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PubMedDate not supplied

Microsatellite marker development and analysis in the eastern oyster (Crassostrea virginica): confirmation of null alleles and non-Mendelian segregation ratios.

Eighteen microsatellite markers were developed for the Crassostrea virginica nuclear genome, including di-, tri-, and tetranucleotide microsatellite repeat regions that included perfect, imperfect, and compound repeat sequences. A reference panel with DNA from the parents and four progeny of 10 full-sib families was used for a preliminary confirmation of polymorphism at these loci and indications of null alleles. Null alleles were discovered at three loci; in two instances, primer redesign enabled their amplification. Two to five representative alleles from each locus were sequenced to ensure that the targeted loci were amplifying. The sequence analysis revealed not only variation in the number of simple sequence repeat units, but also polymorphisms in the microsatellite flanking regions. A total of 3626 bp of combined microsatellite flanking region from the 18 loci was examined, revealing indels as well as nucleotide site substitutions. Overall, 16 indels and 146 substitutions were found with an average of 4.5% polymorphism across all loci. Eight markers were tested on the parents and 39-61 progeny from each of four families for examination of allelic inheritance patterns and genotypic ratios. Twenty-six tests of segregation ratios revealed eight significant departures from expected Mendelian ratios, three of which remained significant after correction for multiple tests. Deviations were observed in both the directions of heterozygote excess and deficiency.

Alleles↗

PubMed1994

Exchange kinetics of individual amide protons in 15N-labeled helical peptides measured by isotope-edited NMR.

Amide proton exchange measured by one-dimensional 15N-edited proton NMR has been used to probe helical structure in an alanine-based peptide. This study is the first report of individual peptide NH exchange rates determined in a simple, repeating sequence peptide whose helical structure can be predicted by helix-coil theory. Measured protection factors directly demonstrate that the ends of the helix are frayed. The protection factors are compared to the Lifson-Roig theory, modified to include N-capping, using known values for helix propensities and N-cap propensities. Base-catalyzed exchange rates are shown to measure the extent of hydrogen bonding of the peptide NHs, and the results are fitted by a simple model in which hydrogen bonding of the peptide NH group provides protection and no exchange occurs from the hydrogen-bonded state. Protection from acid-catalyzed exchange correlates with hydrogen bonding by both the NH and CO groups of a peptide unit: the data are fitted by a model in which exchange occurs only when both hydrogen bonds formed by a peptide unit are broken. This result indicates that acid-catalyzed exchange occurs by the O-protonation mechanism, in agreement with earlier work [Perrin & Arrhenius (1982) J. Am. Chem. Soc. 104, 6693-6696; Perrin et al. (1984) J. Am. Chem. Soc. 106, 2749-2753; Tüchsen & Woodward (1985) J. Mol. Biol. 185, 421-430].

Amides↗

PubMed1995

RNA template requirements for target DNA-primed reverse transcription by the R2 retrotransposable element.

R2 is a non-long terminal repeat-retrotransposable element that inserts specifically in the 28S rRNA gene of most insects. The single protein encoded by R2 has been shown to contain both site-specific endonuclease and reverse transcriptase activities. Integration of the element involves cleavage of one strand of the 28S target DNA and the utilization of the exposed 3' hydroxyl group to prime the reverse transcription of the R2 RNA transcript. We have characterized the RNA requirement of this target DNA-primed reverse transcription reaction and found that the 250 nucleotides corresponding to the 3' untranslated region of the R2 transcript were necessary and sufficient for the reaction. To investigate the sequence requirements at the site of reverse transcription initiation, a series of RNA templates that contained substitutions and deletions at the extreme 3' end of the RNA were tested. The R2 templates used most efficiently had 3' ends which corresponded to the precise boundary of the R2 element with the 28S gene found in vivo. Transcripts containing short polyadenylated tails (8 nucleotides) were not utilized efficiently. R2 RNAs that were truncated at their 3' ends by 3 to 6 nucleotides were used less efficiently as templates and then only after the R2 reverse transcriptase had added extra, apparently nontemplated, nucleotides to the target DNA. The ability of the reverse transcriptase to add additional nucleotides to the target DNA before engaging the RNA template might be a mechanism for the generation of poly(A) or simple repeat sequences found at the 3' end of most non-long terminal repeat-retrotransposable elements.

