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A fragile site at the long arms (q21) of chromosome 16 was found in two persons, each of whom became the parent of a child with a de novo structural chromosome abnormality--a balanced autosomal translocation and an autosomal deletion. The question of an increased risk of structural chromosome abnormalities in the offspring of persons with fragile site long arm 16 is discussed.
We have determined the genomic structure of the mouse fra-1 gene, which consists of four exons and three introns at positions also found in the other members of the fos gene family. Fra-1 is expressed rather highly in the brain and testes of adult mice, and at low levels in most other tissues. Absence of c-Fos leads to significantly reduced serum stimulation of fra-1 expression in gene targeted mouse fibroblasts, demonstrating that mitogen induction of fra-1 is partially mediated by c-Fos/AP-1. A polymorphic (CA)n microsatellite marker was found in intron 2 of fra-1 and used to map the gene to the centromeric region of mouse chromosome 19. Since fra-1 maps to the same genomic region as oc (osteosclerosis), an autosomal recessive disorder leading to the bone remodelling disease osteopetrosis, we tested it as a candidate gene for oc. The segregation of fra-1 in two different crosses of mice carrying oc and an allelism test between oc and a targeted disruption of fra-1 demonstrate that fra-1 and oc are two distinct genes rather than oc being a mutant allele of fra-1.
The consumption of bracken fern (Pteridium aquilinum) as food is associated with a high incidence of cancer in humans and animals. We investigated the cytogenetic effects of bracken-fern extracts (hexane extract-HE, ethanol extract-EE, hot water extract-HWE and cold water extract-CWE) on chromosomes of peritoneal and bone-marrow cells of Swiss mice. In peritoneal cells, all four treatments (HE, EE, HWE and CWE) induced structural chromosome aberrations, but the EE also induced numerical chromosome aberrations. In bone-marrow cells both HE and CWE induced structural chromosome aberrations; additionally, the number of abnormal metaphases was higher in peritoneum than in bone marrow. We suggest that bracken fern induces cytogenetic damage through DNA strand breaks and affects chromosome segregation.
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Common fragile sites are regions showing site-specific gaps and breaks on metaphase chromosomes after partial inhibition of DNA synthesis. Common fragile sites are normally stable in somatic cells. However, following treatment of cultured cells with replication inhibitors, fragile sites display gaps, breaks, rearrangements and other features of unstable DNA. Studies showing that fragile sites and associated genes are frequently deleted or rearranged in many cancer cells have clearly demonstrated their importance in genome instability in cancer. Until recently, little was known about the molecular nature and mechanisms involved in fragile site instability. From studies conducted in many laboratories, it is now known that fragile sites extend over large regions, are associated with genes, exhibit delayed replication, and contain regions of high DNA flexibility. Recent findings from our laboratory showing that the key cell cycle checkpoint genes are important for genome stability at fragile sties have shed new light on these mechanisms and on the significance of these sites in cancer and normal chromosome structure. Since their discovery over two decades ago, much has been learned regarding their significance in chromosome structure and instability in cancer, but a number of key questions remain, including why these sites are 'fragile' and the impact of this instability on associated genes in cancer cells. These and other questions have been addressed by participants of this meeting, which highlighted instability at common fragile sites. This brief review is intended to provide background on common fragile sites that has led up to many of the studies presented in the accompanying reports in this volume and not to summarize the findings presented therein. Some aspects of this review were taken from Glover et al. (T.W. Glover, M.F. Arlt, A.M. Casper, S.G. Durkin, Mechanisms of common fragile site instability, Hum. Molec. Genet. 14 (in press). [1]).
Site-1 protease (S1P) is a subtilisin-related enzyme that cleaves sterol regulatory element-binding proteins (SREBPs) in the lumen of endoplasmic reticulum, thereby initiating the release of transcriptionally active NH2-terminal fragments of SREBPs from membranes. In the experiments reported here, we localized the human S1P gene to chromosome 16q24 by fluorescent in situ hybridization and radiation-hybrid mapping, and determined its genomic structure. This gene is more than 60 kb long and contains 23 exons and 22 introns. Its transcription-initiation site within exon 1 is separate from the initiation codon in exon 2. Analysis of the exon/intron structure revealed that the S1P gene consists of a mosaic of functional units: exon 1 encodes the 5' non-translated region; exon 2 encodes the NH2-terminal signal sequence; and exons 2 and 3 encode the pro-peptide sequence that is released when S1P is self-activated by intramolecular cleavage. Exons 5-10 encode the subtilisin-homology domain that is critical for catalytic activity, and exon 23 encodes the transmembrane region. Analysis of the putative promoter region revealed a highly G/C-rich region containing a binding site for ADD1/SREBP-1, as well as Sp1 and AP2 sites. Therefore, expression of the S1P gene may be under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism. Our data establish a basis for investigations to detect molecular variants in this gene that may alter levels of plasma lipoproteins and/or otherwise disrupt intracellular lipid metabolism.
