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PubMed2002

An orphan gyrB in the Mycobacterium smegmatis genome uncovered by comparative genomics.

DNA gyrase is an essential topoisomerase found in all bacteria. It is encoded by gyrB and gyrA genes. These genes are organized differently in different bacteria. Direct comparison of Mycobacterium tuberculosis and Mycobacterium smegmatis genomes reveals presence of an additional gyrB in M. smegmatis flanked by novel genes. Analysis of the amino acid sequence of GyrB from different organisms suggests that the orphan GyrB in M. smegmatis may have an important cellular role.

Amino Acid Sequence↗

PubMed2000

Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization.

Analysis of small numbers of chromosomes using interphase fluorescent in-situ hybridization (FISH) probes has revealed that 50% of human preimplantation embryos contain abnormal cells. Detection of high levels of mosaicism with so few probes has led some researchers to extrapolate that a full analysis of all 23 pairs of chromosomes would reveal that all human embryos contain a proportion of abnormal cells. However, existing cytogenetic protocols cannot achieve such an analysis due to technical limitations. We have developed a novel technique based on whole genome amplification and comparative genomic hybridization (CGH), which for the first time allows the copy number of every chromosome to be assessed in almost every cell of a cleavage-stage embryo. We have successfully analysed 64 cells (blastomeres) derived from 12 embryos and have detected unusual forms of aneuploidy, high levels of chromosomal mosaicism, non-mosaic aneuploidy and chromosome breakage. This is the first report of a comprehensive assessment of chromosome copy number in human embryos and indicates that, despite high levels of mosaicism, some embryos do have normal chromosome numbers in every cell. Such embryos may have a superior developmental potential, and their low frequency may explain correspondingly low success rates of natural and assisted conception in humans.

Blastomeres↗

PubMed2004

Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines.

Pancreatic carcinomas display highly complex chromosomal abnormalities, including many structural and numerical aberrations. There is ample evidence indicating that some of these abnormalities, such as recurrent amplifications and homozygous deletions, contribute to tumorigenesis by altering expression levels of critical oncogenes and tumor suppressor genes. To increase the understanding of gene copy number changes in pancreatic carcinomas and to identify key amplification/deletion targets, we applied genome-wide array-based comparative genomic hybridization to 31 pancreatic carcinoma cell lines. Two different microarrays were used, one containing 3,565 fluorescence in situ hybridization-verified bacterial artificial chromosome clones and one containing 25,468 cDNA clones representing 17,494 UniGene clusters. Overall, the analyses revealed a high genomic complexity, with several copy number changes detected in each case. Specifically, 60 amplicons at 32 different locations were identified, most frequently located within 8q (8 cases), 12p (7 cases), 7q (5 cases), 18q (5 cases), 19q (5 cases), 6p (4 cases), and 8p (4 cases). Amplifications of 8q and 12p were mainly clustered at 8q23-24 and 12p11-12, respectively, whereas amplifications on other chromosome arms were more dispersed. Furthermore, our analyses identified several novel homozygously deleted segments located to 9p24, 9p21, 9q32, 10p12, 10q22, 12q24, and 18q23. The individual complexity and aberration patterns varied substantially among cases, i.e., some cell lines were characterized mainly by high-level amplifications, whereas others showed primarily whole-arm imbalances and homozygous deletions. The described amplification and deletion targets are likely to contain genes important in pancreatic tumorigenesis.

Cell Line, Tumor↗

PubMed1998

Use of a Mycobacterium tuberculosis H37Rv bacterial artificial chromosome library for genome mapping, sequencing, and comparative genomics.

