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PubMed2003

[Analysis of specific RAPD- and ISSR-fragments in somaclonal maize (Zea mays L.) and development of SCAR markers based on them].

RAPD (Random Amplified Polymorphic DNA) and ISSR (Inter Simple Sequence Repeats) markers were used to analyse the genetic divergence between the regenerated plants derived from callus cultures and the original maize line A188. Analysis of polymorphism by using 38 RAPD- and 10 ISSR-oligonucleotide primers showed that the differences between eight examined somaclones and the original line ranged from 6.5 to 23%. As confirmed using new primers, the regenerants derived from callus cultures grouped into two clusters according to their origin. The regenerants isolated from calluses grown for eight months differed from one another and the original line to a larger extent than the regenerants obtained from two-month callus cultures. In some somaclones, molecular marking of the regenerants revealed specific RAPD and ISSR fragments that were absent in other somaclones or the original maize line. On the basis of six specific fragments (five RAPD and one ISSR), SCAR (Sequence Characterized Amplified Region) markers were developed. Specific polymorphism revealed with random primers was completely confirmed using five SCAR markers. Polymorphism of one SCAR marker differed from that revealed with random primers. Five SCAR fragments were inherited as simple dominant traits. One SCAR fragment displayed codominant inheritance.

Genetic Markers↗

PubMed2004

Homopolymer tract length dependent enrichments in functional regions of 27 eukaryotes and their novel dependence on the organism DNA (G+C)% composition.

BACKGROUND: DNA homopolymer tracts, poly(dA).poly(dT) and poly(dG).poly(dC), are the simplest of simple sequence repeats. Homopolymer tracts have been systematically examined in the coding, intron and flanking regions of a limited number of eukaryotes. As the number of DNA sequences publicly available increases, the representation (over and under) of homopolymer tracts of different lengths in these regions of different genomes can be compared. RESULTS: We carried out a survey of the extent of homopolymer tract over-representation (enrichment) and over-proportional length distribution (above expected length) primarily in the single gene documents, but including some whole chromosomes of 27 eukaryotics across the (G+C)% composition range from 20 - 60%. A total of 5.2 x 10(7) bases from 15,560 cleaned (redundancy removed) sequence documents were analyzed. Calculated frequencies of non-overlapping long homopolymer tracts were found over-represented in non-coding sequences of eukaryotes. Long poly(dA).poly(dT) tracts demonstrated an exponential increase with tract length compared to predicted frequencies. A novel negative slope was observed for all eukaryotes between their (G+C)% composition and the threshold length N where poly(dA).poly(dT) tracts exhibited over-representation and a corresponding positive slope was observed for poly(dG).poly(dC) tracts. Tract size thresholds where over-representation of tracts in different eukaryotes began to occur was between 4 - 11 bp depending upon the organism (G+C)% composition. The higher the GC%, the lower the threshold N value was for poly(dA).poly(dT) tracts, meaning that the over-representation happens at relatively lower tract length in more GC-rich surrounding sequence. We also observed a novel relationship between the highest over-representations, as well as lengths of homopolymer tracts in excess of their random occurrence expected maximum lengths. CONCLUSIONS: We discuss how our novel tract over-representation observations can be accounted for by a few models. A likely model for poly(dA).poly(dT) tract over-representation involves the known insertion into genomes of DNA synthesized from retroviral mRNAs containing 3' polyA tails. A proposed model that can account for a number of our observed results, concerns the origin of the isochore nature of eukaryotic genomes via a non-equilibrium GC% dependent mutation rate mechanism. Our data also suggest that tract lengthening via slip strand replication is not governed by a simple thermodynamic loop energy model.

AT Rich Sequence↗

PubMed1997

Genetic association between monoamine oxidase and manic-depressive illness: comparison of relative risk and haplotype relative risk data.

