Chemical and antiviral properties of the somatic antigens of Phase II Sh. sonnei and of a phage-resistant variant, II/3, 4, 7.
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Antibodies↗
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Structural organization of the meiotic prophase chromatin in the rat testis.
Pachytene nuclei were isolated from rat testes by the unit gravity sedimentation technique and contained histone variants H1a, H1t, TH2A, TH2B, and X2 in addition to the somatic histones H1bde, H1c, H2A, H2B, H3, and H4. The basic organization of the pachytene chromatin namely the nucleosome repeat length and the accessibility to micrococcal nuclease, was similar to that of rat liver interphase chromatin. However, when digested by DNase I, the susceptibility of pachytene chromatin was 25% more than liver chromatin under identical conditions. Nucleosome core particles were isolated from both liver and pachytene nuclei and were characterized for their DNA length and integrity of the nucleoprotein on low ionic strength nucleoprotein gels. While liver core particles contained all the somatic histones H2A, H2B, H3, and H4, in the pachytene core particles, histone variants TH2A, X2, and TH2B had replaced nearly 60% of the respective somatic histones. A comparison of the circular dichroism spectra obtained for pachytene and liver core particles indicated that the pachytene core particles were less compact than the liver core particles. Studies on the thermal denaturation properties of the two types of core particles revealed that the fraction of the pachytene core DNA melting at the premelting temperature region of 55-60 degrees C was significantly higher than that of the liver core DNA.
Animals↗
TSC angiofibroma and ungual fibroma have different mutation signatures, with recurrent mutations in KMT2C.
PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome characterized by tumors affecting multiple tissues, including skin, due to inactivating TSC1/TSC2 variants. Genome-wide profiling of somatic mutations in a unique collection of angiofibroma (FAF) and ungual fibroma (UF) TSC skin tumors was performed. METHODS: Genome sequencing was performed on 9 samples, comprising 4 FAF and 5 UF, along with 6 matched normal samples from 6 individuals with TSC. RESULTS: TSC-FAF and TSC-UF skin tumors have different mutation signatures, with a predominance of UV-related single-nucleotide variant (SNV; SBS7a and SBS7b) and dinucleotide variant (DNV; DBS1) signatures in FAF, and aging-related SNV (SBS1 and SBS5) signatures in UF. We also identified a novel DNV signature for TSC-UF, with frequent TG>CA and TT>GG substitutions. Furthermore, 3 inactivating somatic mutations in KMT2C were observed in 2 of 4 TSC-FAF and 5 mutations in other cancer genes. CONCLUSION: The distinct SNV mutation signatures seen in TSC-FAF and UF indicate that they develop through distinct pathogenic mechanisms, UV-induced mutagenesis in FAF, and aging-related mutagenesis in UF. The mechanism of the novel DNV signature in UFs merits further investigation. Our observation on the occurrence of KMT2C mutations suggests that KMT2C inactivation contributes to the pathogenesis of TSC-FAF.
Humans↗
Antigenic relationships among the proteolytic and nonproteolytic strains of Clostridium botulinum.
Relationships of the somatic antigens among Clostridium botulinum strains have been investigated by tube agglutination and agglutinin absorption tests. Results revealed a relationship by which strains of C. botulinum are grouped by their proteolytic capacity rather than by the type of specific toxin produced. Thus, C. botulinum type E and its nontoxigenic variants, which are nonproteolytic, share common somatic antigens with the nonproteolytic strains of types B and F. Absorption of antiserum of a strain of any one type with antigen of any of the others removes the antibody to all three types. In the same manner, C. botulinum type A shares somatic antigens with the proteolytic strains of types B and F, and absorption of any one antiserum with an antigen of either of the other two types removes the antibody to all three types. Partial cross-agglutination of C. sporogenes, C. tetani, and C. histolyticum with the somatic antisera of the proteolytic group was also observed.
Absorption↗
Absence of somatic alterations of the EB1 gene adenomatous polyposis coli-associated protein in human sporadic colorectal cancers.
