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Genomic profiles in stage I primary non small cell lung cancer using comparative genomic hybridization analysis of cDNA microarrays.

To investigate the genomic aberrations that are involved in lung tumorigenesis and therefore may be developed as biomarkers for lung cancer diagnosis, we characterized the genomic copy number changes associated with individual genes in 14 tumors from patients with primary non small cell lung cancer (NSCLC). Six squamous cell carcinomas (SQCAs) and eight adenocarcinomas (ADCAs) were examined by high-resolution comparative genomic hybridization (CGH) analysis of cDNA microarray. The SQCAs and ADCAs shared common frequency distributions of recurrent genomic gains of 63 genes and losses of 72 genes. Cluster analysis using 57 genes defined the genomic differences between these two major histologic types of NSCLC. Genomic aberrations from a set of 18 genes showed distinct difference of primary ADCAs from their paired normal lung tissues. The genomic copy number of four genes was validated by fluorescence in situ hybridization of 32 primary NSCLC tumors, including those used for cDNA microarray CGH analysis; a strong correlation with cDNA microarray CGH data emerged. The identified genomic aberrations may be involved in the initiation and progression of lung tumorigenesis and, most importantly, may be developed as new biomarkers for the early detection and classification of lung cancer.

Adenocarcinoma↗

PubMed2005

Conventional and array-based comparative genomic hybridization analysis of nasopharyngeal carcinomas from the Mediterranean area.

Nasopharyngeal carcinoma (NPC) occurs with a high incidence in Southeast Asia and to a lesser extent in the Mediterranean area, especially in Tunisia, Algeria, and Morocco. Cellular gene alterations combined with latent Epstein-Barr virus infection are thought to be essential for NPC oncogenesis. To date, chromosome analysis with comparative genomic hybridization (CGH) has been reported exclusively for NPCs from Southeast Asia. Although NPCs from the Mediterranean area have several distinct clinical and epidemiological features, CGH investigations have been lacking. Chromosome analysis was therefore undertaken on a series of NPC xenografts and biopsies derived from patients of Mediterranean origin. Four xenografts were investigated with a combination of conventional CGH, array-based CGH, and comparative expressed sequence hybridization. In addition, 23 fresh NPC biopsies were analyzed with conventional CGH. Data obtained from xenografts and fresh biopsies were consistent, except that amplification of genes at 18p was observed only in xenografts derived from metastatic tissues. Frequent gains associated with gene overexpression were detected at 1q25 approximately qter (64%) and 12p13 (50%). Losses were noticed mainly at 11q14 approximately q23 (50%), 13q12 approximately q31 (50%), 14q24 approximately q31 (43%), and 3p13 approximately p23 (43%). Comparison with previous reports suggests that Mediterranean NPCs have higher frequencies of gains at 1q and losses at 13q than their Asian counterparts.

Adolescent↗

PubMed1999

Meta-analysis of genome searches.

We have developed a method for meta-analysis of genome scans which allows systematic integration of data from published results. The Genome Search Meta-analysis method (GSMA) uses a non-parametric ranking method to identify genetic regions that show consistently increased sharing statistics or lod scores. The GSMA ranks genetic regions according to the lod score or p-value achieved in each scan. The summed rank across studies is compared to its probability distribution assuming ranks are randomly assigned. The GSMA can confirm evidence for regions highlighted in the original genome scans, and identify novel regions, which did not reach significance in any scan. In this paper, the GSMA was applied to four genome screens in multiple sclerosis and across 11 screens from autoimmune disorders. The GSMA is appropriate for studies with different family ascertainment, markers, and statistical analysis methods. The method increases the power to detect individual linkages in a clinically homogeneous dataset and has the potential to detect susceptibility loci in clinically distinct diseases which show involvement of common pathogenetic pathways.

Autoimmune Diseases↗

PubMed2007

Paired-end genomic signature tags: a method for the functional analysis of genomes and epigenomes.

