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PubMed2006

Multiple forms of genetic instability within a 2-Mb chromosomal segment of 3q26.3-q27 are associated with development of esophageal adenocarcinoma.

Gene amplification is one of the mechanisms to activate oncogenes in many cancers, including esophageal adenocarcinoma (EA). In the present study, we used two-dimensional restriction landmark genome scanning to clone a NotI/DpnII fragment that showed increased genomic dosage in 1 of 44 EAs analyzed. This fragment maps to 3q26.3-q27, and subsequent experiments identified two intrachromosomal amplicons within a 10-Mb DNA segment in 7 of 75 (9%) EAs. The distal amplified-core region maps centromeric to the PIK3CA locus, and a microsatellite (D3S1754) within this region exhibited significant instability (MSI), in stark contrast to the genomewide microsatellite stability found in EA. D3S1754-MSI arises in premalignant Barrett's dysplastic cells and preceded amplification of the nascent MSI allele in the corresponding EA. Seven ESTs within the amplified-core were overexpressed in amplicon-containing EAs. One of these, EST AW513672, represents a chimeric transcript that initiated from an antisense promoter sequence in the 5'UTR of a full-length LINE-1 element (L1-5'ASP). Similar chimeric transcripts encoding portions of the MET oncogene and the BCAS3 gene also were overexpressed in EAs, suggesting that L1-5'ASP activation may occur at a broad level in primary EAs. Thus, the fine dissection of a 2-Mb amplified DNA segment in 3q26.3-q27 in EA revealed multiple genetic alterations that had occurred sequentially and/or concurrently during EA development.

5' Untranslated Regions↗
PubMed1995

De novo tandem duplication of chromosome segment 22q11-q12: clinical, cytogenetic, and molecular characterization.

We report on a case of duplication of the segment 22q11-q12 due to a de novo duplication. Molecular cytogenetics studies demonstrated this to be a tandem duplication, flanked proximally by the marker D22Z4, a centromeric alpha satellite DNA repeat, and distally by D22S260, an anonymous DNA marker proximal to the Ewing sarcoma breakpoint. The segment includes the regions responsible for the "cat-eye," Di George, and velo-cardio-facial syndromes and extends distal to the breakpoint cluster region (BCR). The clinical picture is dominated by the cardiac defects and includes findings reminiscent of "cat-eye" syndrome. These findings reinforce the hypothesis that the proximal 22q region contains dosage-sensitive genes involved in development.

Chromosome Aberrations↗
PubMed1998

A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.

The cellular protooncogene MYC encodes a nuclear transcription factor that is involved in regulating important cellular functions, including cell cycle progression, differentiation, and apoptosis. Dysregulated MYC expression appears critical to the development of various types of malignancies, and thus factors involved in regulating MYC expression may also play a key role in the pathogenesis of certain cancers. We have cloned one such MYC regulatory factor, termed CTCF, which is a highly evolutionarily conserved-11-zinc finger transcriptional factor possessing multiple DNA sequence specificity. CTCF binds to a number of important regulatory regions within the 5' noncoding sequence of the human MYC oncogene, and it can regulate its transcription in several experimental systems. CTCF mRNA is expressed in cells of multiple different lineages. Enforced ectopic expression of CTCF inhibits cell growth in culture. Southern blot analyses and fluorescence in situ hybridization (FISH) with normal human metaphase chromosomes showed that the human CTCF is a single-copy gene situated at chromosome locus 16q22. Cytogenetic studies have pointed out that chromosome abnormalities (deletions) at this locus frequently occur in many different human malignancies, suggesting the presence of one or more tumor suppressor genes in the region. To narrow down their localization, several loss of heterozygosity (LOH) studies of chromosome arm 16q in sporadic breast and prostate cancers have been carried out to define the most recurrent and smallest region(s) of overlap (SRO) for commonly deleted chromosome arm 16q material. For CTCF to be considered as a candidate tumor suppressor gene associated with tumorigenesis, it should localize within one of the SROs at 16q. Fine-mapping of CTCF has enabled us to assign the CTCF gene to about a 2 centiMorgan (cM) interval of 16q22.1 between the somatic cell hybrid breakpoints CY130(D) and CY4, which is between markers D16S186 (16AC16-101) and D16S496 (AFM214zg5). This relatively small region, containing the CTCF gene, overlaps the most frequently observed SROs for common chromosomal deletions found in sporadic breast and prostate tumors. In one of four analyzed paired DNA samples from primary breast cancer patients, we have detected a tumor-specific rearrangement of CTCF exons encoding the 11-zinc-finger domain. Therefore, taken together with other CTCF properties, localization of CTCF to a narrow cancer-associated chromosome region suggests that CTCF is a novel candidate tumor suppressor gene at 16q22.1.