The human EB1 gene product was recently found, by a yeast two-hybrid screening, to be associated with the carboxy terminus of the APC (adenomatous polyposis coli) protein, the product of a tumour-suppressor gene thought to act as a gatekeeper in colorectal carcinogenesis. Because virtually all of the APC mutations result in the synthesis of carboxy-terminal truncated proteins, mutant APC proteins are expected to lose their ability to interact with EB1 gene product. Thus, the interaction between APC and EB1 proteins may be important for the tumour-suppressor activity of APC protein, and raises the hypothesis that EB1 is also involved in sporadic colorectal tumorigenesis. To investigate this hypothesis, somatic mutations in the entire coding sequence of EB1 cDNA were searched by reverse transcriptase single-strand conformational polymorphism (SSCP) analysis in 21 sporadic colorectal cancers and seven adenomas. None of these tumours contained somatic mutation, whereas a silent cDNA variant was identified in 14% of alleles. Furthermore, to investigate whether EB1 locus was included within a region subjected to losses of heterozygosity, four polymorphism markers surrounding EB1 locus were surveyed. Only one out of 28 colorectal tumours contained a loss of heterozygosity at the D20S107 marker. In conclusion, the present findings strongly suggest that EB1 gene is not involved in somatic colorectal carcinogenesis.
Adenomatous Polyposis Coli↗
Human testis/sperm-specific histone H2B (hTSH2B). Molecular cloning and characterization.
Human sperm, unlike the sperm of other mammals, contain replacement histones with unknown biological functions. Here, we report the identification of the novel human gene coding for a testis/sperm-specific histone H2B (hTSH2B). This variant histone is 85% homologous to somatic H2B and has over 93% homology with the testis H2B of rodents. Using genomic PCR, two genetic alleles of hTSH2B were found in the human population. The hTSH2B gene is transcribed exclusively in testis, and the corresponding protein is also present in mature sperm. We expressed recombinant hTSH2B and identified this protein with a particular H2B subtype expressed in vivo. The subnuclear distribution of H2B variants in sperm was determined using biochemical fractionation and immunoblotting. The H2B variant associated with telomere-binding activity () was solubilized by Triton X-100 or micrococcal nuclease extraction, whereas hTSH2B was relatively tightly bound in nuclei. Immunofluorescence showed that hTSH2B was concentrated in spots located at the basal nuclear area of a subpopulation (20% of cells) of mature sperm. This fact may be of particular importance, because the hTSH2B "positive" and "negative" sperm cells may undergo significantly different decondensation processes following fertilization.
Amino Acid Sequence↗
Glycophorin A somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene.
We have used the glycophorin A (GPA) in vivo somatic cell mutation assay to assess the genotoxic potential of styrene exposure in 47 reinforced plastics workers occupationally exposed to styrene and 47 unexposed controls matched for age, gender, and active smoking status. GPA variant erythrocyte frequencies (Vf), reflecting GPA allele loss (phi/N) and allele loss and duplication (N/N) somatic mutations arising in vivo in the erythroid progenitor cells of individuals of GPA M/N heterozygous genotype, were flow cytometrically determined in peripheral blood samples from these subjects. Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA8-h) styrene concentration of 155 mg/m3 (37 ppm) in the breathing zone. Mean urinary concentrations of the styrene metabolites mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA+PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next morning), respectively. Multivariate analysis of covariance on log-transformed GPA Vf data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N Vf were nearly significantly increased among all of the exposed workers (adjusted geometric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6.8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA8-h concentration of styrene in the breathing zone of > or = 85 mg/m3 (20 ppm; Finnish threshold limit value). Women in this high exposure group showed especially elevated N/N Vf (adjusted geometric mean 8.5 versus 5.3 in control women; P = 0.020); this elevation was also significant if urinary MA+PGA of > or = 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030). The occupational exposure could not be shown to influence phi/N Vf. Cigarette smoking was associated with