The bacterial artificial chromosome (BAC) cloning system is capable of stably propagating large, complex DNA inserts in Escherichia coli. As part of the Mycobacterium tuberculosis H37Rv genome sequencing project, a BAC library was constructed in the pBeloBAC11 vector and used for genome mapping, confirmation of sequence assembly, and sequencing. The library contains about 5,000 BAC clones, with inserts ranging in size from 25 to 104 kb, representing theoretically a 70-fold coverage of the M. tuberculosis genome (4.4 Mb). A total of 840 sequences from the T7 and SP6 termini of 420 BACs were determined and compared to those of a partial genomic database. These sequences showed excellent correlation between the estimated sizes and positions of the BAC clones and the sizes and positions of previously sequenced cosmids and the resulting contigs. Many BAC clones represent linking clones between sequenced cosmids, allowing full coverage of the H37Rv chromosome, and they are now being shotgun sequenced in the framework of the H37Rv sequencing project. Also, no chimeric, deleted, or rearranged BAC clones were detected, which was of major importance for the correct mapping and assembly of the H37Rv sequence. The minimal overlapping set contains 68 unique BAC clones and spans the whole H37Rv chromosome with the exception of a single gap of approximately 150 kb. As a postgenomic application, the canonical BAC set was used in a comparative study to reveal chromosomal polymorphisms between M. tuberculosis, M. bovis, and M. bovis BCG Pasteur, and a novel 12.7-kb segment present in M. tuberculosis but absent from M. bovis and M. bovis BCG was characterized. This region contains a set of genes whose products show low similarity to proteins involved in polysaccharide biosynthesis. The H37Rv BAC library therefore provides us with a powerful tool both for the generation and confirmation of sequence data as well as for comparative genomics and other postgenomic applications. It represents a major resource for present and future M. tuberculosis research projects.

Chromosome Mapping↗

PubMed2003

The kangaroo genome. Leaps and bounds in comparative genomics.

The kangaroo genome is a rich and unique resource for comparative genomics. Marsupial genetics and cytology have made significant contributions to the understanding of gene function and evolution, and increasing the availability of kangaroo DNA sequence information would provide these benefits on a genomic scale. Here we summarize the contributions from cytogenetic and genetic studies of marsupials, describe the genomic resources currently available and those being developed, and explore the benefits of a kangaroo genome project.

Animals↗

PubMed2004

Comparative genomics: digging for data.

Comparative genomics is a science in its infancy. It has been driven by a huge increase in freely available genome-sequence data, and the development of computer techniques to allow whole-genome sequence analyses. Other approaches, which use hybridization as a method for comparing the gene content of related organisms, are rising alongside these more bioinformatic methods. All these approaches have been pioneered using bacterial genomes because of their simplicity and the large number of complete genome sequences available. The aim of bacterial comparative genomics is to determine what genotypic differences are important for the expression of particular traits. The benefits of such studies will be a deeper understanding of these phenomena; the possibility of exposing novel drug targets, including those for antivirulence drugs; and the development of molecular techniques that reveal patients who are infected with virulent organisms so that health care resources can be allocated appropriately. With more and more genome sequences becoming available, the rise of comparative genomics continues apace.

Bacteria↗

PubMed2003

LineUp: statistical detection of chromosomal homology with application to plant comparative genomics.

The identification of homologous regions between chromosomes forms the basis for studies of genome organization, comparative genomics, and evolutionary genomics. Identification of these regions can be based on either synteny or colinearity, but there are few methods to test statistically for significant evidence of homology. In the present study, we improve a preexisting method that used colinearity as the basis for statistical tests. Improvements include computational efficiency and a relaxation of the colinearity assumption. Two algorithms perform the method: FullPermutation, which searches exhaustively for runs of markers, and FastRuns, which trades faster run times for exhaustive searches. The algorithms described here are available in the LineUp package (http://www.igb.uci.edu/ approximately baldig/lineup). We explore the performance of both algorithms on simulated data and also on genetic map data from maize (Zea mays ssp. mays). The method has reasonable power to detect a homologous region; for example, in >90% of simulations, both algorithms detect a homologous region of 10 markers buried in a random background, even when the homologous regions have diverged by numerous inversion events. The methods were applied to four maize molecular maps. All maps indicate that the maize genome contains extensive regions of genomic duplication and multiplication. Nonetheless, maps differ substantially in the location of homologous regions, probably reflecting the incomplete nature of genetic map data. The variation among maps has important implications for evolutionary inference from genetic map data.

