics on FGF16 orthologs.

We have previously reported comparative genomics analyses on FGF3, FGF4, FGF6, FGF7, FGF8, FGF10, FGF11, FGF17, FGF18, FGF19, FGF20, FGF22 and FGF23 genes. Here, we performed comparative genomics analyses on FGF1, FGF2, FGF5, FGF9, FGF12, FGF13, FGF14, FGF16 and FGF21 genes, and further characterized the FGF16 gene. Chimpanzee FGF16, chicken fgf16, and zebrafish fgf16 genes were identified within NW_121938.1, NW_060344.1, and CR855117.3 genome sequences, respectively. Chimpanzee FGF16 (207 aa), chicken fgf16 (207 aa), and zebrafish fgf16 (203 aa) showed 100%, 89.9%, and 79.2% total amino-acid identity with human FGF16. Because FGF16, FGF9, and FGF20 constitute FGF subfamily without N-terminal signal peptide, we next searched for uncharacterized FGF9 or FGF20 orthologs. Zebrafish fgf9 gene was identified within BX927112.11 genome sequence, and chicken fgf20 gene within NW_060349.1 genome sequence. Although N-terminal part was divergent, middle and C-terminal parts were well conserved among vertebrate FGF16, FGF9 and FGF20 orthologs. Phylogenetic analyses revealed that zebrafish fgf9 and fgf20 were more related to each other than to their chicken or mammalian orthologs. TCF/LEF binding site and TATA box were well conserved among the human FGF16, rat Fgf16, and mouse Fgf16 promoters. Because nuclear complex consisting of TCF/LEF (TCF1, TCF3, TCF4 or LEF1), beta-catenin, PYGO (PYGO1 or PYGO2) and Legless (BCL9 or BCL9L) binds to the TCF/LEF-binding site to up-regulate WNT/beta-catenin target genes, FGF16 gene was characterized as the evolutionarily conserved target of the WNT/beta-catenin signaling pathway, just like FGF18 and FGF20 genes. These facts indicate that FGF16, FGF18 and FGF20 are pharmacogenomics targets in the field of oncology and regenerative medicine.

Amino Acid Sequence↗

PubMed2006

From array to array: confirmation of genomic gains and losses discovered by array-based comparative genomic hybridization utilizing fluorescence in situ hybridization on tissue microarrays.

The combination of array-based comparative genomic hybridization (CGH) with fluorescence in situ hybridization utilizing custom-designed bacterial artificial chromosome (BAC) probes applied to tissue microarrays represents a powerful compendium of techniques-greatly enhancing the throughput of genomic analysis and subsequent target validation. Such approach can be automated at various levels and allows managing large volume of targets and samples in a few experiments. As such, this approach facilitates discovery, validation and implementation of findings in the process of identification of new diagnostic, prognostic and potentially therapeutic molecular markers.

DNA↗

PubMed2005

Genomic alterations in primary cutaneous melanomas detected by metaphase comparative genomic hybridization with laser capture or manual microdissection: 6p gains may predict poor outcome.

To clarify the correlation of genomic alterations with clinical and histological features, we performed metaphase comparative genomic hybridization analysis on 20 primary cutaneous melanomas, which were obtained by laser capture or manual microdissection, and 16 melanoma cell lines. There were no differences in the average number of aberrations between acral melanomas (AM) and non-AM, although gains of 5q and 11q13 were more frequent (P=0.05) and 10q loss was less frequent (P=0.01) in AM than in non-AM. Although tumor thickness is considered a measurable estimate of clinical expression, there were no differences in the average number of aberrations among 4 groups, classified by thickness of the tumor. While the majority of aberrations were equally distributed among the 4 groups, 6p gains were found only in the thickest tumors. Patients with 6p or 1q gains had a lower overall survival rate than those without them (P=0.0002 or P=0.013). While gains of 1q, 2q, 3p, 3q, 7q, 20p, and 20q were more frequent in the cell lines than in the primary tumors (P<0.01), losses of 6q, 9p, 10p, and 10q were equally found in both cell lines and primary tumors. The present study showed that chromosomal aberrations had already occurred in the thinner tumors, and that 6p and 1q gains may be a prognostic factor.

Adult↗

PubMedDate not supplied

Comparing the genetic changes detected in the primary and secondary tumor sites of ovarian cancer using comparative genomic hybridization.