Breast Neoplasms↗
PubMed1996

Purification of Escherichia coli chromosomal segments without cloning.

Pairs of genomic insertions made with elements carrying any one of several frequently used rare restriction sites allow physical purification of insertion delimited genes. However, native rare restriction sites can, either by causing (i) fragmentation of targeted intervals or (ii) generation of additional fragments that overlap electrophoretically with targeted ones, place severe limitations on this approach. We present a series of Escherichia coli mini-Tn10 insertions containing the rare-cutting polylinker 2 (RCP2) of rare restriction sites, which includes the 18-base-pair I-SceI site (absent from native E. coli sequences). Pulsed-field gel purification from RCP2 double insertion mutants of both an I-SceI fragment from strain K-12 (containing approximately 90-95 min) and an allelic I-SceI fragment from a pathogenic strain is demonstrated. The complete series of RCP2 insertions, containing different antibiotic resistances at intervals of approximately 35 kb in prototype K-12 strain MG1655, allows rapid purification of the genes from any E. coli chromosomal interval as an isolated I-SceI fragment.

Bacillus subtilis↗
PubMed1979

Proximal chiasma localization within an interstitial chromosome segment, a likely correlate of adjacent-2 segregation of translocation causing multivalents in the mouse.

Two T7OH/+ translocation-carrying male mice were used in an investigation into the relation between the segregation pattern of the translocation caused multivalent at anaphase I and the position of the only chiasma in a long interstitial segment. Moreover, the relation between meiotic stage (from early diakinesis to metaphase I) and chiasma movement was assessed. It appeared that pronounced movement of a chiasma within the multivalent was linked with chiasma terminalization in an adjacent segment, either on the same side of the translocation breakpoint or on the other side. On summing the CIV and CIII+I configurations (making up 97.9% of all configurations found) and focusing on the multivalents from late meiotic cells, 41.3% had a proximal chiasma in the long interstitial segment of the multivalent. In total, a percentage of 33.5% of all secondary spermatocytes were characteristic of adjacent-2 segregation (i.e., homologous centromeres move to the same pole at anaphase I). Results obtained with T7OH translocation trisomics, which are briefly discussed in this paper, confirm the tendency of proximal chiasma frequencies in late meiotic cells to coincide with the frequency of absence of homologous centromere separation within the T7OH translocation multivalent. The importance of this phenomenon for normal bivalent behavior during anaphase I is considered.

Anaphase↗
PubMed1995

Apoptosis regulatory gene NEDD2 maps to human chromosome segment 7q34-35, a region frequently affected in haematological neoplasms.

Developmentally regulated mouse gene Nedd2 encodes a protein similar to the product of the nematode Caenorhabditis elegans cell death gene ced-3 and the mammalian interleukin-1 beta-converting enzyme. Overexpression of Nedd2 in cultured mammalian cells induces apoptosis that can be blocked by proto-oncogene BCL2. We have isolated cDNA clones for the human homologue of the mouse gene and, by using these as probes, mapped the human NEDD2 gene to 7q34-35 by fluorescence in situ hybridisation. The potential tumour suppressor function of NEDD2 is discussed.