Because paired-end genomic signature tags are sequenced-based, they have the potential to become an alternate tool to tiled microarray hybridization as a method for genome-wide localization of transcription factors and other sequence-specific DNA binding proteins. As outlined here the method also can be used for global analysis of DNA methylation. One advantage of this approach is the ability to easily switch between different genome types without having to fabricate a new microarray for each and every DNA type. However, the method does have some disadvantages. Among the most rate-limiting steps of our PE-GST protocol are the need to concatemerize the diTAGs, size fractionate them and then clone them prior to sequencing. This is usually followed by additional steps to amplify and size select for long (> or = 500) concatemer inserts prior to sequencing. These time-consuming steps are important for standard DNA sequencing as they increase efficiency approximately 20-30-fold since each amplified concatemer can now provide information on multiple tags; the limitation on data acqui- sition is read length during sequencing. However, the development of new sequencing methods such as Life Sciences' 454 new nanotechnology-based sequencing instrument (41) could increase tag sequencing efficiency by several orders of magnitude (> or = 100,000 diTAG reads/run), which is sufficient to provide in-depth global analysis of all ChIP PE-GSTs in a single run. This is because the lengths of our paired-end diTAGs (approximately 60 bp) fall well within the region of high accuracy for read lengths on this instrument. In principle, sequence analysis of diTAGs could begin as soon as they are generated, thereby completely bypassing the need for the concatemerization, sizing, downstream cloning steps and sequencing template purification. In addition, our protocol places any one of several unique four-base long nucleotide sequences, such as GATC, between each and every diTAG pair, which could be used to help the instrument's software keep base register and also provide a well-located peak height indicator in the middle of every sequence run. This additional feature could permit multiplexing of the data by simultaneous sequencing of several pooled libraries if each used a different linker sequence during diTAG formation (Figure 4).

Base Sequence↗

PubMed2004

A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer.

In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S-transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3'-untranslated region (3'UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 (P=0.037), 3.25 for GSTP1-105 (P=0.072), 2.05 for ERCC1-118 (P=0.037), and 1.65 for TS-3'UTR (P=0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing > or =2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P<0.001). Polymorphisms in the TS-3'UTR and GSTP1-105 gene were also associated with time to progression. After adjustment for performance status, patients with an unfavourable TS-3'UTR genotype had a relative risk of disease progression of 1.76 (P=0.020) and those with the unfavourable GSTP1-105 genotype showed a relative risk of progression of 2.00 (P=0.018). The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3'UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy. These findings require independent prospective confirmation.

Acyltransferases↗

PubMed2026

Establishment of a multi-targeted magnetic combined enrichment system for circulating tumor cells in gastric cancer and analysis of their genomic profiles.

Background: This study aims to establish an efficient Circulating tumor cells (CTCs) multi-targeted magnetic combined sorting system for Gastric cancer (GC), while comparing it with tissue and circulating tumor DNA (ctDNA) samples to evaluate its feasibility and consistency for genomic profiling analysis. Method: Establish an efficient CTCs sorting system for GC targeting epithelial cell adhesion molecule, cell surface vimentin, and protein tyrosine kinase 7, and evaluate its physicochemical properties and cell capture efficiency. Assess the feasibility of tumor cell detection through animal experiments. Sixty-eight GC patients underwent CTCs detection. Clinical information was analyzed to evaluate the clinical utility of CTCs in the auxiliary diagnosis of GC. Next-generation sequencing was performed on GC tissue, CTCs, and ctDNA samples to assess the consistency of genetic mutations across different sample types. Results: The constructed CTCs sorting system exhibits excellent physicochemical properties, achieving a capture rate of 94.68%. Animal studies confirm a positive correlation between tumor cells count and tumor volume. The number of CTCs in the blood of GC patients is significantly correlated with tumor size, stage, and metastasis. The CTCs count in GC patients is significantly higher than in healthy individuals and high-risk groups for cancer, with diagnostic sensitivity and specificity of 97.29% and 97.73%, respectively. The mutation detection rate in CTCs samples was significantly higher than that in tissue and ctDNA samples. The concordance rate between CTCs and tissue mutations was 24.32%, while the concordance rate between CTCs and ctDNA mutations was 19.05%. Conclusion: This study successfully established a multi-target combined CTCs multi-targeted magnetic combined sorting system for GC. CTCs detection based on this system can be used for the auxiliary diagnosis of GC patients. Furthermore, compared to GC tissue and ctDNA samples, CTCs detection enables more comprehensive genomic profiling analysis and serves as an important supplement to GC genomic analysis.

Humans↗

PubMed2004

Computational assignment of the EC numbers for genomic-scale analysis of enzymatic reactions.