There have been several conflicting reports of association of monoamine oxidase (MAO) A gene polymorphisms and bipolar affective disorder. In order to determine the possible role of the MAO region in susceptibility to affective disorders in an independent sample, we have genotyped 83 probands of bipolar affective disorder families, 56 sets of parents of bipolar probands, and 84 normal controls for intronic simple sequence repeat polymorphisms of the MAO-A and MAO-B genes. For MAO-A there were no significant differences in allele frequencies between bipolar and normal control groups for both genders. However, for MAO-B there were significant differences between groups for both genders. In contrast, allele-wise haplotype relative risk analysis for the 56 bipolar proband-parent trios found no significant differences between transmitted and non-transmitted allele frequencies for MAO-A or B. These data do not support the association of MAO-A or B with bipolar affective disorder but do demonstrate that undetected population stratification can be an important source of bias in case-control studies.

Alleles↗

PubMed1996

Mutations of the transforming growth factor-beta type II receptor gene are strongly related to sporadic proximal colon carcinomas with microsatellite instability.

BACKGROUND: Mutations of the transforming growth factor-beta type II receptor gene (TGF-beta RII) have been found in several replication error-positive sporadic colorectal carcinomas and hereditary nonpolyposis colorectal carcinoma cell lines. The aim of this study was to clarify the role of TGF-beta RII in sporadic colorectal carcinogenesis. METHODS: The authors screened for mutations at simple repeated sequences in the TGF-beta RII gene by polymerase chain reaction-single strand conformation polymorphism. They also examined genomic instability, using five microsatellite DNA markers in 69 sporadic colorectal carcinomas. When the carcinomas exhibited the TGF-beta RII mutations, the authors screened further for mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. RESULTS: Seven of the 69 cancers (10%) showed one or two A deletions in TGF-beta RII and resultant frameshift mutations in nucleotide positions 709-718 containing a (A) 10 repeated sequence; but none of these appeared in the corresponding normal DNA, indicating a somatic mutation. All of the seven cancers were located in the proximal colon; there were none in the distal colon (P < 0.01). On the other hand, 22 of the 69 carcinomas (32%) showed the replication error-positive phenotype. The frequency of replication errors in proximal colon carcinomas was higher than that in distal colon carcinomas (P < 0.05). All 7 cancers with TGF-beta RII mutations showed replication errors. One of them revealed a nonsense mutation at codon 413, and 1 revealed a loss of heterozygosity in hMSH2. CONCLUSIONS: These data indicate that mutations of TGF-beta RII are strongly related to proximal colon carcinomas with microsatellite instability and that the mechanism of carcinogenesis in some proximal colon carcinomas is similar to that in hereditary nonpolyposis colorectal carcinoma.

Aged↗

PubMed1996

Mutations of the transforming growth factor beta type II receptor gene and microsatellite instability in gastric cancer.

Forty-three sporadic gastric cancers were analyzed with regard to whether mutations of simple repeated sequences in the transforming growth factor beta type II receptor (TbetaR-II) gene are associated with microsatellite instability (MSI) and gastric carcinogenesis. In 12 of the 43 cancers (28%), MSI was observed at least at 1 of the 2 microsatellite loci. Frameshift mutations of the TbetaR-II gene, all of which were 1 base deletion of 10 adenine repeats, were detected in 3 of 6 cancers, with MSI at 2 loci. However, mutations were not detected in 6 cancers, with MSI only at 1 locus and 31 cancers without MSI. Moreover, microanalysis in these cases revealed that the mutant-type alleles of TbetaR-II were invariably common in different areas within the tumor, in contrast to the markedly variable alleles of microsatellite loci. Our results suggest that frameshift mutation of the TbetaR-II gene may be a critical event associated with MSI and may contribute to carcinogenesis of the stomach. One of the possible mechanisms of escape from growth control by TGFbeta during gastric carcinogenesis could involve frameshift mutations of the TbetaR-II gene caused by DNA replication errors.

Adenine↗

PubMed1999

Molecular characteristics of poorly differentiated adenocarcinoma and signet-ring-cell carcinoma of colorectum.