Our objective was to compare the genetic abnormalities in the primary tumors of epithelial ovarian cancer and their associated secondary peritoneal implants using comparative genomic hybridization (CGH). CGH was performed on seven apparent stage III ovarian serous cancer cases. Dissected tissue samples from the primary tumor and from the metastatic peritoneal implant were obtained at initial surgical staging and analyzed in each case. We used CGH as this technique allows the entire genome of the tumor to be examined simultaneously for chromosomal imbalances without the need for tissue culture or targeting of specific loci. The chromosomal abnormalities detected in the distinct sites were then reviewed and compared. CGH studies were successful in all 14 samples from the seven patients. The analysis revealed chromosomal aberrations in six patients with certain repeated changes as amplification of 1q, 2p, 2q, 3q, 6q, 8q, and 12p and underrepresentation of 18q and X chromosomes. Comparing the genomes of the primary tumors with the metastatic samples showed four cases with a balanced metastatic CGH profile while the primary site was aberrant. Greater chromosomal complexity associated with the primary site was detected in two other patients. In one case, both primary and secondary sites had no detectable chromosomal imbalances. The cytogenetic patterns in six of the seven primary tumors showed complex karyotypic changes, unlike the inconsistent findings that were associated with the secondary sites. The chromosomes of the secondary sites expressed either normal genomes or fewer genetic aberrations. Such genomic heterogeneity between the primary and secondary sites may indicate that the secondary peritoneal implants are de novo carcinogenesis occurrences. The results may support the concept that at least part of advanced ovarian cancer is a multicentric disease in the early stages. Further genetic studies are needed to reassess this assumption.

Chromosome Aberrations↗

PubMed2006

Regression as a method to predict copy numbers in comparative genomic hybridization studies on bacteria.

Comparative genomic hybridizations (CGH) using microarrays are performed with bacteria in order to determine the level of genomic similarity between various strains. The microarrays applied in CGH experiments are constructed on the basis of the genome sequence of one strain, which is used as a control, or reference, in each experiment. A strain being compared with the known strain is called the unknown strain. The ratios of fluorescent intensities obtained from the spots on the microarrays can be used to determine which genes are divergent in the unknown strain, as well as to predict the copy number of actual genes in the unknown strain. In this paper, we focus on the prediction of gene copy number based on data from CGH experiments. We assumed a linear connection between the log2 of the copy number and the observed log2-ratios, then predictors based on the factor analysis model and the linear random model were proposed in an attempt to identify the copy numbers. These predictors were compared to using the ratio of the intensities directly. Simulations indicated that the proposed predictors improved the prediction of the copy number in most situations. The predictors were applied on CGH data obtained from experiments with Enterococcus faecalis strains in order to determine copy number of relevant genes in five different strains.

Algorithms↗

PubMed2004

Large-scale comparative genomics meta-analysis of Campylobacter jejuni isolates reveals low level of genome plasticity.

We have used comparative genomic hybridization (CGH) on a full-genome Campylobacter jejuni microarray to examine genome-wide gene conservation patterns among 51 strains isolated from food and clinical sources. These data have been integrated with data from three previous C. jejuni CGH studies to perform a meta-analysis that included 97 strains from the four separate data sets. Although many genes were found to be divergent across multiple strains (n = 350), many genes (n = 249) were uniquely variable in single strains. Thus, the strains in each data set comprise strains with a unique genetic diversity not found in the strains in the other data sets. Despite the large increase in the collective number of variable C. jejuni genes (n = 599) found in the meta-analysis data set, nearly half of these (n = 276) mapped to previously defined variable loci, and it therefore appears that large regions of the C. jejuni genome are genetically stable. A detailed analysis of the microarray data revealed that divergent genes could be differentiated on the basis of the amplitudes of their differential microarray signals. Of 599 variable genes, 122 could be classified as highly divergent on the basis of CGH data. Nearly all highly divergent genes (117 of 122) had divergent neighbors and showed high levels of intraspecies variability. The approach outlined here has enabled us to distinguish global trends of gene conservation in C. jejuni and has enabled us to define this group of genes as a robust set of variable markers that can become the cornerstone of a new generation of genotyping methods that use genome-wide C. jejuni gene variability data.

Animals↗

PubMed2002

Identification of four distinct regions of allelic imbalances on chromosome 1 by the combined comparative genomic hybridization and microsatellite analysis on hepatocellular carcinoma.