Chromosome Mapping↗

PubMed2001

Identification of extensive genomic loss and gain by comparative genomic hybridisation in malignant astrocytoma in children and young adults.

Although astrocytomas are the most common central nervous system tumours in all age groups, there is substantial evidence that tumours arising in young patients (< 25 years of age) do not have the same genetic abnormalities that are characteristic of tumours in older patients. Furthermore, novel, consistent changes have not been identified in astrocytomas in children and young adults. We analysed 13 malignant astrocytomas from young patients using comparative genomic hybridisation. Regions of genomic imbalance were identified in 10 cases. The most common recurrent copy number aberrations were loss of 16p (54% of cases), 17p (38%), 19p (38%), and 22 (38%) and gain on 2q (38%), 12q (38%), 13 (38%), 4q (31%), 5q (31%), and 8q (31%). Seven regions of high copy number amplification were observed at 8q21-22 (three cases), 7q22-23 (two cases), and 1p21-22, 2q22, 12q13-pter, 12q15-21, and 13q11-14 (one case each). This study provides evidence of new characteristic chromosomal imbalances from which potential candidate genes involved in the development of malignant astrocytoma in children and young adults may be identified.

Adolescent↗

PubMed2004

Application of comparative genomics to the analysis of vertebrate regulatory elements.

Gene regulatory regions (also known as 'cis-regulatory modules') in vertebrates are poorly understood and annotated by comparison with protein-coding sequences. The short and degenerate sequences of regulatory elements and their distribution over large intergenic and intronic regions pose a major challenge to genomics scientists. Comparative genomics can be used to identify putative regulatory regions, and to analyse regulatory regions into their constituent transcription factor binding sites. There is need for high throughput assay systems to analyse the function of predicted vertebrate gene regulatory regions.

Animals↗

PubMed2004

MolliGen, a database dedicated to the comparative genomics of Mollicutes.

Bacteria belonging to the class Mollicutes were among the first ones to be selected for complete genome sequencing because of the minimal size of their genomes and their pathogenicity for humans and a broad range of animals and plants. At this time six genome sequences have been publicly released (Mycoplasma genitalium, Mycoplasma pneumoniae, Ureaplasma urealyticum-parvum, Mycoplasma pulmonis, Mycoplasma penetrans and Mycoplasma gallisepticum) and as the number of available mollicute genomes increases, comparative genomics analysis within this model group of organisms becomes more and more instructive. However, such an analysis is difficult to carry out without a suitable platform gathering not only the original annotations but also relevant information available in public databases or obtained by applying common bioinformatics methods. With the aim of solving these difficulties, we have developed a web-accessible database named MolliGen (http://cbi.labri.fr/outils/molligen/). After selecting a set of genomes the user can launch various types of search based on annotation, position on the chromosomes or sequence similarity. In addition, relationships of putative orthology have been precomputed to allow differential genome queries. The results are presented in table format with multiple links to public databases and to bioinformatic analyses such as multiple alignments or BLAST search. Specific tools were also developed for the graphical visualization of the results, including a multi- genome browser for displaying dynamic pictures with clickable objects and for viewing relationships of precomputed similarity. MolliGen is designed to integrate all the complete genomes of mollicutes as they become available.

Computational Biology↗

PubMed1998

Genomic changes in glioblastoma cell lines detected by comparative genomic hybridization.

Comparative genomic hybridization serves as a screening test for regions of copy number changes in tumor genomes. We have applied the technique to map DNA gains and losses in 5 cell lines derived from glioblastoma multiforme, the most common primary neoplasm of the central nervous system. The most frequent losses occurred on chromosomes 10 and 13. The most common gains were observed on chromosomes 5, 6, 7 and 20. Some novel sites of genomic alterations were also observed. Analysis of common areas of loss and gain in these cell lines provides a basis for future attempts to more finely map these genetic changes and for elucidation of genes involved in tumor progression.