In a series of 45 poorly differentiated adenocarcinomas (por) and 7 signet-ring-cell carcinomas (sig) of the colorectum, K-ras gene mutation, p53 immunostaining and microsatellite instability (MSI) were analyzed for a comparison with 46 cases of colorectal carcinomas of the well or moderately differentiated type (well/mod). In addition, the mutations of simple repeated sequences in the transforming-growth-factor-beta type-II receptor (T beta R-II) gene and the BAX gene were analyzed as possible targets for DNA replication errors. Mutation of the K-ras gene in the por, sig and well/mod specimens was detected in, respectively, 22%, 11% and 48%, positive immunostaining for p53 in 41.8%, 28.6% and 60.3%, and MSI in 36%, 30% and 4%. Frameshift mutation of the T beta R-II gene was detected in 27.5% of the por and none of the sig specimens, while corresponding figures for mutation of the BAX gene were 15.7% and 0%. Significant differences between the por and well/mod tumors were found in the occurrence of K-ras mutation at codons 12 and 13, and MSI. Clinicopathologically, the tumor status of por with MSI was found to significantly correlate with the tumor's location in the proximal colon. In cases without MSI and sig, no frameshift mutation of either the T beta R-II or the BAX gene was found. These results suggest that poorly differentiated and signet-ring-cell carcinomas have a genetic background different from that of well or moderately differentiated carcinomas of the colorectum, and that DNA-replication error is at least partly involved in the carcinogenesis of these specific types of colorectal carcinomas.

Adenocarcinoma↗

PubMed1998

Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours.

The roles of the intrinsic mutation rate and genomic instability in tumorigenesis are currently controversial. In most colorectal tumours, it is generally supposed that the first mutations occur at the adenomatous polyposis coli (APC) locus; APC mutations are thought to provide cells with a selective advantage but have no known effect on the mutation rate. It has also been suggested that genomic instability is the initiating event in colorectal tumorigenesis and, if this is true, mutations of DNA mismatch repair (MMR) genes (or at similar loci) are the most likely candidates. If defective MMR precedes APC mutations, the APC mutations of colon tumours with defective MMR and hence replication errors (RER+) should differ from those of RER- tumours, in at least three specific ways: (1) a higher frequency of allele loss at APC in RER- tumours; (2) more frameshift than nonsense mutations in RER+ tumours; and (3) APC mutations in simple repeat sequences [(N)n, (N1N2)n, or (N1N2N3)n] in RER+ tumours. We found no evidence that sporadic RER+ and RER- colon cancers (including cell lines) differ in any of these three ways. Although it remains possible that MMR is abnormal in tumours from HNPCC families before APC mutations occur, it is likely that in sporadic colon tumours, APC mutations, rather than genomic instability, are the initiating events in tumorigenesis.

Alleles↗

PubMed1996

Allelotypic and cytogenetic characterization of chemically induced mouse mammary tumors: high frequency of chromosome 4 loss of heterozygosity at advanced stages of progression.

Loss of heterozygosity (LOH) is one of the most common genetic abnormalities in cancer. To define the role of LOH and chromosomal abnormalities at various stages of mouse mammary cancer progression, we analyzed the allelotypes and karyotypes of primary mammary tumors induced in CD2F, mice by two basic protocols, the classical multiple-dose 7,12-dimethylbenz[a]anthracene (DMBA) protocol and a novel protocol of combined medroxyprogesterone acetate (MPA) and DMBA. The advantage of the latter protocol is that its latency for tumor development is much shorter and its tumor incidence is higher than those of DMBA alone. To study more advanced stages of mammary tumor progression, we also analyzed mouse mammary tumors that had acquired autonomous growth and were transplantable into syngeneic hosts. The allelotypic studies were performed by means of microsatellite length polymorphism analysis with a minimum of two simple-sequence repeat markers per chromosome. We observed that MPA-DMBA-induced mammary adenocarcinomas, which in general arose earlier because of the growth promotion exerted by MPA, did not show any significant LOH and were essentially diploid. Tumors induced by DMBA alone, which on average took longer to develop, showed a higher frequency of allelic losses. LOH on chromosome 11 was observed in 30% of the cases. Chromosomes 4 and 8 were affected in 25% and 20% of the tumors, respectively. Interestingly, advanced stages of mammary tumor progression, represented by transplantable mammary tumors, showed a much higher level of genomic instability, specifically a very high frequency (66%) of LOH on chromosome 4. These findings indicate that chromosome 4 harbors a gene whose inactivation may play a role in the acquisition of more aggressive characteristics such as autonomous growth and transplantation ability.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1999