Apoptosis↗
PubMed2003

Alloplasmic male sterile Brassica napus with Enarthrocarpus lyratus cytoplasm: introgression and molecular mapping of an E. lyratus chromosome segment carrying a fertility restoring gene.

A cytoplasmic male sterility (CMS) system for Brassica napus (2n = 38; AACC) was developed by backcross substitution of its nucleus into the cytoplasm of a wild crucifer, Enarthrocarpus lyratus. Male sterility was complete, stable, and expressed in small flowers with rudimentary anthers. Since the B. napus germplasm lines were complete or partial maintainers of male sterility, the required fertility restorer gene (Rfl) was introgressed from the cytoplasm donor species. Inheritance studies carried out on F1 and F2 populations derived from hybridizing cytoplasmic male sterile and male fertile near-isogenic (PNILs) lines of B. napus 'Westar', revealed a monogenic dominant control for fertility restoration. Bulked segregant analysis with 215 RAPD primers helped in the identification of putative primers associated with fertility restoration. Co-segregation analysis of eight such primers with Rfl gene revealed two markers, OPK 15700 and OPZ 061300, which flank the Rfl locus on either side at a distance of 8.2 and 2.5 cM, respectively. These DNA markers will be useful in marker-assisted selection for improving the commercial potential of this newly developed CMS-fertility-restorer system for hybrid seed production programs in rapeseed.

Brassica↗
PubMed1999

Distinct deleted regions on chromosome segment 16q23-24 associated with metastases in prostate cancer.

Cadherins (CDH) are cell adhesion molecules and their dysfunctions have been implicated in the development of cancer metastases. Several cadherin genes are tandemly located on 16q, which is frequently deleted in prostate cancer. We therefore used 22 markers on 16q to localize important deleted regions in metastases of this tumor. We found 16q deletions in 24/32 (75%) tumors. All lymph node and brain metastases showed extensive deletions, while 52% of primary tumors displayed limited deletions. Commonly deleted regions (CDRs) on 16q23-24, CDR2 (D16S515-D16S516) and CDR4 (D16S520-D13S3028), were strongly associated with metastases and increased Gleason score. Reduced CDH1 (E-cadherin) expression was seen in 16/32 (50%) tumors, but the CDH1 gene is not within either of these two regions. Sequencing analysis for all 16 exons of the CDH1 gene did not reveal any mutations in 10 tumors, including three brain metastases with both 16q22.1 deletion and absent E-cadherin expression. Our results implicate other, yet unidentified genes on 16q23-24 to be the frequent targets of mutations and deletions in prostate cancer metastases.

Aged↗
PubMed2005

Chromosome segment duplications in Neurospora crassa and their effects on repeat-induced point mutation and meiotic silencing by unpaired DNA.

The size and extent of four Neurospora crassa duplications, Dp(AR17), Dp(IBj5), Dp(OY329), and Dp(B362i), was determined by testing the coverage of RFLP markers. The first three duplications were all > approximately 350 kb and have been shown in earlier studies to act as dominant suppressors of repeat-induced point mutation (RIP) in gene-sized duplications, possibly via titration of the RIP machinery. Dp(B362i), which is only approximately 117 kb long, failed to suppress RIP. RIP suppression in gene-sized duplications by large duplications was demonstrated using another test gene, dow, and supposedly applies generally. Crosses homozygous for Dp(AR17) or Dp(IBj5) were as barren as heterozygous crosses. Barrenness of the heterozygous but not the homozygous crosses was suppressible by Sad-1, a semidominant suppressor of RNAi-dependent meiotic silencing by unpaired DNA. A model is proposed in which large duplications recessively suppress semidominant Sad-1 mutations. The wild-isolated Sugartown strain is hypothesized to contain a duplication that confers not only dominant suppression of RIP but also a barren phenotype, which is linked (9%) to supercontig 7.118 in LG VII.

Chromosome Mapping↗
PubMed2000

Structural domains and matrix attachment regions along colinear chromosomal segments of maize and sorghum.