The EC (Enzyme Commission) numbers represent a hierarchical classification of enzymatic reactions, but they are also commonly utilized as identifiers of enzymes or enzyme genes in the analysis of complete genomes. This duality of the EC numbers makes it possible to link the genomic repertoire of enzyme genes to the chemical repertoire of metabolic pathways, the process called metabolic reconstruction. Unfortunately, there are numerous reactions known to be present in various pathways, but they will never get EC numbers because the EC number assignment requires published articles on full characterization of enzymes. Here we report a computerized method to automatically assign the EC numbers up to the sub-subclasses, i.e., without the fourth serial number for substrate specificity, given pairs of substrates and products. The method is based on a new classification scheme of enzymatic reactions, named the RC (reaction classification) number. Each reaction in the current dataset of the EC numbers is first decomposed into reactant pairs. Each pair is then structurally aligned to identify the reaction center, the matched region, and the difference region. The RC number represents the conversion patterns of atom types in these three regions. We examined the correspondence between computationally assigned RC numbers and manually assigned EC numbers by the jackknife cross-validation test and found that the EC sub-subclasses could be assigned with the accuracy of about 90%. Furthermore, we examined the correlation with genomic information as represented by the KEGG ortholog clusters (OC) and confirmed that the RC numbers are correlated not only with elementary reaction mechanisms but also with protein families.

Computers↗

PubMed2025

A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders.

Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

Humans↗

PubMed2002

Eating behavior in the Old Order Amish: heritability analysis and a genome-wide linkage analysis.

BACKGROUND: Eating behavior and thus dietary intake affect the development of obesity-related diseases such as diabetes, hypertension, and hyperlipidemia. OBJECTIVE: We investigated the genetic underpinnings of eating behavior. DESIGN: We administered a standardized eating behavior inventory to 624 adults from 28 families participating in the Amish Family Diabetes Study. Three quantifiable components of eating behavior were measured: restraint, disinhibition, and hunger. Associations between eating behavior scores and physical characteristics were evaluated. Heritability analysis and a genome-wide multipoint linkage analysis were performed. RESULTS: Eating behavior scores were associated with obesity and obesity-related phenotypes. Heritability estimates were 0.28 +/- 0.09 for restraint, 0.40 +/- 0.10 for disinhibition, and 0.23 +/- 0.09 for hunger (P < 0.001). The linkage analysis showed 4 regions of suggestive linkage. We observed suggestive evidence for linkage of restraint scores to 2 chromosomal regions, near markers D3S1304 [LOD (log of odds) = 2.5, P = 0.0003] and D6S276 (LOD = 2.3, P = 0.0006). We previously reported that D3S1304 is linked to a locus influencing percentage body fat in this same population (LOD = 1.6), suggesting that this behavioral phenotype may be secondary to obesity. The maximum LOD scores for disinhibition were 1.6 (P = 0.003) near marker D7S657 and 1.4 (P = 0.005) near marker D16S752. The maximum LOD score for hunger was 1.4 (P = 0.005) near marker D3S1278. CONCLUSION: Significant familial effects on eating behavior and suggestive genetic linkage were found in Amish adults.

Chromosome Mapping↗

PubMed2000

WIT: integrated system for high-throughput genome sequence analysis and metabolic reconstruction.

The WIT (What Is There) (http://wit.mcs.anl.gov/WIT2/) system has been designed to support comparative analysis of sequenced genomes and to generate metabolic reconstructions based on chromosomal sequences and metabolic modules from the EMP/MPW family of databases. This system contains data derived from about 40 completed or nearly completed genomes. Sequence homologies, various ORF-clustering algorithms, relative gene positions on the chromosome and placement of gene products in metabolic pathways (metabolic reconstruction) can be used for the assignment of gene functions and for development of overviews of genomes within WIT. The integration of a large number of phylogenetically diverse genomes in WIT facilitates the understanding of the physiology of different organisms.

Databases, Factual↗

PubMed1987

Characterisation of rotavirus isolates from sub-clinically infected calves by genome profile analysis.

Rotaviruses isolated from 43 sub-clinically infected calves from a single farm were analysed by genome profile analysis. The isolates showed genomic variation and eight different profiles were observed, including one which was atypical for Group A rotaviruses. The 3' terminal labelling method for the analysis of genome profiles used in this study required only 1 ng of viral RNA, an increase of 1000-fold in sensitivity over ethidium bromide staining for detecting all rotavirus genome segments. However, dual infections involving two rotaviruses with distinct profiles could not be detected if the concentrations of the viruses differed by greater than 10-fold.

Animals↗

PubMed2004

Genomic constitution and variation in five partial amphiploids of wheat--Thinopyrum intermedium as revealed by GISH, multicolor GISH and seed storage protein analysis.

