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Genomic Changes (genomic + change)

Distribution by Scientific Domains

Medical Sciences	46%
Life Sciences	40%

Selected Abstracts

Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer,

GENES, CHROMOSOMES AND CANCER, Issue 7 2007
Virginia Rodriguez
Genomic changes in chromosome 8 are commonly observed in breast cancer cell lines and tumors. To fine map such genomic changes by comparative genomic hybridization (CGH), a high resolution (100 kb) chromosome 8 array that can detect single copy changes was developed using Phi29 DNA polymerase amplified BAC (bacterial artificial chromosome) DNA. The BAC array CGH resolved the two known amplified regions (8q21 and 8q24) of a breast cancer cell line (SKBR3) into nine separate regions including six amplicons and three deleted regions, all of which were verified by Fluorescence in situ hybridization. The extent of the gain/loss for each region was validated by qPCR. CGH was performed with a total of 8 breast cancer cell lines, and common regions of genomic amplification/deletion were identified by segmentation analysis. A 1.2-Mb region (125.3,126.5 Mb) and a 1.0-Mb region (128.1,129.1 Mb) in 8q24 were amplified in 7/8 cell lines. A global expression analysis was performed to evaluate expression changes associated with genomic amplification/deletion: a novel gene, TRMT12 (at 125.5 Mb), amplified in 7/8 cell lines, showed highest expression in these cell lines. Further analysis by RT-qPCR using RNA from 30 breast tumors showed that TRMT12 was overexpressed >2 fold in 87% (26/30) of the tumors. TRMT12 is a homologue of a yeast gene encoding a tRNA methyltransferase involved in the posttranscriptional modification of tRNAPhe, and exploring the biological consequence of its altered expression, may reveal novel pathways in tumorigenesis. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. Published 2007 Wiley-Liss, Inc. [source]

The plasticity of immunoglobulin gene systems in evolution

IMMUNOLOGICAL REVIEWS, Issue 1 2006
Ellen Hsu
Summary:, The mechanism of recombination-activating gene (RAG)-mediated rearrangement exists in all jawed vertebrates, but the organization and structure of immunoglobulin (Ig) genes, as they differ in fish and among fish species, reveal their capability for rapid evolution. In systems where there can exist 100 Ig loci, exon restructuring and sequence changes of the constant regions led to divergence of effector functions. Recombination among these loci created hybrid genes, the strangest of which encode variable (V) regions that function as part of secreted molecules and, as the result of an ancient translocation, are also grafted onto the T-cell receptor. Genomic changes in V-gene structure, created by RAG recombinase acting on germline recombination signal sequences, led variously to the generation of fixed receptor specificities, pseudogene templates for gene conversion, and ultimately to Ig sequences that evolved away from Ig function. The presence of so many Ig loci in fishes raises interesting questions not only as to how their regulation is achieved but also how successive whole-locus duplications are accommodated by a system whose function in other vertebrates is based on clonal antigen receptor expression. [source]

Homoeologous recombination in allopolyploids: the polyploid ratchet

NEW PHYTOLOGIST, Issue 1 2010
Robert T. Gaeta
Summary Polyploidization and recombination are two important processes driving evolution through the building and reshaping of genomes. Allopolyploids arise from hybridization and chromosome doubling among distinct, yet related species. Polyploids may display novel variation relative to their progenitors, and the sources of this variation lie not only in the acquisition of extra gene dosages, but also in the genomic changes that occur after divergent genomes unite. Genomic changes (deletions, duplications, and translocations) have been detected in both recently formed natural polyploids and resynthesized polyploids. In resynthesized Brassica napus allopolyploids, there is evidence that many genetic changes are the consequence of homoeologous recombination. Homoeologous recombination can generate novel gene combinations and phenotypes, but may also destabilize the karyotype and lead to aberrant meiotic behavior and reduced fertility. Thus, natural selection plays a role in the establishment and maintenance of fertile natural allopolyploids that have stabilized chromosome inheritance and a few advantageous chromosomal rearrangements. We discuss the evidence for genome rearrangements that result from homoeologous recombination in resynthesized B. napus and how these observations may inform phenomena such as chromosome replacement, aneuploidy, non-reciprocal translocations and gene conversion seen in other polyploids. [source]

Bioenergetics and the epigenome: Interface between the environment and genes in common diseases