Circular dichroism spectroscopy analysis of conformational transitions of a 54 base pair DNA duplex composed of alternating CGCGCG and TATATA blocks.

CD spectroscopy was used to analyze conformational properties of a self-complementary 54-mer DNA composed of alternating (CG)3 and (TA)3 hexamers. NaCl induced the Z-form in poly(GC), but the 54-mer remained the B-form under the same conditions. The B-Z transition was induced only after the addition of NiCl2. However, the Z-form was adopted by the whole molecule, not by the (CG)3 blocks alone. Two orders of magnitude higher concentrations of NiCl2 were required to induce the Z-form in poly(AT). The Z-form was also induced in poly(GC) by CsF that switched poly(AT) into the X-form, which seems to be a solution counterpart of D-DNA. Under these conditions the CD spectrum of the 54-mer was consistent with the (TA)3 blocks being in the X-form and the (CG)3 blocks in the B-form. At high concentrations of ethanol or trifluoroethanol, poly(AT) was an A-form, while poly(GC) adopted either Z-form, A-form or Z'-form. At the high trifluoroethanol concentrations the 54-mer cooperatively switched into a conformation whose CD spectrum was most consistent with the A-form in the (TA)3 blocks and the Z'-form in the (CG)3 blocks. This suggests that the base pairs are tilted in the Z'-form as in the A-form. The present article illustrates that CD spectroscopy can provide interesting pieces of information about conformational isomerizations and coexistence of multiple conformations in DNA molecules containing blocks of different simple sequence repeats.

Base Pairing↗

PubMed2001

No evidence for BCL10 mutation in endometrial cancers with microsatellite instability.

Previous reports have suggested that the mononucleotide repeats in BCL10 frequently are mutated in both hematologic malignancies and solid tumors. We set out to determine whether these repeats, like simple repeat sequences in other genes, are a target for mutation in endometrial cancers with defective DNA mismatch repair. Primary endometrial cancers (n = 42) and endometrial cancer cell lines (n=5) with microsatellite instability (MSI) were investigated. BCL10 exons 2 and 3 were amplified by PCR and evaluated for mutation using denaturing high-performance liquid chromatography (DHPLC) and single stand conformational variant (SSCV) analysis. Variants were directly sequenced. No BCL10 mutations were detected in exons 2 or 3 by DHPLC or SSCV. A polymorphism in exon 3 (638G-->A) was seen in 4/42 (9.5%) MSI-positive endometrial cancers and 0/5 MSI-positive endometrial cancer cell lines. Thus, mutation in the mononucleotide repeat tracts of BCL10 is not a feature of endometrial cancers with defective DNA mismatch repair.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Somatic Apc mutations are selected upon their capacity to inactivate the beta-catenin downregulating activity.