The human cytogenetic assays presently available for biomonitoring are still inadequate for use in routine surveillance procedures and they must be applied with care. Knowledge of the effects of the agents concerned in experimental systems is a prerequisite, and confounding factors should be assessed. Consequently, the methods are useful and informative under carefully selected conditions and can indicate agents and exposures that are capable of causing chromosomal damage in humans, hinting at possible human cancer risk. Established and potential human carcinogens have frequently been shown to induce chromosomal aberrations in humans in vivo. It is also well documented that chromosomal rearrangements play an important role in the development of neoplasia. These combined lines of evidence suggest that structural chromosomal aberration in vivo has advantages over other cytogenetic end-points in predicting potential human cancer risk. Preliminary findings in a prospective follow-up study suggest that subjects with a high percentage of structural chromosomal aberrations but not sister chromatid exchanges may be at elevated risk for cancer.
BACKGROUND: Occupational, environmental, or experimental exposure of people, animals, and cell cultures to radon has been the subject of numerous studies. The present study comprised 120 miners, occupationally exposed to radon and heavy metals in a Pb-Zn mine; 57 female subjects environmentally exposed (control group 1); and 100 subjects from the urban population (control group 2). METHODS: Radon measurements were performed, and the effective equivalent radiation doses over a 2-year period were calculated. The following end points were studied: conventional analysis of structural chromosomal aberrations, micronuclei, and sister chromatid exchanges (SCE). RESULTS: The mean values of the percentage of structural chromosomal aberration frequency were 4.09% in miners, 1.43% in control group 1, and 1.88% in control group 2. The difference in frequencies was statistically significant (AV/FP 0.000). The frequency of micronuclei was 13.00 +/- 3.54 per 500 CB cell in miners and 6.4 +/- 2.11 per 500 CB cells in control subjects (AV/FP 0.000). The frequency of SCE was 7.97 per cell in miners (range 6.2-13.1) and 6.17 and 6.63 for the two control groups, respectively (AV/FP 0.000). CONCLUSIONS: Comparative analysis of the cytogenetic results for all three groups showed significant differences between the miners and the two control groups. The findings of this study need to be interpreted with regard to simultaneous exposure to radon and metals, i.e., lead, cadmium, and zinc.
Mouse leukemia P388 sublines that acquired the resistance to multiple drugs as a result of treatment in vivo with anthracyclines (rubomycin, ruboxyl) and/or vincristine were studied. The mdr gene amplification was found in all tested cell lines: in four of five sublines all three members of the mdr gene family showed increased copy numbers, and in one cell line, developed after treatment with ruboxyl, mdr1a and mdr1b genes were amplified to the same degree, whereas the mdr2 gene was not amplified at all. The levels of amplification of mdr genes varied in different cell lines from 30-fold to 50-fold. Unusual cytological manifestations--relatively large newly formed chromosomelike structures, were revealed in four of five long-term independent sublines. Some of these structures did not contained C blocks; the others, in contrast, were enriched by C-heterochromatin. In situ hybridization showed the presence of mdr genes in newly formed bodies. In the majority of cases, the formation of chromosomelike structures was preceded by the appearance of other, smaller size, structures: the so-called "small chromatin bodies" (minichromosomes) and/or homogeneously G-positive small ring chromosomes.
We analyzed BAC genomic clones encoding the murine coxsackievirus and adenovirus receptor (mCAR). The mCAR gene is situated on the distal portion of murine chromosome 16, and is composed of at least eight exons, with intron-exon boundaries similar to those reported for the human CAR gene. We previously described two cDNAs encoding mCAR isoforms: the extracellular and transmembrane portions of both are encoded by exons 1-6; the cytoplasmic domain of mCAR 1 is encoded by exon 7, whereas mCAR 2 results from an RNA splice linking the proximal portion of exon 7 to an alternative exon 8. RT-PCR analysis of the mCAR RNA 5'-terminus suggests that transcription may begin 141-161 nucleotides upstream of the ATG translational start site.
In 90 patients aged 17 to 35 who suffered from Hodgkin's disease (HD) or had testicular tumors (TT), the location of chromosome and chromatid breaks on individual chromosome segments was reviewed using an adapted Funes-Cravioto scheme, in addition to examining the percentage of structural chromosomal aberrations. On the basis of an analysis of 1121 breaks in patients with HD or TT, the results were presented graphically as multiples of the expected number of breaks for the normal population. Before the beginning of treatment, the number of structural chromosomal aberrations (SCA) in patients with TT or HD was equal to that in a control group of subjects with malignant diseases. This, however, does not apply to the location of chromosome and chromatid breaks. In patients with HD, the dominant unstable sites are located on group A2 chromosomes, segments 2 and 5, and on group B chromosomes, segment 5. In patients with TT, the number of chromosome and chromatid breaks is also increased on group A2 chromosomes, segments 2 and 5, and in addition, also on group B chromosomes, segment 4.
A double-blind study with 170 smokers and 124 non-smokers revealed a doubling of the frequencies of exchange-type aberrations in the peripheral blood lymphocytes of smokers as compared with non-smokers. Smokers (N = 24) had 1 SCE more per metaphase than non-smokers (N = 20), an effect that is significant but low when compared with the effect on structural chromosomal aberrations. These results show that structural chromosomal aberrations are better indicators of the genetical effects of low chronic exposures to mutagens in man than SCEs. The frequencies of micronuclei in 3-day lymphocyte cultures showed no differences in smokers (N = 95) and non-smokers (N = 39). Non-smokers (N = 99) had significantly higher frequencies of 2nd metaphases in 48-h cultures in vitro than smokers (N = 141), indicating an effect of smoking on the stimulation of lymphocytes by PHA in vitro.