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2010
Douglas C. Wallace
Abstract Extensive efforts have been directed at using genome-wide association studies (GWAS) to identify the genes responsible for common metabolic and degenerative diseases, cancer, and aging, but with limited success. While environmental factors have been evoked to explain this conundrum, the nature of these environmental factors remains unexplained. The availability of and demands for energy constitute one of the most important aspects of the environment. The flow of energy through the cell is primarily mediated by the mitochondrion, which oxidizes reducing equivalents from hydrocarbons via acetyl-CoA, NADH + H+, and FADH2 to generate ATP through oxidative phosphorylation (OXPHOS). The mitochondrial genome encompasses hundreds of nuclear DNA (nDNA)-encoded genes plus 37 mitochondrial DNA (mtDNA)-encoded genes. Although the mtDNA has a high mutation rate, only milder, potentially adaptive mutations are introduced into the population through female oocytes. In contrast, nDNA-encoded bioenergetic genes have a low mutation rate. However, their expression is modulated by histone phosphorylation and acetylation using mitochondrially-generated ATP and acetyl-CoA, which permits increased gene expression, growth, and reproduction when calories are abundant. Phosphorylation, acetylaton, and cellular redox state also regulate most signal transduction pathways and activities of multiple transcription factors. Thus, mtDNA mutations provide heritable and stable adaptation to regional differences while mitochondrially-mediated changes in the epigenome permit reversible modulation of gene expression in response to fluctuations in the energy environment. The most common genomic changes that interface with the environment and cause complex disease must, therefore, be mitochondrial and epigenomic in origin. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:114,119. [source]

Dermal benzene and trichloroethylene induce aneuploidy in immature hematopoietic subpopulations in vivo

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2001
Cynthia R. Giver
Abstract Accumulation of genetic damage in long-lived cell populations with proliferative capacity is implicated in tumorigenesis. Hematopoietic stem cells (hsc) maintain lifetime hematopoiesis, and recent studies demonstrate that hsc in leukemic patients are cytogenetically aberrant. We postulated that exposure to agents associated with increased leukemia risk would induce genomic changes in cells in the hsc compartment. Aneusomy involving chromosomes 2 and 11 in sorted hsc (Lin,c-kit+Sca-1+) and maturing lymphoid and myeloid cells from mice that received topical doses of benzene (bz) or trichloroethylene (TCE) was quantified using fluorescence in situ hybridization. Six days after bz or TCE exposure, aneuploid cells in the hsc compartment increase four- to eightfold in a dose- and schedule-independent manner. Aneuploid lymphoid and myeloid cells from bz- and TCE-treated mice approximate controls, except after repeated benzene exposures. Aneuploid cells are more frequent in the hsc compartment than in mature hematopoietic subpopulations. Hematotoxicity was also quantified in bz- and TCE-exposed hematopoietic subpopulations using two colony-forming assays: CFU-GM (colony-forming units/granulocyte-macrophage progenitors) and CAFC (cobblestone area,forming cells). Data indicate that bz is transiently cytotoxic (,1 week) to hsc subpopulations, and induces more persistent toxicity (>2 weeks) in maturing, committed progenitor subpopulations. TCE is not hematotoxic at the doses applied. In conclusion, we provide direct evidence for induction of aneuploidy in cells in the hsc compartment by topical exposure to bz and TCE. Disruption of genomic integrity and/or toxicity in hsc subpopulations may be one step in leukemic progression. Environ. Mol. Mutagen. 37:185,194, 2001. © 2001 Wiley-Liss, Inc. [source]

THE IMPORTANCE OF PREADAPTED GENOMES IN THE ORIGIN OF THE ANIMAL BODYPLANS AND THE CAMBRIAN EXPLOSION

EVOLUTION, Issue 5 2010
Charles R. Marshall
The genomes of taxa whose stem lineages branched early in metazoan history, and of allied protistan groups, provide a tantalizing outline of the morphological and genomic changes that accompanied the origin and early diversifications of animals. Genome comparisons show that the early clades increasingly contain genes that mediate development of complex features only seen in later metazoan branches. Peak additions of protein-coding regulatory genes occurred deep in the metazoan tree, evidently within stem groups of metazoans and eumetazoans. However, the bodyplans of these early-branching clades are relatively simple. The existence of major elements of the bilaterian developmental toolkit in these simpler organisms implies that these components evolved for functions other than the production of complex morphology, preadapting the genome for the morphological differentiation that occurred higher in metazoan phylogeny. Stem lineages of the bilaterian phyla apparently required few additional genes beyond their diploblastic ancestors. As disparate bodyplans appeared and diversified during the Cambrian explosion, increasing complexity was accommodated largely through changes in cis -regulatory networks, accompanied by some additional gene novelties. Subsequently, protein-coding genic richness appears to have essentially plateaued. Some genomic evidence suggests that similar stages of genomic evolution may have accompanied the rise of land plants. [source]

Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer,

Profiling genomic copy number changes in retinoblastoma beyond loss of RB1

GENES, CHROMOSOMES AND CANCER, Issue 2 2007
Ella Bowles
Loss of both RB1 alleles is rate limiting for development of retinoblastoma (RB), but genomic copy number gain or loss may impact oncogene(s) and tumor suppressor genes, facilitating tumor progression. We used quantitative multiplex polymerase chain reaction to profile "hot spot" genomic copy number changes for gain at 1q32.1, 6p22, and MYCN, and loss at 16q22 in 87 primary RB and 7 cell lines. Loss at 16q22 (48%) negatively associated with MYCN gain (18%) (Fisher's exact P = 0.031), gain at 1q32.1 (62%) positively associated with 6p "hot spot" gain (43%) (P = 0.033), and there was a trend for positive association between 1q and MYCN gain (P = 0.095). Cell lines had a higher frequency of MYCN amplification than primary tumors (29% versus 3%; P= 0.043). Novel high-level amplification of 1q32.1 in one primary tumor, confirmed by fluorescence in situ hybridization, strongly supports the presence of oncogene(s) in this region, possibly the mitotic kinesin, KIF14. Gene-specific quantitative multiplex polymerase chain reaction of candidate oncogenes at 1q32.1 (KIF14), 6p22 (E2F3 and DEK), and tumor suppressor genes at 16q22 (CDH11) and 17q21 (NGFR) showed the most common gene gains in RB to be KIF14 in cell lines (80%) and E2F3 in primary tumors (70%). The patterns of gain/loss were qualitatively different in 25 RB compared with 12 primary hepatocellular carcinoma and 12 breast cancer cell lines. Gene specific analysis of one bone marrow metastasis of RB, prechemotherapy and postchemotherapy, showed the typical genomic changes of RB pretreatment, which normalized after chemotherapy. © 2006 Wiley-Liss, Inc. [source]

Understanding the recent evolution of the human genome: insights from human,chimpanzee genome comparisons,

HUMAN MUTATION, Issue 2 2007
Hildegard Kehrer-Sawatzki
Abstract The sequencing of the chimpanzee genome and the comparison with its human counterpart have begun to reveal the spectrum of genetic changes that has accompanied human evolution. In addition to gross karyotypic rearrangements such as the fusion that formed human chromosome 2 and the human-specific pericentric inversions of chromosomes 1 and 18, there is considerable submicroscopic structural variation involving deletions, duplications, and inversions. Lineage-specific segmental duplications, detected by array comparative genomic hybridization and direct sequence comparison, have made a very significant contribution to this structural divergence, which is at least three-fold greater than that due to nucleotide substitutions. Since structural genomic changes may have given rise to irreversible functional differences between the diverging species, their detailed analysis could help to identify the biological processes that have accompanied speciation. To this end, interspecies comparisons have revealed numerous human-specific gains and losses of genes as well as changes in gene expression. The very considerable structural diversity (polymorphism) evident within both lineages has, however, hampered the analysis of the structural divergence between the human and chimpanzee genomes. The concomitant evaluation of genetic divergence and diversity at the nucleotide level has nevertheless served to identify many genes that have evolved under positive selection and may thus have been involved in the development of human lineage-specific traits. Genes that display signs of weak negative selection have also been identified and could represent candidate loci for complex genomic disorders. Here, we review recent progress in comparing the human and chimpanzee genomes and discuss how the differences detected have improved our understanding of the evolution of the human genome. Hum Mutat 28(2), 99,130, 2007. © 2006 Wiley-Liss, Inc. [source]

Multiple roles of the candidate oncogene ZNF217 in ovarian epithelial neoplastic progression