Aged↗

PubMed2002

Plant genome evolution: lessons from comparative genomics at the DNA level.

Angiosperm genomes show tremendous variability in genome size and chromosome number. Nevertheless, comparative genetic mapping has revealed genome collinearity of closely related species. Sequence-based comparisons were used to assess the conservation of gene arrangements. Numerous small rearrangements, insertions/deletions, duplications, inversions and translocations have been detected. Importantly, comparative sequence analyses have unambiguously shown micro-collinearity of distantly related plant species. Duplications and subsequent gene loss have been identified as a particular important factor in the evolution of plant genomes.

Base Composition↗

PubMed1999

Loss of chromosome 13 is the most frequent genomic imbalance in malignant fibrous histiocytomas. A comparative genomic hybridization analysis of a series of 30 cases.

Regional chromosome localizations of DNA copy number imbalances were studied by comparative genomic hybridization in 30 malignant fibrous histiocytomas: 13 primary tumors (2 myxoid, 9 storiform pleomorphic, and 2 with more undifferentiated phenotype) and 17 local recurrences (2 myxoid, 11 storiform pleomorphic, and 4 with more undifferentiated phenotype). Abnormal comparative genomic hybridization (CGH) profiles were observed in 25 tumors (83%). The most frequent gains (ratio > 1.2) corresponded, by order of frequency, to entire Xp, and bands 1q21, 19q13.1, 19p13, 5p13-p14, 1p31, 17p, 18p, 20q, 1p35, 17q23, and 22q12. High levels of gains (ratio > 1.5) were recurrently detected for Xp (10 cases), and in bands 1q21-q22 (8 cases), 3q27 (4 cases), 5p13-p14 (3 cases), 13q32-q34 (3 cases), 15q22-q26 (3 cases), and 17p11-p12 (3 cases). Losses of 13q12-q14 or 13q21 were observed in a large proportion of tumors (17 cases), suggesting that a gene localized in this region could act as a tumor suppressor gene. Losses of 11q23, 2q32, 11p13, 10p, 1q4, 9p2, 16q12, 4q3, 10q25, 3p23, 2p24, and 12p were also recurrently observed. Taken together, these results provide an overview of chromosome imbalances present in MFH, which could be of use for diagnostic purposes. They point to various chromosome regions which may harbor genes important for malignant fibrous histiocytomas (MFH) oncogenesis and progression.

Chromosome Aberrations↗

PubMed1999

Inferring tree models for oncogenesis from comparative genome hybridization data.

Comparative genome hybridization (CGH) is a laboratory method to measure gains and losses of chromosomal regions in tumor cells. It is believed that DNA gains and losses in tumor cells do not occur entirely at random, but partly through some flow of causality. Models that relate tumor progression to the occurrence of DNA gains and losses could be very useful in hunting cancer genes and in cancer diagnosis. We lay some mathematical foundations for inferring a model of tumor progression from a CGH data set. We consider a class of tree models that are more general than a path model that has been developed for colorectal cancer. We derive a tree model inference algorithm based on the idea of a maximum-weight branching in a graph, and we show that under plausible assumptions our algorithm infers the correct tree. We have implemented our methods in software, and we illustrate with a CGH data set for renal cancer.

Chromosome Aberrations↗

PubMed2003

[Fundamental and applied aspects of comparative genomics of vertebrates].

The Human Genome Project stimulated the development of efficient strategies and relevant hardware for complete genome sequencing. The comparative genomic approach extends the possibilities of using the sequencing data to identify new genes or conserved regulatory regions by means of nucleotide sequence alignment of the particular regions of the mouse and human genomes, or to trace the evolutionary events resulting in the genome structure of modern mammals. The review focuses on the use of new molecular cytogenetic methods along with computer-aided analysis of the genomes in vertebrates. Several factors hindering data analysis are considered. The currently available information on gene evolution rate inferred from comparative genomic data is presented. The origin and evolution of the genomes of several species are discussed.