Frequent chromosome 1 abnormalities detected in human hepatocellular carcinoma have been implicated in early genetic events of liver carcinogenesis. Recurrent loss of 1p with a common deleted region 1p36-p34 has been reported from microsatellite analysis, whereas common gain of the whole chromosome q-arm was described from several comparative genomic hybridization studies. The relationships between copy number changes and allelic status however remains unclear. In this study, we have conducted a simultaneous comparative genomic hybridization and microsatellite analysis study on chromosome 1 in 31 hepatocellular carcinoma cases. Microsatellite analysis revealed frequent loss of heterozygosity on 1p at loci D1S468 (74%), D1S450 (67%), D1S2667 (65%), D1S2697 (75%), D1S199 (52%), and D1S234 (67%) corresponded to the distal 1p36 region and coincided with 12 cases (86%) that presented losses on 1p by comparative genomic hybridization analysis. Although comparative genomic hybridization indicated a common deleted region of 1p36-p35 in the current series, microsatellite analysis has refined the smallest overlapping region (SOR) to 1p36.13-p36.22. Gain of 1q as revealed by comparative genomic hybridization suggested low and high-level gains, and cases that displayed an amplicon below the heterochromatic region 1q21-q25. Common allelic imbalances of polymorphic markers D1S2635 (64%), D1S484 (67%), D1S2878 (65%), D1S196 (70%), D1S249 (64%) D1S2785 (75%), D1S2842 (73%) and D1S2836 (74%) that corresponded to the regions 1q23.1-q24.2, 1q32.1 and 1q43-q44 were detected. Three distinct regions of allelic imbalances were thus suggested on recurring 1q gain found in hepatocellular carcinoma. Furthermore, microsatellite analysis has enabled a mapping of common overrepresented regions and suggested SOR on 1q23.1-q23.3 (D1S2635-D1S2878), 1q25.1-q31.1 (D1S452-D1S238), and 1q43 (D1S2785-D1S2842). Our current study has refined chromosome 1 aberrations in hepatocellular carcinoma to four regions of allelic imbalances. The SORs delineated should provide basis for further molecular investigation in hepatocarcinogenesis on genes residing on these chromosomal regions.

Adult↗

PubMed2000

Predicting regulons and their cis-regulatory motifs by comparative genomics.

We have combined and compared three techniques for predicting functional interactions based on comparative genomics (methods based on conserved operons, protein fusions and correlated evolution) and optimized these methods to predict coregulated sets of genes in 24 complete genomes, including Saccharomyces cerevisiae, Caenorhabditis elegans and 22 prokaryotes. The method based on conserved operons was the most useful for this purpose. Upstream regions of the genes comprising these predicted regulons were then used to search for regulatory motifs in 22 prokaryotic genomes using the motif-discovery program AlignACE. Many significant upstream motifs, including five known Escherichia coli regulatory motifs, were identified in this manner. The presence of a significant regulatory motif was used to refine the members of the predicted regulons to generate a final set of predicted regulons that share significant regulatory elements.

Animals↗

PubMed2001

Comparative genomics of microbial drug efflux systems.

The complete genome sequences of 36 microorganisms have now been published and this wealth of genome data has enabled the development of comparative genomic and functional genomic approaches to investigate the biology of these organisms. Comparative genomic analyses of membrane transport systems have revealed that transporter substrate specificities correlate with an organism's lifestyle. The types and numbers of predicted drug efflux systems vary dramatically amongst sequenced organisms. Microarray and gene knockout studies to date have suggested that predicted drug efflux genes often appear to be a) non-essential and b) expressed at detectable levels under standard laboratory growth conditions.

Bacteria↗

PubMed2003

ACGT-a comparative genomics tool.

SUMMARY: ACGT (a comparative genomics tool) is a genomic DNA sequence comparison viewer and analyzer. It can read a pair of DNA sequences in GenBank, Embl or Fasta formats, with or without a comparison file, and provide users with many options to view and analyze the similarities between the input sequences. It is written in Java and can be run on Unix, Linux and Windows platforms. AVAILABILITY: The ACGT program is freely available with documentation and examples at website: http://db.systemsbiology.net/projects/local/mhc/acgt/

Computer Graphics↗

PubMed2006

Phytome: a platform for plant comparative genomics.

Phytome is an online comparative genomics resource that can be applied to functional plant genomics, molecular breeding and evolutionary studies. It contains predicted protein sequences, protein family assignments, multiple sequence alignments, phylogenies and functional annotations for proteins from a large, phylogenetically diverse set of plant taxa. Phytome serves as a glue between disparate plant gene databases both by identifying the evolutionary relationships among orthologous and paralogous protein sequences from different species and by enabling cross-references between different versions of the same gene curated independently by different database groups. The web interface enables sophisticated queries on lineage-specific patterns of gene/protein family proliferation and loss. This rich dataset is serving as a platform for the unification of sequence-anchored comparative maps across taxonomic families of plants. The Phytome web interface can be accessed at the following URL: http://www.phytome.org. Batch homology searches and bulk downloads are available upon free registration.

Databases, Genetic↗

PubMed1995

Detection of multiple gains and losses of genetic material in ten glioma cell lines by comparative genomic hybridization.

A protocol for comparative genomic hybridization by use of nucleotides directly labeled with fluorochromes was used to map regions of deletion and amplification in ten glioma cell lines. The protocol greatly reduced experimental artifacts. We detected several genetic aberrations, including whole chromosome loss and gain, partial loss and gain, possible isochromosome, and higher level DNA amplification. The most frequent losses (in order of frequency) occurred on chromosomes 10, 18, 13, 11, 9, 14, 4, 6, 1, and X. The most common gain occurred on chromosome 7. Several sites of previously known and unknown amplifications were observed.