The APC gene, originally identified as the gene for familial adenomatous polyposis (FAP), is now considered as the true "gatekeeper" of colonic epithelial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular beta-catenin signaling. Most somatic APC mutations are detected between codons 1286 and 1513, the mutation cluster region (MCR). This clustering can be explained either by the presence of mutation-prone sequences within the MCR, or by the selective advantage provided by the resulting truncated polypeptides. Here, a Msh2-deficient mouse model (Msh2(delta 7N) ) was generated and bred with Apc(1638N) and Apc(Min) that allowed the comparison of the somatic mutation spectra along the Apc gene in the different allelic combinations. Mutations identified in Msh2(delta 7N/delta 7N) tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Apc polypeptides that partially retain the 20 a.a. beta-catenin downregulating motifs. In contrast, the somatic mutations identified in the wild type Apc allele of Msh2(delta 7N/delta 7N) /Apc(+/1638N) and Msh2(delta 7N/delta 7N) /Apc(+/Min) tumors are clustered more to the 5' end, thereby completely inactivating the beta-catenin downregulating activity of APC. These results indicate that somatic Apc mutations are selected during intestinal tumorigenesis and that inactivation of the beta-catenin downregulating function of APC is likely to represent the main selective factor.

Adenomatous Polyposis Coli↗

PubMed1994

Genomic scan for genes predisposing to schizophrenia.

We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than -2.0 at theta = 0.0, 101 DNA markers gave lod scores less than -2.0 at theta = 0.05, while 5 DNA loci produced maximum lod scores greater than 1: D4S35, D14S17, D15S1, D22S84, and D22S55. Of the DNA markers yielding lod scores greater than 1, D4S35 and D22S55 also were suggestive of linkage when the Affected-Pedigree-Member method was used. The families were then genotyped with four highly polymorphic simple sequence repeat markers; possible linkage diminished with DNA markers mapping nearby D4S35, while suggestive evidence of linkage remained with loci in the region of D22S55. Although follow-up investigation of these chromosomal regions may be warranted, our linkage results should be viewed as preliminary observations, as 35 unaffected persons are not past the age of risk.

Adolescent↗

PubMed1995

Polymerase chain reaction-based assays for the characterisation of plant genetic resources.

Plant genetic resources are an important component of biodiversity and provide the basic genetic variability that allow new and improved cultivars to be developed. Numerous germplasm collections have been established and it is important to established that such collections are representative and accessible to breeders and biotechnologists. Molecular markers provide the best estimate of genetic diversity since they are independent of the confounding effects of environmental factors. Assays based on the polymerase chain reaction (PCR) are considered to meet both the technical and genetical requirements for the characterisation of plant and animal genetic resources. Two main approaches are described, based on anonymous and defined primers. The use of both randomly amplified polymorphic DNA (RAPD) and microsatellites or simple sequence repeats (SSR) for the characterisation of perennial tree species, and distribution of variability within gene pools is reported. The detection of interspecific gene introgression between coffee species with RAPD markers is described together with the use of microsatellites to genotype potato. The use of PCR-based assays will facilitate the evaluation and utilisation of plant genetic resources.

Base Sequence↗

PubMed1998

Nonradioactive sequence-tagged microsatellite site analyses: a method transferable to the tropics.

Utilization of existing isozyme analysis facilities to detect sequence-tagged microsatellite site (STMS) polymorphism or any simple sequence repeat (SSR) variation is described. Different parameters concerning the difficulties in transferring molecular techniques to less sophisticated laboratory infrastructures (i.e. tropical outstations) are discussed (e.g. reproducibility, efficacy, precision). Nonradioactive STMS analysis is bound to foster collaborative research between "biodiversity" and "biotechnology" centers.

Base Sequence↗

PubMed2003

Loss of heterozygosity analysis of mouse pulmonary adenomas induced by coal tar.