Animals↗

PubMed2000

Hairpins involving both inverted and direct repeats are associated with homoplasious indels in non-coding chloroplast DNA of Taraxacum (Lactuceae: Asteraceae).

Sequence variation in 2.2 kb of non-coding regions of the chloroplast genome of eight dandelions (Taraxacum: Lactuceae) from Asia and Europe is interpreted in the light of the phylogenetic signal of base substitutions vs. indels (insertions-deletions). The four non-coding regions displayed a total of approximately 30 structural mutations of which 9 are potentially phylogenetically informative. Insertions, deletions, and an inversion were found that involved consecutive stretches of up to 172 bases. When compared to phylogenetic relationships of the chloroplast genomes based on nucleotide substitutions only, many homoplasious indels (33%) were detected that differed considerably in length and did not comprise simple sequence repeats typically associated with replication slippage. Though many indels in the intergenic spacers were associated with direct repeats, frequently, the variable stretches participated in inverted repeat stabilized hairpins. In each intergenic spacer or intron examined, nucleotide stretches ranging from 30 to 60 bp were able to fold into stabilized secondary structures. When these indels were homoplasious, they always ranked among the most stabilized hairpins in the non-coding regions. The association of higher order structures that involve both classes of repeats and parallel structural mutations in hot spot regions of the chloroplast genome can be used to differentiate among mutations that differ in phylogenetic reliability.

Asteraceae↗

PubMed2003

Use of transcriptional sequencing in difficult to read areas of the genome.

In genome and cDNA sequencing projects, current cycle sequencing often encounters difficult-to-sequence templates which have unique secondary structures due to GC-rich composition or repeated regions. Due to the formation of stable secondary structures, remarkable decreases in fluorescent signals are observed in cycle sequencing reactions. It is not easy to determine the nucleotide sequences of these regions. Although several modifications of sequencing reactions have been tried to overcome these problems, some unreadable regions remain as gaps in genome sequencing projects. Here, we further developed transcriptional sequencing technology and evaluated the sequencing accuracy in these regions. The method was successively applied to artificial GC cluster templates and putative secondary structure-forming templates from genomic and cDNA clones. Our results indicate that transcriptional sequencing is a powerful and accurate method for GC-rich regions, simple sequence repeats, hairpins (inverted repeats), tandem repeat DNA templates, and gap-closing in draft sequencing data.

Animals↗

PubMedDate not supplied

Characterization of microsatellites in Bambusa arundinacea and cross species amplification in other bamboos.

Microsatellites, tandem repeats of short nucleotide (1-6 bp) sequences, are the DNA marker of choice because of their highly polymorphic, ubiquitous distribution within genome, ease of genotyping through polymerase chain reaction (PCR), selectively neutral, co-dominant and multi allelic nature. Six microsatellites, three polymorphic and three monomorphic, have been characterized for the first time in a bamboo species, Bambusa arudinacea belonging to the family Poaceae. The number of alleles per locus ranges form 2 to 13. Allelic diversity ranges from 0.041 to 0.870. Polymorphic information content (PIC) values for two loci were > 0.3, an indicator of polymorphic allele. Cross species amplification has been tested in other 18 bamboo species. Monomorphic simple sequence repeats (SSRs) have been found to be cross amplified in most of the tested species while polymorphic ones in only three to four species. The utility of the SSR loci in genetic diversity study of B. arundinacea and other cross amplified bamboo species have been discussed.

Bambusa↗

PubMed2002

Sequence complexity profiles of prokaryotic genomic sequences: a fast algorithm for calculating linguistic complexity.

MOTIVATION: One of the major features of genomic DNA sequences, distinguishing them from texts in most spoken or artificial languages, is their high repetitiveness. Variation in the repetitiveness of genomic texts reflects the presence and density of different biologically important messages. Thus, deviation from an expected number of repeats in both directions indicates a possible presence of a biological signal. Linguistic complexity corresponds to repetitiveness of a genomic text, and potential regulatory sites may be discovered through construction of typical patterns of complexity distribution. RESULTS: We developed software for fast calculation of linguistic sequence complexity of DNA sequences. Our program utilizes suffix trees to compute the number of subwords present in genomic sequences, thereby allowing calculation of linguistic complexity in time linear in genome size. The measure of linguistic complexity was applied to the complete genome of Haemophilus influenzae. Maps of complexity along the entire genome were obtained using sliding windows of 40, 100, and 2000 nucleotides. This approach provided an efficient way to detect simple sequence repeats in this genome. In addition, local profiles of complexity distribution around the starts of translation were constructed for 21 complete prokaryotic genomes. We hypothesize that complexity profiles correspond to evolutionary relationships between organisms. We found principal differences in profiles of the GC-rich and other (non-GC-rich) genomes. We also found characteristic differences in profiles of AT genomes, which probably reflect individual species variations in translational regulation. AVAILABILITY: The program is available upon request from Alexander Bolshoy or at http://csweb.haifa.ac.il/library/#complex.