Brain Neoplasms↗

PubMed2000

Comparative genomic hybridization: uses and limitations.

Comparative genomic hybridization (CGH) has contributed significantly to the current knowledge of genomic alterations in hematologic malignancies. Characteristic patterns of genomic imbalances not only have confirmed recent classification schemes in non-Hodgkin's lymphoma, but they provide a basis for the successful identification of genes with previously unrecognized pathogenic roles in the development of different lymphomas. Based on its technical limitations, there is little reason to apply CGH to chromosomes of metaphase cells in routine diagnostic settings. However, the new approach of CGH to DNA microarrays, a procedure termed matrix-CGH, overcomes most of the limitations and opens new approaches for diagnostics and identification of genetically defined leukemia and lymphoma subgroups. Current efforts to develop leukemia specific matrix-CGH DNA chips, which are designed to meet the clinical needs, are presented and discussed.

Hematologic Neoplasms↗

PubMed2002

Analysis of kidney tumors by comparative genomic hybridization and conventional cytogenetics.

Comparative genomic hybridization (CGH) and conventional cytogenetic karyotyping were used to screen for losses and gains of DNA sequences along chromosomes in ten renal tumors (RCC) of different histologic types (clear-cell RCC, papillary RCC, and one oncocytoma). Loss of 3p was the most common change in clear-cell RCC. All papillary tumors, either adenomas or carcinomas revealed gains of chromosomes 7 and 17q without limitation to size and grade. Homozygotic loss of the pseudoautosomal Xp or Yp region was detected in three RCC tumors. A dicentric (Y;14) was present as the sole chromosome abnormality in the oncocytoma. Both techniques showed concordant results in tumors with homogeneous karyotype. However, in tumors with several composite clones some discrepancies were observed, especially in cases of clear-cell RCC where chromosomal abnormalities present in a low number of metaphases could not be detected by CGH.

Carcinoma, Renal Cell↗

PubMed2002

Genome-wide survey for chromosomal imbalances in ganglioglioma using comparative genomic hybridization.

Ganglioglioma is a mixed neuronal and glial tumor first described by Perkin in 1926. Because of its rare occurrence in the central nervous system, the pathogenesis of this neoplasm is still largely unknown. Previous studies of ganglioglioma mainly focused on histologic features, immunohistochemical analysis, clinical treatment, and patient outcome. Very few cytogenetic and molecular genetic studies have been reported on this neoplasm. To better understand the mechanism underlying the development of ganglioglioma, we performed comparative genomic hybridization analysis to investigate chromosomal imbalances across the entire genome in five cases of gangliogliomas. Loss of genetic material on the short arm of chromosome 9 was a common genetic alteration found in three of five cases. Overrepresentation of partial or the whole chromosome 7 was another recurrent chromosomal imbalance, confirmed by fluorescence in situ hybridization. Immunohistochemical analysis was performed; all five cases revealed no reaction or low expression for epidermal growth factor receptor antibody. Our study highlights chromosomal regions for further fine mapping and investigation of candidate tumor suppressor genes involved in the pathogenesis of ganglioglioma.

Adolescent↗

PubMed1999

Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis.

Comparative genomic hybridization (CGH) and conventional cytogenetic karyotyping were used to screen for losses and gains of DNA sequences along all chromosome arms in 16 bladder tumors. Cytogenetic results were highly complex. The most frequently affected chromosomes were 5, 8, 9, 21, and Y as determined by karyotyping. There was close correlation between the CGH data and cytogenetic results in near-diploid tumors with simple karyotypes. However, some unexpected results were observed by CGH in tumors with several composite clones. Common amplification of copy numbers of DNA sequences by CGH were seen at 1q, 3q, 4q, 5p, 6p/q, 7p, 8q, 11q, 12q, 13q, 17q, 18q, and 20p/q (more than 20% of cases). High level amplification was noted at 1p32, 3p21, 3q24, 4q26, 8q21-qter, 11q14-22, 12q15-21, 12q21-24, 13q21-31, 17q22, and 18q22. Deletions were noted at 2q21-qter. 4q13-23, 5q, 8p12-22, 9p/q, and 11p13-15 (more than 20% of cases). Although most amplifications and deletions have been previously described in the literature, our study showed some intriguing and uncommon regions, different from those found in past studies. These were the amplification of 7p, 8q, 11q14-qter 12q24-24, 13q21-31, and 18q22, and deletion on 4q13-23, even though loss of heterozygosity was not detected at this locus. In spite of the very complex pattern of genetic changes in bladder tumors, most of these uncommon aberrations have to be implicated in bladder tumors, and further molecular genetic methods are necessary to establish whether the chromosomal regions contain candidate genes which contributed to the initiation and progression of bladder tumors.

Aged↗