Genomic in situ hybridization (GISH) and multicolor GISH (mcGISH) methodology were used to establish the cytogenetic constitution of five partial amphiploid lines obtained from wheat x Thinopyrum intermedium hybridizations. Line Zhong 1, 2 n=52, contained 14 chromosomes from each of the wheat genomes plus ten Th. intermedium chromosomes, with one pair of A-genome chromosomes having a Th. intermedium chromosomal segment translocated to the short arm. Line Zhong 2, 2 n=54, had intact ABD wheat genome chromosomes plus 12 Th. intermedium chromosomes. The multicolor GISH results, using different fluorochrome labeled Th. intermedium and the various diploid wheat genomic DNAs as probes, indicated that both Zhong 1 and Zhong 2 contained one pair of Th. intermedium chromosomes with a significant homology to the wheat D genome. High-molecular-weight (HMW) glutenin and gliadin analysis revealed that Zhong 1 and Zhong 2 had identical banding patterns that contained all of the wheat bands and a specific HMW band from Th. intermedium. Zhong 1 and Zhong 2 had good HMW subunits for wheat breeding. Zhong 3 and Zhong 5, both 2 n=56, possessed no gross chromosomal aberrations or translocations that were detectable at the GISH level. Zhong 4 also had a chromosome number of 2 n=56 and contained the complete wheat ABD-genome chromosomes plus 14 Th. intermedium chromosomes, with one pair of Th. intermedium chromosomes being markedly smaller. Multicolor GISH results indicated that Zhong 4 also contained two pairs of reciprocally translocated chromosomes involving the A and D genomes. Zhong 3, Zhong 4 and Zhong 5 contained a specific gliadin band from Th. intermedium. Based on the above data, it was concluded that inter-genomic transfer of chromosomal segments and/or sequence introgression had occurred in these newly synthesized partial amphiploids despite their diploid-like meiotic behavior and disomic inheritance.

Breeding↗

PubMed1998

Assignment of folds for proteins of unknown function in three microbial genomes.

Analysis of DNA sequences of several microbial genomes has revealed that a large fraction of predicted coding regions has no known protein function. Information about the three-dimensional folds of these proteins may provide insight into their possible functions. To predict the folds for protein sequences with little or no homology to proteins of known function, we used computational neural networks trained on the database of proteins with known three-dimensional structures. Global descriptions of protein sequences based on physical and structural properties of the constituent amino acids were used as inputs for neural networks. Of the 131, 498, and 868 protein sequences of unknown function from Mycoplasma genitalium, Haemophilus influenzae, and Methanococcus jannaschii (Fleischmann et al. 1995), we have made high-confidence fold assignments for 4, 10, and 19 sequences, respectively.

Amino Acid Sequence↗

PubMed1993

Presence of one linear and one circular chromosome in the Agrobacterium tumefaciens C58 genome.

Analysis of the entire Agrobacterium tumefaciens C58 genome by pulsed-field gel electrophoresis (PFGE) reveals four replicons: two large molecules of 3,000 and 2,100 kb, the 450-kb cryptic plasmid, and the 200-kb Ti plasmid. Digestion by PacI or SwaI generated 12 or 14 fragments, respectively. The two megabase-sized replicons, used as probes, hybridize with different restriction fragments, showing that these replicons are two independent genetic entities. A 16S rRNA probe and genes encoding functions essential to the metabolism of the organism were found to hybridize with both replicons, suggesting their chromosomal nature. In PFGE, megabase-sized circular DNA does not enter the gel. The 2.1-Mb chromosome always generated an intense band, while the 3-Mb band was barely visible. After linearization of the DNA by X-irradiation, the intensity of the 3-Mb band increased while that of the 2.1-Mb remained constant. This suggests that the 3-Mb chromosome is circular and that the 2.1-Mb chromosome is linear. To confirm this hypothesis, genomic DNA, trapped in an agarose plug, was first submitted to PFGE to remove any linear DNA present. The plug was then recovered, and the remaining DNA was digested with either PacI or SwaI and then separated by PFGE. The fragments corresponding to the small chromosome were found to be absent, while those corresponding to the circular replicon remained, further proof of the linear nature of the 2.1-Mb chromosome.

Agrobacterium tumefaciens↗

PubMed2004

Comparative analysis of four Campylobacterales.