The significance of the spatial organization of chromosomes in germline tissue as a positional system controlling segregation in oogenesis is considered. The history of the problem is reviewed. The author's data on reorganization of chromosome structure in germline tissue considered in terms of systemic mutations are systematized. The notion of specific morphogenetic field based on chromosome structure, which controls ooplasmic segregation and subsequent developmental stages, is developed.
OBJECTIVE: To accurately evaluate the incidence of -7/7q- abnormality in acute myeloblastic leukemia (AML) and myelodysplastic syndrome (MDS) patients and investigate the value of fluorescence in situ hybridization (FISH) technique in the detection and identification of -7 and 7q abnormality. METHODS: A FISH assay was performed to analyze 70 AML/MDS patients who had received conventional cytogenetic analysis (CCA). The dual color probes CEP 7 labeled by SpectrumGreen and D7S486 (locus at 7q31) labeled by SpectrumOrange were used. RESULTS: The incidence of -7/7q- in AML and MDS patients was 4.51% (31 out of 687 cases) and 5.71% (28 out of 490 cases), respectively, and was 5.68% and 10.29% in these patients with abnormal karyotype, respectively. The common deletion region of 7q- was 7q21a222 (ten cases) and 7q31-35(ten cases). FISH assay confirmed the -7/7q- aberration in those with clonal -7/7q- abnormalities, but failed in those with random -7/7q- and normal karyotype. In 7q- group, FISH revealed seven of eleven cases with monosomy 7 clone detected in the same specimen, but the numbers of 7q- interphases cells were much greater than those of monosomy 7 cells (average 42.5% vs 8.4%, P=0.025). FISH also provided precise refinement for three chromosomal structural abnormalities associated with 7q seen in CAA, one case with del(7)(q22) being refined as chromosomal translocation, one case with 7q+ being confirmed as dup(7q), and one case with complex translocation involving 7q being also proved to be true. CONCLUSION: FISH is a powerful tool to identify or refine chromosomal structural aberrations involving 7q, and it provides accurate evaluation of -7/7q- in all the patients. -7 and 7q- clone frequently coexist in the same specimen, and the significantly increasing percentage of 7q- cells implies that -7 clone secondary to 7q- clone is a result from loss of 7q-.
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The functional relationship between the transformations of chromosome structure and parallel changes of its major components, i. e. DNA, histones and non-histone proteins (NHP) has been analysed. These changes of chromosome have been checked in the early development, in the highly differentiated undividing cells, in the mitotic and meiotic cells, till the gamete formation. The analysis performed enable us to propose that chromosomal non-histone proteins play the main role in the transformation of chromosome structure, decreasing its genetic activity. NHPs aged without renewal in the undivided nuclei and chromosomes. These proteins take part in the formation of synaptonemal complex (SC) in the early meiotic prophase during chromosome pairing; SC is subsequently eliminated in the diplotene. Thus mature sperms and eggs are characterized by NHP deficiency. NHPs are synthesized de novo in the chromosomes after fertilization providing genetic function of the chromosomes in the development and differentiation of cell systems in new generation of organisms.
The S. cerevisiae MCD1 (mitotic chromosome determinant) gene was identified in genetic screens for genes important for chromosome structure. MCD1 is essential for viability and homologs are found from yeast to humans. Analysis of the mcd1 mutant and cell cycle-dependent expression pattern of Mcd1p suggest that this protein functions in chromosome morphogenesis from S phase through mitosis. The mcd1 mutant is defective in sister chromatid cohesion and chromosome condensation. The physical association between Mcd1p and Smc1p, one of the SMC family of chromosomal proteins, further suggests that Mcd1p functions directly on chromosomes. These data implicate Mcd1p as a nexus between cohesion and condensation. We present a model for mitotic chromosome structure that incorporates this previously unsuspected link.
The gene encoding myosin light chain kinase (MYLK) is duplicated on human chromosome 3 (HSA3; 3p13;3q21) and on a chromosome with conserved synteny to HSA3 in most non-human primate species. In human, the functional copy resides on 3q21, whereas the 3p13 site contains a pseudogene. To trace the origin of the duplication, we characterized the mouse gene Mylk. A single sequence corresponding to the functional Mylk was detected. We sequenced a 180-kb bacterial artificial chromosome clone containing the 24 first exons of Mylk; the complete mouse gene is expected to span >200 kb. Comparisons with the draft of the human genome revealed that the sequence and structure of MYLK are conserved in mammals. Fluorescence in situ hybridization (FISH) analysis indicated that the mouse gene localizes to a single site on chromosome 16B4-B5, a region with conserved synteny with HSA3q. Our study provides information on both the structure and the evolution of MYLK in mammals and suggests that it was duplicated after the divergence of rodents and primates.