Algorithms↗

PubMed2002

Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.

The serotonin transporter gene (SLC6A4, MIM 182138) is a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR.

Autistic Disorder↗

PubMed1996

Charcot-Marie-Tooth disease type 1A: a family study with microsatellites.

Charcot-Marie-Tooth (CMT) disease (also called Hereditary Motor and Sensory Neuropathy) is an inherited peripheral neuropathy with a prevalence rate of 1 in 2,500. Charcot-Marie-Tooth disease type 1A (CMT1A), the most common autosomal dominant form of the disease, is associated with a duplication of a segment of chromosome 17 (17p11.2). In this report we present a three-generation family with CMT1A where simple sequence repeats (di- or tri-nucleotide repeats, also called microsatellites) were used in conjunction with polymerase chain reaction (PCR) to identify the duplication. The presence of three alleles or the presence of two alleles with a dosage ratio of 1:2 for the markers D17S839 and D17S921 indicates the presence of the duplicated segment in affected family members, whereas two alleles with a ratio of 1:1 indicate absence of the duplication. Several markers outside the duplication region which have two alleles with a dosage ratio of 1:1 were used as controls. Seven CMT1A patients in this family carry the CMT1A duplication. One 12-year-old boy who has not exhibited any clinical symptoms does not have the CMT1A duplication. We believe that this is a simple, rapid, and effective method to identify the CMT1A duplication in most patients suspected of having CMT1A.

Adult↗

PubMed2004

Complete chloroplast genome sequences from Korean ginseng (Panax schinseng Nees) and comparative analysis of sequence evolution among 17 vascular plants.

The nucleotide sequence of Korean ginseng (Panax schinseng Nees) chloroplast genome has been completed (AY582139). The circular double-stranded DNA, which consists of 156,318 bp, contains a pair of inverted repeat regions (IRa and IRb) with 26,071 bp each, which are separated by small and large single copy regions of 86,106 bp and 18,070 bp, respectively. The inverted repeat region is further extended into a large single copy region which includes the 5' parts of the rpsl9 gene. Four short inversions associated with short palindromic sequences that form stem-loop structures were also observed in the chloroplast genome of P. schinseng compared to that of Nicotiana tabacum. The genome content and the relative positions of 114 genes (75 peptide-encoding genes, 30 tRNA genes, 4 rRNA genes, and 5 conserved open reading frames [ycfs]), however, are identical with the chloroplast DNA of N. tabacum. Sixteen genes contain one intron while two genes have two introns. Of these introns, only one (trnL-UAA) belongs to the self-splicing group I; all remaining introns have the characteristics of six domains belonging to group II. Eighteen simple sequence repeats have been identified from the chloroplast genome of Korean ginseng. Several of these SSR loci show infra-specific variations. A detailed comparison of 17 known completed chloroplast genomes from the vascular plants allowed the identification of evolutionary modes of coding segments and intron sequences, as well as the evaluation of the phylogenetic utilities of chloroplast genes. Furthermore, through the detailed comparisons of several chloroplast genomes, evolutionary hotspots predominated by the inversion end points, indel mutation events, and high frequencies of base substitutions were identified. Large-sized indels were often associated with direct repeats at the end of the sequences facilitating intra-molecular recombination.

Base Sequence↗

PubMed2001

Mapping genetic factors affecting the reaction to Xanthomonas axonopodis pv. phaseoli in Phaseolus vulgaris L. under field conditions.