Comparative genome analysis can be used to identify species-specific genes and gene clusters, and analysis of these genes can give an insight into the mechanisms involved in a specific bacteria-host interaction. Comparative analysis can also provide important information on the genome dynamics and degree of recombination in a particular species. This article describes the comparative genome analysis of representatives of four different Campylobacterales species - two pathogens of humans, Helicobacter pylori and Campylobacter jejuni, as well as Helicobacter hepaticus, which is associated with liver cancer in rodents, and the non-pathogenic commensal species, Wolinella succinogenes.

Campylobacter jejuni↗

PubMed2004

Origin and diversity of the SOX transcription factor gene family: genome-wide analysis in Fugu rubripes.

The SOX family of transcription factors are found throughout the animal kingdom and are important in a variety of developmental contexts. Genome analysis has identified 20 Sox genes in human and mouse, which can be subdivided into 8 groups, based on sequence comparison and intron-exon structure. Most of the SOX groups identified in mammals are represented by a single SOX sequence in invertebrate model organisms, suggesting a duplication and divergence mechanism has operated during vertebrate evolution. We have now analysed the Sox gene complement in the pufferfish, Fugu rubripes, in order to shed further light on the diversity and origins of the Sox gene family. Major differences were found between the Sox family in Fugu and those in humans and mice. In particular, Fugu does not have orthologues of Sry, Sox15 and Sox30, which appear to be specific to mammals, while Sox19, found in Fugu and zebrafish but absent in mammals, seems to be specific to fishes. Six mammalian Sox genes are represented by two copies each in Fugu, indicating a large-scale gene duplication in the fish lineage. These findings point to recent Sox gene loss, duplication and divergence occurring during the evolution of tetrapod and teleost lineages, and provide further evidence for large-scale segmental or a whole-genome duplication occurring early in the radiation of teleosts.

Animals↗

PubMed2005

Phydbac "Gene Function Predictor": a gene annotation tool based on genomic context analysis.

BACKGROUND: The large amount of completely sequenced genomes allows genomic context analysis to predict reliable functional associations between prokaryotic proteins. Major methods rely on the fact that genes encoding physically interacting partners or members of shared metabolic pathways tend to be proximate on the genome, to evolve in a correlated manner and to be fused as a single sequence in another organism. RESULTS: The new "Gene Function Predictor", linked to the web server Phydbac proposes putative associations between Escherichia coli K-12 proteins derived from a combination of these methods. We show that associations made by this tool are more accurate than linkages found in the other established databases. Predicted assignments to GO categories, based on pre-existing functional annotations of associated proteins are also available. This new database currently holds 9,379 pairwise links at an expected success rate of at least 80%, the 6,466 functional predictions to GO terms derived from these links having a level of accuracy higher than 70%. CONCLUSION: The "Gene Function Predictor" is an automatic tool that aims to help biologists by providing them hypothetical functional predictions out of genomic context characteristics. The "Gene Function predictor" is available at http://www.igs.cnrs-mrs.fr/phydbac/indexPS.html.

Algorithms↗

PubMed2004

High-speed conversion of cytosine to uracil in bisulfite genomic sequencing analysis of DNA methylation.

Bisulfite genomic sequencing is a widely used technique for analyzing cytosine-methylation of DNA. By treating DNA with bisulfite, cytosine residues are deaminated to uracil, while leaving 5-methylcytosine largely intact. Subsequent PCR and nucleotide sequence analysis permit unequivocal determination of the methylation status at cytosine residues. A major caveat associated with the currently practiced procedure is that it takes 16-20 hr for completion of the conversion of cytosine to uracil. Here we report that a complete deamination of cytosine to uracil can be achieved in shorter periods by using a highly concentrated bisulfite solution at an elevated temperature. Time course experiments demonstrated that treating DNA with 9 M bisulfite for 20 min at 90 degrees C or 40 min at 70 degrees C all cytosine residues in the DNA were converted to uracil. Under these conditions, the majority of 5-methylcytosines remained intact. When a high molecular weight DNA derived from a cell line (containing a number of genes whose methylation status was known) was treated with bisulfite under the above conditions and amplified and sequenced, the results obtained were consistent with those reported in the literature. Although some degradation of DNA occurred during this process, the amount of treated DNA required for the amplification was nearly equal to that required for the conventional bisulfite genomic sequencing procedure. The increased speed of DNA methylation analysis with this novel procedure is expected to advance various aspects of DNA sciences.

Base Sequence↗