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PubMed2000

Structure of chromosomal duplicons and their role in mediating human genomic disorders.

Chromosome-specific low-copy repeats, or duplicons, occur in multiple regions of the human genome. Homologous recombination between different duplicon copies leads to chromosomal rearrangements, such as deletions, duplications, inversions, and inverted duplications, depending on the orientation of the recombining duplicons. When such rearrangements cause dosage imbalance of a developmentally important gene(s), genetic diseases now termed genomic disorders result, at a frequency of 0.7-1/1000 births. Duplicons can have simple or very complex structures, with variation in copy number from 2 to >10 repeats, and each varying in size from a few kilobases in length to hundreds of kilobases. Analysis of the different duplicons involved in human genomic disorders identifies features that may predispose to recombination, including large size and high sequence identity between the recombining copies, putative recombination promoting features, and the presence of multiple genes/pseudogenes that may include genes expressed in germ cells. Most of the chromosome rearrangements involve duplicons near pericentromeric regions, which may relate to the propensity of such regions to accumulate duplicons. Detailed analyses of the structure, polymorphic variation, and mechanisms of recombination in genomic disorders, as well as the evolutionary origin of various duplicons will further our understanding of the structure, function, and fluidity of the human genome.

Animals↗

PubMed1997

A longitudinal study of human age-related chromosomal analysis in skin fibroblasts.

Previous chromosomal analyses related to human aging used mainly cross-sectional data on metaphase chromosomes. However, it is difficult to directly relate the cross-sectional results to the specific type(s) of chromosomal mutations possibly occurring within a specific individual with advancing age, because the unique genetic endowment of each individual for longevity might be a modulating factor. We therefore have performed, for the first time, a longitudinal study of both numerical and structural chromosome analyses of skin fibroblasts at interphase and at metaphase derived from eight donors participating in the Baltimore Longitudinal Study. We have used the FISH method with chromosome-specific DNA probes and the data on total aneuploidy of 17 different chromosomes in each of the 16 cell cultures (2 from each of eight individuals) indicate that significantly higher percentages of aneuploid cells are detected at interphase than at metaphase. Mostly, the levels of chromosome-specific aneuploidy increase with the donor's advancing age and, in most individuals, chromosomes 1, 4, 6, 8, 10, and 15 show significantly higher frequencies of aneuploidy at interphase than those of the 11 other chromosomes studied. Although the significance of relatively higher levels of aneuploidy of certain chromosomes with aging remains unclear, it is intriguing to note that some of these chromosomes, such as 1, 4, and 6, have already been assigned to harbor senescence genes and chromosome 8 is known to house the gene for Werner Syndrome (progeroid syndrome), which shows very limited proliferative capacity of fibroblasts. It is conceivable that the degree and/or type of chromosome-specific aneuploidy might have some gene dosage effects in the control of cellular proliferation and selection during aging. We also show that a combination of both interphase and metaphase aneuploidy analyses provides more comprehensive and insightful information on intraindividual cellular dynamics and chromosomal aneuploidy as a function of age. Occasionally, very small proportions of cells in two individuals showed age-related structural chromosome aberrations, such as an acentric fragment derived from an X chromosome and an achromatic gap in chromosome 7. Thus, a comparative analysis of both intra- and interindividual longitudinal studies is very useful in detecting the pattern(s) of chromosome-specific alterations with increasing age.

Adult↗

PubMed2021

Functional impact of cancer-associated cohesin variants on gene expression and cellular identity.

Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.

Animals↗

PubMed1999

Structure and chromosomal assignment of the sterol 12alpha-hydroxylase gene (CYP8B1) in human and mouse: eukaryotic cytochrome P-450 gene devoid of introns.

Sterol 12alpha-hydroxylase (CYP8B1) is a hepatic cytochrome P-450 that controls the ratio of cholic acid over chenodeoxycholic acid in bile and thus controls the solubility of cholesterol. Both the human and the mouse CYP8B1 complementary DNA and gene were cloned and structurally characterized. Surprisingly, the genomic DNA from both species was found to lack introns. The major transcript of the human gene was estimated to be 3950 bp, and the putative promoter region was estimated to be at least 1360 bp. The murine structural gene was found to span approximately 3 kb. By using FISH and radiation hybrid mapping techniques, the human CYP8B1 gene was located to chromosome 3p21.3-p22, whereas FISH mapped the murine counterpart to chromosome 9qF4, a region that is homologous to the third human chromosome. The results from the chromosome mapping and Southern blotting indicated that the gene is present in a single copy. Transcription of the mouse and human CYP8B1 genes was initiated from a position situated 51 and 35 bases, respectively, downstream of a consensus TATA box. A homology of 21% for the promoter regions of mouse and human may indicate differences in transcriptional regulation. Although a potent induction of CYP8B1 mRNA was observed upon starvation of mice, the mechanism behind this effect was not revealed by analysis of the promoter for potential cis-acting elements. In the human promoter, several possible cis-acting regions were identified but none of them could be directly related to bile acid metabolism. After transfection of COS cells with the human coding region, mRNA and enzymatic activity for the 12alpha-hydroxylase were identified. This is the first mammalian cytochrome P-450 gene reported to lack introns. The importance of this structural feature for evolution and gene regulation is discussed.