Although a gene's location can greatly influence its expression, genome sequencing has shown that orthologous genes may exist in very different environments in the genomes of closely related species. Four genes in the maize alcohol dehydrogenase (adh1) region represent solitary genes dispersed among large repetitive blocks, whereas the orthologous genes in sorghum are located in a different setting surrounded by low-copy-number DNAs. A specific class of DNA sequences, matrix attachment regions (MARs), was found to be in comparable positions in the two species, often flanking individual genes. If these MARs define structural domains, then the orthologous genes in maize and sorghum should experience similar chromatin environments. In addition, MARs were divided into two groups, based on the competitive affinity of their association with the matrix. The "durable" MARs retained matrix associations at the highest concentrations of competitor DNA. Most of the durable MARs mapped outside genes, defining the borders of putative chromatin loops. The "unstable" MARs lost their association with the matrix under similar competitor conditions and mapped mainly within introns. These results suggest that MARs possess both domain-defining and regulatory roles. Miniature inverted repeat transposable elements (MITEs) often were found on the same fragments as the MARs. Our studies showed that many MITEs can bind to isolated nuclear matrices, suggesting that MITEs may function as MARs in vivo.

Alcohol Dehydrogenase↗
PubMed1998

[Comparative genomic hybridization (CGH) for detecting a heretofore undescribed amplified chromosomal segment in high-grade medullary osteosarcoma].

Osteosarcoma is one of the most commonly biopsied primary tumor of bone. High-grade osteosarcomas in particular exhibit a wide spectrum of cytogenetic changes. Molecular cytogenetic studies on osteosarcomas have shown that genomic amplification, especially of both the TP53-binding MDM2 gene and the flanking SAS gene, plays an important role in the biology of these tumors. We applied CGH in order to obtain a global view of DNA-sequence losses and gains in osteosarcoma. CGH was performed on 20 high-grade medullary osteosarcomas (13 primary tumors prior to chemotherapy, 5 tumors after chemotherapy, 2 established cell lines [MB63, HOS58]) using genomic DNA of snap-frozen tumor specimens. CGH revealed DNA copy number aberrations, mostly gains, in all the tumors studied with an average of 18.5 aberrations/tumor (range 8-32). High-level amplifications were observed in all cases (average 4.1 amplifications/tumor [range 1-10]). Amplicons affecting at least five tumors were mapped to 1p21-31 (9/20 cases), 3q25-qter (6/20), 6p12-21 (6/20), 8q12-qter (10/20), 12p11-12 (9/20), 12q12-15 (enclosing MDM2 and SAS loci, 7/20). Losses were most frequently seen at 3p, 10q, 11p and 13 (all 10/20). In conclusion, our CGH data indicated that genomic amplification plays an important role in the biology of osteosarcoma. CGH demonstrated the complexity of genetic aberrations in osteosarcomas. The detection of novel non-random DNA amplifications in our study has defined regions for further targeted molecular genetic research aimed at identifying those oncogenes that are characteristic of osteosarcoma development.

Bone Neoplasms↗
PubMed2003

Plant genome archaeology: evidence for conserved ancestral chromosome segments in dicotyledonous plant species.

We have developed genetic maps, based on expressed sequence tags (ESTs) that are homologous to Arabidopsis genes, in four dicotyledonous crop plant species from different families. A comparison of these maps with the physical map of Arabidopsis reveals common genome segments that appear to have been conserved throughout the evolution of the dicots. In the four crop species analysed these segments comprise between 16 and 33% of the Arabidopsis genome. Our findings extend the synteny patterns previously observed only within plant families, and indicate that structural and functional information from the model species will be, at least in part, applicable in crop plants with large genomes.

Journal Article↗
PubMed1980

Murine T cell Ia antigens: specificity Iat.46 maps in I-J to I-E chromosomal segment of H-2 complex.