The objectives of the present study were to evaluate the field effects of Xanthomonas axonopodis pv. phaseoli (Xap), which causes common bacterial blight (CBB) on common bean (Phaseolus vulgaris L.), and to identify genetic factors for resistance to CBB using a linkage map constructed with random amplified polymorphic DNA (RAPD), restriction fragment length polymorphism (RFLP), simple sequence repeat (SSR), and amplified fragment length polymorphism (AFLP) markers. One hundred and forty-two F2:4 lines, derived from a cross between 'OAC Seaforth' and 'OAC 95-4', and the parents were evaluated for their field reaction to CBB. In the inoculated plots, the reaction to CBB was negatively correlated with seed yield, days to maturity, plant height, hypocotyl diameter, pods per plant, and harvest index. A reduction in seed yield and its components was observed when disease-free and CBB-inoculated plots were compared. The broad-sense heritability estimate of the reaction to CBB was 0.74. The disease segregation ratio was not significantly different from the expected segregation ratio for a single locus in an F2 generation. The major gene for CBB resistance was localized on linkage group (LG) G5. A simple interval mapping procedure identified three genomic regions associated with the reaction to CBB. One quantitative trait loci (QTL), each on LG G2 (BNG71Dra1), G3 (BNG21EcoRV), and G5 (PHVPVPK-1) explained 36.3%, 10.2%, and 42.2% of the phenotypic variation for the reaction to CBB, respectively. Together, these loci explained 68.4% of the phenotypic variation. The relative positions of these QTL on the core common bean map and their comparison with the previous QTL for CBB resistance are discussed.

Chromosome Mapping↗

PubMed1987

Structure of the major block of alphoid satellite DNA on the human Y chromosome.

Alphoid DNA is a family of tandemly repeated simple sequences found mainly at the centromeres of the chromosomes of many primates. This paper describes the structure of the alphoid DNA at the centromere of the human Y chromosome. We have used pulsedfield gradient gel electrophoresis, cosmid cloning and DNA sequencing to determine the organization of the alphoid DNA on each of the Y chromosomes present in two somatic cell hybrids. In each case there is a single major block of alphoid DNA. This is approximately 470,000 bases (475 kb) long on one chromosome and approximately 575 kb long on the other. Apart from the size difference, the structures of the two blocks and the surrounding sequences are very similar. However, one restriction enzyme, AvaII, detects two clusters of sites within one block but does not cleave the other. The alphoid DNA within each block is organized into tandemly repeating units, most of which are about 5.7 kb long. A few variant units present on one chromosome are about 6.0 kb long. These variants, like the AvaII site variants, are clustered. The 5.7 kb and 6.0 kb units themselves consist of tandemly repeating 170 base-pair subunits. The 6.0 kb unit has two more of these subunits than the 5.7 kb unit. Our results provide a basis for further structural analysis of the human Y chromosome centromeric region, and suggest that long-range structural polymorphisms of tandemly repeated sequence families may be frequent.

Base Sequence↗

PubMed2003

Identification of putative QTL that underlie yield in interspecific soybean backcross populations.

Glycine soja, the wild progenitor of soybean, is a potential source of useful genetic variation in soybean improvement. The objective of our study was to map quantitative trait loci (QTL) from G. soja that could improve the crop. Five populations of BC(2)F(4)-derived lines were developed using the Glycine max cultivar IA2008 as a recurrent parent and the G. soja plant introduction (PI) 468916 as a donor parent. There were between 57 and 112 BC(2)F(4)-derived lines in each population and a total of 468 lines for the five populations. The lines were evaluated with simple sequence repeat markers and in field tests for yield, maturity, plant height, and lodging. The field testing was done over 2 years and at two locations each year. Marker data were analyzed for linkage and combined with field data to identify QTL. Using an experimentwise significance threshold of P=0.05, four yield QTL were identified across environments on linkage groups C2, E, K, and M. For these yield QTL, the IA2008 marker allele was associated with significantly greater yield than the marker allele from G. soja. In addition, one lodging QTL, four maturity QTL, and five QTL for plant height were identified across environments. Of the 14 QTL identified, eight mapped to regions where QTL with similar effects were previously mapped. Many regions carrying the yield QTL were also significant for other traits, such as plant height and lodging. When the significance threshold was reduced and the data were analyzed with simple linear regression, four QTL with a positive allele for yield from G. soja were mapped. One epistatic interaction between two genetic regions was identified for yield using an experimentwise significance threshold of P=0.05. Additional research is needed to establish whether multiple trait associations are the result of pleiotropy or genetic linkage and to retest QTL with a positive effect from G. soja.

Analysis of Variance↗

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↗