Amino Acid Sequence↗

PubMed1984

Chromosome stabilizing structures in mitotic Indian muntjac (Muntiacus muntjak) cells.

A new technique which removes all membranes, cytoskeletal elements, organelles, but preserves intact metaphase, anaphase and telophase configurations is combined with scanning electron microscopy (SEM) as an approach for direct visualization of chromosomal behavior in late mitosis. With this approach we are able to confirm the presence of a centromeric ring which stabilizes the centromeres during the cell cycle and present evidence for a lattice-like sheet of interchromatidic fibers in late mitosis.

Anaphase↗

PubMed1970

Chromosomal aberrations in infective hepatitis.

Structural chromosomal aberrations, in the form of breaks, were found in a significantly higher proportion of bone marrow cells in patients with infective hepatitis than in controls. These anomalies were observed during the first and third weeks after the onset of jaundice but had subsided by the sixth week. Chromosomal aberrations did not appear to be related to the severity of infective hepatitis or to the sex or age of the patients.The distribution of chromosomal abnormalities did not appear to be random; they were observed predominantly in the A(2) and B(4-5) series. Since no abnormalities were detected in the G-group chromosomes, no evidence in support of a relationship between infective hepatitis and Down's syndrome was obtained. Numerical chromosomal aberrations were not observed, nor was any evidence obtained that mitotic activity of bone marrow cells is suppressed in patients with infective hepatitis.

Adolescent↗

PubMed1992

Genomic structure and chromosomal mapping of the mouse N-cadherin gene.

N-cadherin is a member of the cadherin cell-cell adhesion receptor family that includes P-, E-, and R-cadherin and liver cell adhesion molecule (L-CAM). In this study, we determined the structure of the mouse N-cadherin gene by analyzing overlapping genomic clones obtained from a mouse genomic library. This gene consists of 16 exons that disperse over greater than 200 kilobases of genomic DNA. This large size of the N-cadherin gene, compared with its cDNA (4.3 kilobases), is ascribed to the fact that the first and second introns are 34.2 kilobases and greater than 100 kilobases long, respectively. When the N-cadherin gene was compared with that of L-CAM and P-cadherin, the exon-intron boundaries were found to be fully conserved between them, except that the P-cadherin first exon includes the first and second exons of the other two genes. Also, the second intron, which is equivalent to the first intron in P-cadherin, is exceptionally large and this structural feature is conserved in all of these genes. An interesting feature of the N-cadherin gene is that this gene has an extra 16th exon that is almost identical to the other exon, 100% in the coding region and 99% in the 3' untranslated region in the nucleotide level. We also determined the chromosomal localization of the N-cadherin gene by interspecific backcross analysis and found that this gene is localized in the proximal region of mouse chromosome 18. The E- and P-cadherin genes are tightly linked and located on chromosome 8 in this species. Thus, N-cadherin is unlinked to these other cadherin loci.

Amino Acid Sequence↗

PubMedDate not supplied

It's all in the timing: linking S phase to chromatin structure and chromosome dynamics.

Many aspects of chromosome biology are fundamentally linked to events that occur during the DNA synthesis (S) phase of the cell cycle. The DNA must be duplicated once, and once exactly, each S phase. Local chromatin structure must also be re-assembled each S phase to incorporate newly replicated sister chromatids. The replication fork is the one complex that potentially interacts with every nucleotide of the genome, providing a mechanism to couple chromatin assembly to S phase passage. Importantly, eukaryotic genomes contain regions of structurally distinct chromatin, such as heterochromatin, defined by distinct patterns of histone modification and specific protein associations. Heterochromatin is generally associated with repeated sequence elements near centromeres, telomeres and other sites. Evidence suggests that heterochromatin assembled during S phase supports the association of multiprotein complexes required for many chromosome transactions, including transcriptional silencing, sister-chromatid cohesion, and kinetochore function. These complexes are in turn essential for regulated gene expression, equal chromosome segregation and genomic stability. Intriguingly, recent studies indicate that these processes are linked to S phase by temporal mechanisms as well as by replication-dependent activities.