An alloantiserum was prepared in C57BL/10 mice hyperimmunized with concanavalin A-stimulated B10.HTG thymocytes. Absorption with separated B10.A(3R)B and T lymphocytes, followed by titration on these cell types, revealed a new I-region controlled T-cell specificity, Iat.46. The determinant is present on a subpopulation of mature peripheral T cells but not on B lymphocytes, thymocytes, or bone marrow cells. It is also observed using (A.TH X B10.HTT)F1 anti-A.TL antiserum on B10.A(3R) T lymphocytes. The k and d haplotypes are fully crossreactive with regard to Iat.46 expression. B10.HTT, C57BL/10, and BSVS do not carry the Iat.46-encoding allele. Moreover, Iat.46 is not a determinant formed by I-A--I-E gene complementation. The Iat.46-controlling gene, Ia-8, may be positioned to the left of the B10.HTT crossover and to the right of the B10.A(3R) recombinational event. Thus, this determinant may be considered either to represent complexity within the I-J subregion or to demarcate a new I subregion between I-J and I-E.

Animals↗
PubMed1991

Rare chromosomal aberrations induced by vincristine. Partial endoreduplication and pseudoendoreduplication, segmentally endoreduplicated chromosomes, and segmental premature chromosome condensation.

Vincristine (VCR) is capable of inducing a cell containing both conventional chromosomes (monochromosomes) and diplochromosomes. A total of 124 such metaphases were examined by 5-bromodeoxyuridine (BrdU) incorporation and fluorescence plus Giemsa (FPG) technique to analyze cell cycle kinetics. The majority of cells (119 metaphases) showed differential BrdU incorporation between the two kinds of chromosomes, indicating that partial endoreduplication occurred in these cells. In addition, existence of partially endoreduplicated cells with premature chromosome condensation (PCC) in either mono- or diplochromosomes suggests that the timing of monochromosome-replication was very variable in individual cells. On the other hand, the remaining five metaphases showed that both mono- and diplochromosomes incorporated BrdU similarly, indicating that diplochromosomes are formed by pseudoendoreduplication. Two kinds of chromosomal aberrations probably caused by delay of DNA synthesis on chromosome segments, segmental endoreduplication, and segmental PCC were also reported. Segmental endoreduplication was defined as endoreduplication that occurred on some segments of chromosomes. Out of 119 partially endoreduplicated cells, 3 contained a chromosome consisting of both mono- and diplochromosomal segments, indicating that the former segments missed one round of DNA synthesis. Segmental PCC was defined as PCC restricted to only some segments of chromosomes. Two types of segmental PCC, segmental S-PCC and G2-PCC, were observed in VCR-induced ordinary polyploidy. Although both segmental endoreduplication and segmental PCC occurred with very low frequency, these phenomena suggest that DNA synthesis was disturbed in some part of the nucleus.

Aneuploidy↗
PubMed2002

Search for a shared segment on chromosome 10q26 in patients with bipolar affective disorder or schizophrenia from the Faroe Islands.

Previous linkage studies have suggested a new locus for bipolar affective disorder and possibly also for schizophrenia on chromosome 10q26. We searched for allelic association and chromosome segment and haplotype sharing on chromosome 10q26 among distantly related patients with bipolar affective disorder or schizophrenia and controls from the relatively isolated population of the Faroe Islands by investigating 22 microsatellite markers from a 35 cM region. We used a combined approach with both assumption free tests and tests based on genealogical relationships. The 6.5 cM region between D10S1230 and D10S2322, which has been implied in previous linkage analyses, received some support. A search for segment sharing yielded empirical P-values around 0.02 among patients with bipolar affective disorder and around 0.03 for patients with schizophrenia. For both disorders combined allelic association yielded empirical P-values around 0.003 at marker D10S1723. A haplotype data mining approach supported haplotype sharing in this region. In another, more distal, 11.5 cM region between markers D10S214 and D10S505, which has received support in previous linkage studies, increased haplotype sharing in patients with bipolar affective disorder was supported by Fisher's exact test, tests based on genealogy and by haplotype data mining. Our findings yield some support for a risk gene for bipolar affective disorder and possibly also for schizophrenia.

Alleles↗