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2007
Peixiang Li
Abstract The transcription factor ZNF217 is often amplified in ovarian cancer, but its role in neoplastic progression is unknown. We introduced ZNF217 -HA by adenoviral and retroviral infection into normal human ovarian surface epithelial cells (OSE), i.e., the source of ovarian cancer, and into SV40 Tag/tag expressing, p53/pRB-deficient OSE with extended but finite life spans (IOSE). In OSE, ZNF217-HA reduced cell,substratum adhesion and accelerated loss of senescent cells, but caused no obvious proneoplastic changes. In contrast, ZNF217-HA transduction into IOSE yielded two permanent lines, I-80RZ and I-144RZ, which exhibited telomerase activity, stable telomere lengths, anchorage independence and reduced serum dependence, but were not tumorigenic in SCID mice. This immortalization required short-term EGF treatment near the time of crisis. The permanent lines were EGF-independent, but ZNF217-dependent since siRNA to ZNF217 inhibited anchorage independence and arrested growth. Array CGH revealed genomic changes resembling those of ovarian carcinomas, such as amplicons at 3q and 20q, and deletions at 4q and 18, associated with underexpressed annexin A10, N-cadherin, desmocollin 3 and PAI-2, which have been reported as tumor suppressors. The lines overexpressed EEF1A2, SMARA3 and STAT1 and underexpressed other oncogenes, tumor suppressors and extracellular matrix/adhesion genes. The results implicate ZNF217 as an ovarian oncogene, which is detrimental to senescing normal OSE cells but contributes to neoplastic progression in OSE with inactivated p53/RB. The resemblance of the genomic changes in the ZNF217-overexpressing lines to ovarian carcinomas provides a unique model to investigate interrelationships between these changes and ovarian neoplastic phenotypes. © 2007 Wiley-Liss, Inc. [source]

8q24 Copy number gains and expression of the c- myc mRNA stabilizing protein CRD-BP in primary breast carcinomas

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2003
Panayotis Ioannidis
Abstract The coding region determinant binding protein (CRD-BP) was isolated by virtue of its high affinity to the c- myc mRNA coding region stability determinant and shown to shield this message from nucleolytic attack, prolonging its half-life. CRD-BP is normally expressed during fetal life but is also activated de novo in tumors. Considering that aberrant CRD-BP expression may represent an additional mechanism interfering with c- myc regulation, we screened 118 primary breast carcinomas for CRD-BP expression, 60 of which had also been analyzed by comparative genomic hybridization (CGH). Copy number gains encompassing 8q24, the chromosome band that contains the c- myc locus, were detected in 48.3% (29/60) of tumors, whereas gains involving band 17q21, which contains the CRD-BP locus, were observed in 18.3% (11/60) of tumors. CRD-BP expression was detected in 58.5% (69/118) of tumors, implying mechanisms of activation alternative to gene amplification. Altogether, some 75% of the tumors had alterations pertaining to c- myc since they either harbored 8q24 gains and/or expressed CRD-BP. Significant associations were detected between CRD-BP expression and the absence of estrogen receptors (p = 0.005) and between the presence of 8q24 gains and an increased number of genomic changes as measured by CGH (p = 0.0017). Tumors were divided into 4 groups according to CRD-BP expression and 8q24 gains. The odds for tumors having both characteristics to be classified as poorly differentiated (grade III vs. grade I and II) were 19.6 times the corresponding odds for tumors neither expressing CRD-BP nor harboring 8q24 gains. For tumors either harboring 8q24 gains only or expressing CRD-BP alone, the corresponding odds were 6.4 and 3, respectively. © 2002 Wiley-Liss, Inc. [source]

Oncogene expression profiles in K6/ODC mouse skin and papillomas following a chronic exposure to monomethylarsonous acid,