Animals↗

PubMed1997

Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution.

We have cloned a novel member of the matrix metalloproteinase (MMP) family of proteins from a human liver cDNA library. The isolated cDNA contains an open reading frame coding for a polypeptide of 508 amino acids, which has been tentatively called MMP-19. This protein exhibits the domain structure characteristic of previously described MMPs, including a signal sequence, a prodomain with the cysteine residue essential for maintaining the latency of these enzymes, an activation locus with the zinc-binding site, and a COOH-terminal fragment with sequence similarity to hemopexin. However, it lacks a series of structural features distinctive of the diverse MMP subclasses, including the Asp, Tyr, and Gly residues located close to the zinc-binding site in collagenases, the fibronectin-like domain of gelatinases, the transmembrane domain of membrane-type (MT) MMPs, and the furin-activation sequence common to stromelysin-3 and MT-MMPs. In addition, the 9-residue insertion rich in hydrophobic amino acids present at the hinge region in stromelysins is replaced in MMP-19 by a longer insertion very rich in acidic residues. On the basis of these structural characteristics, we propose that MMP-19 does not belong to any of the previously defined MMP-subclasses and may represent the first member of a new MMP subfamily. Chromosomal location of the MMP-19 gene revealed that it maps to chromosome 12q14, which is also a unique location for any MMPs mapped to date. The cDNA encoding a full-length MMP-19 was expressed in Escherichia coli, and after purification and refolding, the recombinant protein was able to degrade synthetic substrates for MMPs. MMP-19 proteolytic activity was abolished by TIMP-2 and EDTA, thus providing additional evidence that the isolated cDNA codes for an authentic MMP. Northern blot analysis of polyadenylated RNAs isolated from a variety of human tissues revealed that MMP-19 is mainly expressed in placenta, lung, pancreas, ovary, spleen, and intestine, suggesting that it may play a specialized role in these tissues.

Amino Acid Sequence↗

PubMed1999

Genomic structure and chromosome mapping of the genes encoding clathrin-associated adaptor medium chains mu1A (Ap1m1) and mu1B (Ap1m2).

The protein mu1B is a member of the medium chain family of the clathrin-associated adaptor complex and is expressed exclusively in epithelial cells. We determined the genomic structure of previously cloned murine genes for mu1B (Ap1m2) and its closely related homolog, mu1A (Ap1m1). Comparison of their genomic structures revealed that the positions of introns are identical between these two genes, except for the insertion of an additional intron in Ap1m1 (intron 4). By contrast, these structures are different from that of the more distantly related Ap2m1 gene encoding mu2. Taken together with the similarity of amino acid sequences among these genes, the data presented in this study suggest that Ap1m1/2 and Ap2m1 diverged long before the separation of Ap1m1 and Ap1m2, which most likely resulted from a relatively recent gene duplication. We also mapped AP1M2 to human chromosome 19p13.2 and Ap1m2 to the proximal region of mouse chromosome 9. The results are consistent with the fact that these regions are syntenic.

Adaptor Protein Complex 1↗

PubMed1990

Structure and chromosomal localization of the human thrombospondin gene.

Thrombospondin (THBS1) is a large modular glycoprotein component of the extracellular matrix and contains a variety of distinct domains, including three repeating subunits (types I, II, and III) that share homology to an assortment of other proteins. Determination of THBS1 gene structure has revealed that the type I repeat modules are encoded by symmetrical exons and that the heparin-binding domain is encoded by a single exon. To further elucidate the higher level organization of THBS1, the gene was localized to the q11-qter region of chromosome 15.

Amino Acid Sequence↗

PubMed2005

Comparative genomics of Gossypium and Arabidopsis: unraveling the consequences of both ancient and recent polyploidy.