Manufactured gas plant (MGP) residues, commonly known as coal tars, were generated several decades ago as a byproduct of residential and industrial gas production from the distillation of coal. Previous short-term exposure studies have shown MGP residues to be tumorigenic in mouse liver and lung. In order to gain further insight into carcinogenesis by complex mixtures of environmental chemicals containing known carcinogenic polycyclic aromatic hydrocarbons, we investigated mouse pulmonary tumors for loss of heterozygosity (LOH) as a result of multiple exposure to MGP residues. Twenty mouse lung adenomas produced in (C57BL/6 x C3H)F1 hybrid mice and manually microdissected were selected to examine genome-wide allelic losses at 58 microsatellite loci. Regions of chromosomes 1, 4, 5, 8, and 11 were affected in 30-40% of tumors. The elevated rates of allelic imbalance in these chromosomes may indicate the location of unknown tumor suppressor genes significant to neoplastic transformation in mouse lung tissues. Laser capture microdissection-based LOH analysis of pulmonary adenomas showed that contamination of nonneoplastic tissues was not masking the allelic losses in the manually microdissected tumor analysis. The low frequency of chromosome instability in these tumors, measured by means of inter-simple sequence repeat PCR, suggests the presence of discrete regions of LOH instead of extensive structural rearrangements.

Adenoma↗

PubMed2006

Functional polymorphisms in dopamine and serotonin pathway genes.

There is mounting evidence on the functional significance of single nucleotide and simple repeat sequence polymorphisms in both the coding and regulatory regions of genes in the monoamine neurotransmitter pathways. Many of these gene variants have been associated with human behavioral disorders and traits, and thus have important clinical relevance. This review summarizes the literature on the published functional studies from a molecular, cellular, and neurobiological perspective, and notes their possible behavioral consequences. Functional studies have adopted a variety of strategies. Pharmacological studies have focused on the effects of gene variation at the protein level in terms of binding to ligands or drugs. Other key investigations have determined effects on gene expression at the level of transcription in mammalian cell cultures, lymphoblasts, and/or human postmortem brain tissue. This has enabled the comparison of in vitro and in vivo data, and furthermore provides an improved perceptive of their respective advantages. Additionally, molecular biological approaches have identified transcription factors (DNA-binding proteins) that interact with the motifs within the polymorphisms themselves. Various neuroimaging studies have further determined the relationship of genotype with protein availability in the brain, and thus have contributed to our understanding of the in vivo functional significance of gene variants. Finally, there is growing evidence from both human and animal studies on the interaction of functional polymorphisms with the environment in determining a behavioral outcome. Taken together, these findings have contributed to a greater understanding of the plausible molecular mechanisms that underpin the functional significance of polymorphisms in monoamine neurotransmitter pathway genes, and how they may influence behavioral phenotypes.

Animals↗

PubMed2001

Microsatellite instability in squamous cell carcinoma of head and neck from the Indian patient population.

Genomic instability in simple repeated sequences has been observed in several human cancers. We have analyzed 50 squamous cell carcinomas of the head and neck (SCCHN) and 5 pre-malignant severe dysplastic tissues from Indian patient populations for microsatellite instability in 18 different loci spread over eight different chromosomes. Among the tumors analyzed, 45% exhibited instability at two or more loci, and 15% exhibited instability at 40% of the markers tested. Similar analysis of SCCHN tumors from other populations (British, American and French) showed much less frequency of instability. SCCHN tumors in the present study did not show any instability in the mononucleotide repeat sequences. There is also a clear distinction in the nature of the instability in these tumors in comparison with colorectal tumors. These results suggest that the underlying mechanism generating this type of instability is different from those reported for colorectal tumors.

Adult↗

PubMed2007

The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer.

We investigated the relationships between genetic factors and clinical outcome in Japanese non-small-cell lung cancer (NSCLC) patients treated with gefitinib. Ninety-eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18-21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA-SSR1) and single nucleotide polymorphisms in the promoter region (-216G/T and -191C/A), using a PCR-based assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug-sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p = 0.0002), the overall survival (OS) (p = 0.0036), and prolonged progression-free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA-SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug-sensitive EGFR mutation, although this difference was not significant (p = 0.13). Thus, drug-sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib-treated Japanese patients with NSCLC. Our findings also suggest that the CA-SSR1 length may influence the clinical outcome in patients with a drug-sensitive EGFR mutation.

Aged↗