Animals↗

PubMed1999

Assessment of genomic imbalances in malignant fibrous histiocytomas by comparative genomic hybridization.

In order to investigate genomic imbalances, comparative genomic hybridization was applied to 20 malignant fibrous histiocytomas. Deletions were rare and found mainly in chromosomes 2q33-35, 4q32-qter, 8p, 9p21-pter, 12p and 19p, whereas, over-representations frequently affected chromosomes 3, 4q31, 5p, 6, 7, 14q22-ter, 18p, as well as, five distinct amplifications within the regions 12q12-15 and 15q24-qter. The total number of genetic imbalances per tumor was slightly increased in primary tumors when compared to relapses. No relationship was found between the patterns of gain and loss when compared to the histological subtype, tumor grading, the clinical outcome and the p53 mutation status.

Aneuploidy↗

PubMed1995

[Detection of DNA amplifications and deletions in oral squamous cell carcinoma cell lines by comparative genomic hybridization (CGH)].

Comparative genomic hybridization (CGH) has recently developed for surveying DNA sequence copy number in tumors. The purpose of this study is to find and map chromosomal regions with amplifications and deletions in oral cancers by CGH. The results were further compared to those obtained by Southern hybridization and fluorescence in situ hybridization to investigate the mechanism of CGH identifying the amplification of oncogenes. DNAs extracted from 17 oral squamous cell carcinoma cell lines were labeled with biotin and hybridized to a normal metaphase spread together with digoxigenin-labeled normal reference DNA. The relative intensities of tumor DNA (detected using FITC) and normal DNA (detected with rhodamine) were measured by fluorescence imaging analysis system. Recurrent loci for amplification were observed on 8q22-q26, 3q25-q27, 7p12, 11q13, 13q33, 14q, 15q and 20q13. Deletions were seen on 3p, 18q21, 5q21-q22, 7q31 and 8p. There was a strong concordance for amplification detected by the CGH and Southern hybridization methods. These results indicated that these loci may contain previously unknown genes. Thus, CGH provides a useful approach for rapid identification of putative oncogenes as well as finding specific genetic markers for oral cancers.

Carcinoma, Squamous Cell↗

PubMed1998

Analysis of hematologic diseases using conventional karyotyping, fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH).

Comparative genomic hybridization (CGH) has been proven to be an important tool in interphase cytogenetics of solid tumors. Although, because of methodological implications, balanced aberrations are not detected by CGH, the technique has uncovered a variety of new and interesting imbalanced karyotype changes. However, only a few studies deal with its application to hematologic disorders, although this is a main topic of cytogenetics. The aim of our study was, therefore, to evaluate the usefulness of CGH in the examination of hematologic neoplasms. For this purpose, bone marrow aspirates of 33 patients with different hematologic disorders were examined with CGH and the results compared with conventional cytogenetics (CC) and fluorescence in situ hybridization (FISH). CGH showed chromosome changes in 8 of 33 cases. CC found balanced aberrations in 4 of 33 and unbalanced changes in 9 of 33 samples. Differences between CGH and CC in unbalanced aberrations were seen in four cases. In these samples, either the number of aberrant cells found by CC was low and, therefore, difficult to detect by CGH, or complex aberrations in different cell clones as seen in CC were lumped together as one karyotype by CGH. In one sample, CC was not capable of giving any results at all, whereas CGH showed trisomy 8. CGH was also helpful in defining the bands involved in the structural aberrations, which was difficult by CC in some cases because of the low quality of metaphase spreads. All results obtained by CGH were confirmed by FISH, whereas CC and FISH were discordant in one case. Although CGH was not able to detect all aberrations, it gave important additional information for the correct localization of the aberrations found in CC, and it was most helpful in samples not processed successfully in CC. These advantages would open up a new field of application for CGH not only for research, but also for diagnostic purposes.

Adult↗