Both ancient and recent polyploidy, together with post-polyploidization loss of many duplicated gene copies, complicates angiosperm comparative genomics. To explore an approach by which these challenges might be mitigated, genetic maps of extant diploid and tetraploid cottons (Gossypium spp.) were used to infer the approximate order of 3016 loci along the chromosomes of their hypothetical common ancestor. The inferred Gossypium gene order corresponded more closely than the original maps did to a similarly inferred ancestral gene order predating an independent paleopolyploidization (alpha) in Arabidopsis. At least 59% of the cotton map and 53% of the Arabidopsis transcriptome showed correspondence in multilocus gene arrangements based on one or both of two software packages (CrimeStatII, FISH). Genomic regions in which chromosome structural rearrangement has been rapid (obscuring gene order correspondence) have also been subject to greater divergence of individual gene sequences. About 26%-44% of corresponding regions involved multiple Arabidopsis or cotton chromosomes, in some cases consistent with known, more ancient, duplications. The genomic distributions of multiple-locus probes provided early insight into the consequences for chromosome structure of an ancient large-scale duplication in cotton. Inferences that mitigate the consequences of ancient duplications improve leveraging of genomic information for model organisms in the study of more complex genomes.

Arabidopsis↗

PubMed1994

Preferential pericentric lesions and aneuploidy induced in mouse oocytes by the topoisomerase II inhibitor etoposide.

Etoposide (VP-16) is used as an antineoplastic drug in humans. It inhibits topoisomerase II(topoII) activity by forming a ternary complex (DNA-etoposide-topoII). This complex prevents the DNA-strand rejoining activity of topo II, which results in DNA-strand breaks and the formation of structural chromosome aberrations. Topo II activity is also required for removing regions of DNA catenation prior to chromosome segregation. The possibility exists that patients undergoing etoposide chemotherapy may incur genetic damage and, consequently, may be at a greater risk for developing secondary tumors and having genetically abnormal offspring. We studied the ability of etoposide for inducing both structural chromosome aberrations and aneuploidy in mouse oocytes. Different dosages of etoposide were given to female mice at various times before and after human chronic gonadotrophin injection, and ovulated oocytes were collected 17 h later. The proportions of chromatid acentric fragments and of hyperploid metaphase II oocytes were significantly higher (P < 0.01) in the etoposide groups than in concurrent controls. These results indicate that both structural and numerical aberrations can be induced without direct interaction with DNA or with the various organelles associated with chromosome segregation. Additionally, unlike other compounds (vinblastine, colchicine, benomyl, and griseofulvin) that induce both meiotic delay (ovulated metaphase I oocytes and polyploidy) and aneuploidy, etoposide did not cause meiotic delay in oocyte maturation.

Aneuploidy↗

PubMed2000

Experimental condensation inhibition in constitutive and facultative heterochromatin of mammalian chromosomes.

What drives the dramatic changes in chromosome structure during the cell cycle is one of the oldest questions in genetics. During mitosis, all chromosomes become highly condensed and, as the cell completes mitosis, most of the chromatin decondenses again. Only chromosome regions containing constitutive or facultative heterochromatin remain in a more condensed state throughout interphase. One approach to understanding chromosome condensation is to experimentally induce condensation defects. 5-Azacytidine (5-aza-C) and 5-azadeoxycytidine (5-aza-dC) drastically inhibit condensation in mammalian constitutive heterochromatin, in particular in human chromosomes 1, 9, 15, 16, and Y, as well as in facultative heterochromatin (inactive X chromosome), when incorporated into late-replicating DNA during the last hours of cell culture. The decondensing effects of 5-aza-C analogs, which do not interfere with normal base pairing in substituted duplex DNA, have been correlated with global DNA hypomethylation. In contrast, decondensation of constitutive heterochromatin by incorporation of 5-iododeoxyuridine (IdU) or other non-demethylating base analogs, or binding of AT-specific DNA ligands, such as berenil and Hoechst 33258, may reflect an altered steric configuration of substituted or minor-groove-bound duplex DNA. Consequently, these compounds exert relatively specific effects on certain subsets of AT-rich constitutive heterochromatin, i.e. IdU on human chromosome 9, berenil on human Y, and Hoechst 33258 on mouse chromosomes, which provide high local concentrations of IdU incorporation sites or DNA-ligand-binding sites. None of these non-demethylating compounds affect the inactive X chromosome condensation. Structural features of chromosomes are largely determined by chromosome-associated proteins. In this light, we propose that both DNA hypomethylation and steric alterations in chromosomal DNA may interfere with the binding of specific proteins or multi-protein complexes that are required for chromosome condensation. The association between chromosome condensation defects, genomic instability, and epigenetic reprogramming is discussed. Chromosome condensation may represent a key ancestral mechanism for modulating chromatin structure that has since been realloted to other nuclear processes.