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2009
Don A. Delker
Abstract We have previously observed that a chronic drinking water exposure to monomethylarsonous acid [MMA(III)], a cellular metabolite of inorganic arsenic, increases tumor frequency in the skin of keratin VI/ornithine decarboxylase (K6/ODC) transgenic mice. To characterize gene expression profiles predictive of MMA(III) exposure and mode of action of carcinogenesis, skin and papilloma RNA was isolated from K6/ODC mice administered 0, 10, 50, and 100 ppm MMA(III) in their drinking water for 26 weeks. Following RNA processing, the resulting cRNA samples were hybridized to Affymetrix Mouse Genome 430A 2.0 GeneChips®. Micoarray data were normalized using MAS 5.0 software, and statistically significant genes were determined using a regularized t -test. Significant changes in bZIP transcription factors, MAP kinase signaling, chromatin remodeling, and lipid metabolism gene transcripts were observed following MMA(III) exposure as determined using the Database for Annotation, Visualization and Integrated Discovery 2.1 (DAVID) (Dennis et al., Genome Biol 2003;4(5):P3). MMA(III) also caused dose-dependent changes in multiple Rho guanine nucleotide triphosphatase (GTPase) and cell cycle related genes as determined by linear regression analyses. Observed increases in transcript abundance of Fosl1, Myc, and Rac1 oncogenes in mouse skin support previous reports on the inducibility of these oncogenes in response to arsenic and support the relevance of these genomic changes in skin tumor induction in the K6/ODC mouse model. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:406,418, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20304 [source]

Homoeologous recombination in allopolyploids: the polyploid ratchet

IDENTIFICATION OF MOLECULAR MARKERS IN DCIS RECURRENCE

PATHOLOGY INTERNATIONAL, Issue 12 2001
Provenzano E
Background: DCIS represents preinvasive malignant change. With screening mammography DCIS has become a common entity. Its natural history is poorly understood and treatment remains controversial. Using a retrospective population based cohort, we have identified histological and molecular variables predictive of recurrence. Methods: All cases of DCIS reported in Victoria between 1988 and 1992 were entered into the Victorian Cancer Registry. In Situ and Small Cancer Register (ISSIBCR) and followed up annually regarding treatment, the event of recurrence and its nature and location. From this register a cohort of 66 DCIS lesions with subsequent recurrence as in situ or invasive disease were studied histologically, immunohistochemically and with CGH-based genetic analyses comparing them to a nested randomized control group of DCIS without recurrence matched for patient age and year of diagnosis. Recurrences have been analysed by the same techniques to compare them to the primary lesion. Results: 13 histological features were evaluated and lesion size, nuclear pleomorphism, cellular polarity, micropapillary architecture and central necrosis were all significant predictors of recurrence (p < 0.05). Immunohistochemistry showed p21 overexpression, bcl2 negativity and ERBB2 positivity to be markers of recurrence. In the case of ERBB2, positivity was a predictor of recurrence even when its overexpression was focal. Primary and recurrent DCIS lesions had similar morphological appearances, and grade of primary DCIS correlated with grade of subsequent invasive cancer. This morphological similarity was paralleled by similar protein expression and genomic changes in both in situ and invasive recurrences. Conclusion: We have identified histological and immunohistochemical markers of recurrence in DCIS, and shown similarities in morphology, protein expression and genetic changes between primary DCIS and its recurrence. [source]

Genome redundancy and plasticity within ancient and recent Brassica crop species

BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 4 2004
LEWIS N. LUKENS
The crop species within the genus Brassica have highly replicated genomes. Three base ,diploid' species, Brassica oleracea, B. nigra and B. rapa, are likely ancient polyploids, and three derived allopolyploid species, B. carinata, B. juncea and B. napus, are created from the interspecific hybridization of these base genomes. The base Brassica genome is thought to have hexaploid ancestry, and both recent and ancient polyploidization events have been proposed to generate a large number of genome rearrangements and novel genetic variation for important traits. Here, we revisit and refine these hypotheses. We have examined the B. oleracea linkage map using the Arabidopsis thaliana genome sequence as a template and suggest that there is strong evidence for genome replication and rearrangement within the base Brassicas, but less evidence for genome triplication. We show that novel phenotypic variation within the base Brassicas can be achieved by replication of a single gene, BrFLC, that acts additively to influence flowering time. Within the derived allopolyploids, intergenomic heterozygosity is associated with higher seed yields. Some studies have reported that de novo genomic variation occurs within derived polyploid genomes, whereas other studies have not detected these changes. We discuss reasons for these different findings. Large translocations and tetrasomic inheritance can explain some but not all genomic changes within the polyploids. Transpositions and other small-scale sequence changes probably also have contributed to genomic novelty. Our results have shown that the Brassica genomes are remarkably plastic, and that polyploidy generates novel genetic variation through gene duplication, intergenomic heterozygosity and perhaps epigenetic change. © 2004 The Linnean Society of London, Biological Journal of the Linnean Society, 2004, 82, 665,674. [source]