Animals↗

PubMed2003

[cDNA cloning, subcellular localization and tissue expression of a new human Krüppel-like transcription factor: human basic Krüppel-like factor (hBKLF)].

The FLD4585 clone from the cDNA library of human fetal liver may encode a hematopoietic related transcription factor. Here we tried to clone its full-length cDNA from the 22 weeks-gestation human fetal liver and study its functional domains, genomic structure, chromosomal localization, subcellular site and expression pattern. To obtain the full-length cDNA of FLD4585 clone, 5' RACE technique was used. Bioinformatics was used to analyze its genomic structure, chromosomal localization and potential functional domains. Its subcellular localization was shown by GFP fusion technique. The expression pattern was studied by Northern blot, RT-PCR and Western blot. The results show the full-length cDNA encoded by FLD4585 clone is 1810 bp long and encodes a 345 amino acids protein with high homology to mouse BKLF (basic Krüppel-like factor). Its characteristic C-terminal three contiguous C2H2 zinc fingers place it within the family of Krüppel-like factors. Bioinformatics studies show hBKLF gene spans over 33 kb on chromosome 4p15.2-4p16.1 and contains 6 exons and 5 introns. GFP-hBKLF fusion technique showed hBKLF was present in the nuclei of COS-7 cells in a punctate pattern, whereas it was absent in the nucleoli. By Northern blot, hBKLF has two transcripts, one between 4.4 kb-7.5 kb and the other between 1.35 kb-2.4 kb. The larger transcript exists widely in human tissues. However, the smaller transcript was more restricted in blood leukocytes, liver and bone marrow. RT-PCR showed erythrocytes and granulocytes could both express hBKLF and its level increased as they matured. The expression level in fetal liver decreased as it developed towards adult liver and its hematopoietic function gradually lost. Taken together, in this paper we have successfully cloned the full length cDNA of hBKLF. Expression study suggests it may have broad functions in vivo, especially the functions in hematopoietic tissues.

Amino Acid Sequence↗

PubMed2006

Epigenetic instability and chromosomal instability in hepatocellular carcinoma.

The aim of this study was to clarify the association between the epigenetic instability phenotype and the chromosomal instability phenotype in primary hepatocellular carcinoma (HCC). Sixty primary HCC tumors were examined. Methylation status for nine CpG islands (the p16, COX2, GSTP1, RASSF1A, E-cadherin, and APC gene promoters, and the MINT 1, 25, and 31 clones) was evaluated by methylation-specific polymerase chain reaction. Chromosomal structural alterations of these 60 HCC tumors were characterized in our previous study by using whole genomic array-based comparative genomic hybridization. We found that the epigenetic instability phenotype and the chromosomal instability phenotype are not mutually exclusive in hepatocarcinogenesis and that they do not show a simple cause-and-effect relationship. Hepatitis virus infection in the background liver was significantly associated with these instability phenotypes. Furthermore, we identified an epigenetic instability-dependent HCC that shows frequent epigenetic aberrations without chromosomal instability. It was noteworthy that epigenetic instability-positive and -negative HCCs displayed distinctive combinations of chromosomal structural alterations. In summary, by combined analyses of genetic and epigenetic aberration profiles in HCC, we obtained a comprehensive view of genomic alterations in hepatocarcinogenesis. Our results have clinical relevance because epigenetic instability-dependent HCCs may respond well to methylation inhibitory therapies.

Adult↗

PubMedDate not supplied

Structure of chromosomal rearrangements induced by the FB transposable element in Drosophila.

Examination of 10 chromosomal rearrangements induced by foldback transposable elements in Drosophila demonstrates that sequences located between two closely linked elements are frequently deleted. Rearrangement and recombination events occurring within or adjacent to a foldback element are also observed. The type and frequency of rearrangement generated depend on element structure and the organization of flanking DNA.

Alleles↗

PubMed1995

Structure and chromosomal localization of the human anti-müllerian hormone type II receptor gene.

Using the rat anti-müllerian hormone type II receptor (AMHRII) cDNA as a probe, two overlapping lambda phage clones containing the AMHRII gene were isolated from a human genomic library. Sequence analysis of the exons was performed and the exon/intron boundaries were determined. The coding region was found to consist of 11 exons, divided over 8 kb. The genomic structure resembles that of the related activin type II receptor gene. The AMHRII gene was mapped to human chromosome 12q12-q13. The results reported are essential for identification of AMHRII gene alterations in patients with persistent müllerian duct syndrome.

Amino Acid Sequence↗