significantly elevated GPA Vf among active smokers (P = 0.042 for phi/N and P = 0.020 for N/N) and among active and ex-smokers combined (P = 0.014 for N/N). Its influence on phi/N Vf was especially clear among active smokers in the control group (P = 0.005). An effect of smoking, nearly statistically significant, was also observed for the phi/N Vf of control ex-smokers (P = 0.055) and of all active and ex-smokers combined (P = 0.050). Thus, the two characterized chemical exposures experienced by this group of workers and controls appear to produce differential effects on the two independent classes of GPA variants enumerated in the assay. This result suggests that the genotoxicity of these agents is mediated, at least in part, by different genetic mechanisms. Styrene exposure is associated with a specific increase in GPA N/N Vf; these allele loss and duplication variants reflect predominantly somatic recombination mechanisms in erythroid progenitor cells. Tobacco smoke exposure in active and ex-smokers is also associated not only with an increase in N/N Vf but also with an increase in phi/N Vf, reflecting the induction of GPA gene-inactivating mutations, including point mutations and deletions. This finding is consistent with a broad mechanistic spectrum of tobacco smoke genotoxicity associated with this complex mixture of chemical mutagens. Finally, there was no detectable effect of age on phi/N Vf; however, a highly significant (P = 0.0002) increase in N/N Vf with age, even after adjustment for other variables, was observed.
Adult↗
Expression of the germ cell-specific transcription factor ALF in Xenopus oocytes compensates for translational inactivation of the somatic factor TFIIA.
The discovery of germ cell-specific general transcription factor and coactivator variants has suggested that reproductive tissues control gene expression somewhat differently than somatic tissues. One of these factors, ALF (TFIIAtau), was first described as a testis-specific counterpart of the large (alpha/beta) subunit of TFIIA. Here we characterize endogenous ALF and TFIIA activities in the African clawed frog Xenopus laevis. ALF is present in both testis and ovary in this organism, and it completely replaces TFIIA in immature oocytes. When oocytes undergo progesterone-induced maturation, ALF activity disappears, and TFIIA activity is restored. Reactivation occurs through the translational up-regulation of two maternal TFIIAalpha/beta mRNAs and involves polyadenylation of a conserved 3'-untranslated region module. The effects of ALF overexpression and ALF immunodepletion on a thymidine kinase promoter construct demonstrate that this factor serves as an active replacement for TFIIA. In contrast, overexpression of TFIIA inhibits transcription, indicating that the somatic factor fails to function properly in the context of the oocyte transcription machinery. Overall, the results show that the translationally regulated reciprocal expression of ALF and TFIIA allows for the production of an active TFIIA-like general transcription factor throughout oogenesis.
3' Untranslated Regions↗
[Comparative characteristics of somatic polysaccharide-containing antigens, isolated from strain EB and its Streptomycin-resistant variant].
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Antigens, Bacterial↗
Receptor-associated protein in an oviparous species is correlated with the expression of a receptor variant.
The biosynthesis of proteins containing cysteine-rich domains requires chaperones for their correct folding. For instance, the 39-kDa receptor-associated protein (RAP) aides in the cell-surface targeting of newly synthesized members of the mammalian low density lipoprotein receptor (LDLR) gene family, which contains tandemly arranged clusters of hexacysteine repeats. In the chicken, an LDLR relative with eight such repeats is expressed as two different splice variant forms in cell type-specific fashion (Bujo, H., Lindstedt, K. A., Hermann, M., Mola Dalmau, L., Nimpf, J., and Schneider, W. J. (1995) J. Biol. Chem. 270, 23546-23551). To learn more about evolutionary aspects of RAP, its role in escorting of these different receptor splice variants, and other potential functions, we have extended our studies on the avian LDLR family to RAP. cDNA cloning, determination of tissue expression at both the transcript and the protein level, stable expression in COS cells, and binding studies with chicken RAP revealed that mammalian RAPs have retained many features of the non-amniotic proteins. However, structural details, e.g. the well defined internal triplicate repeats in the chicken protein, have been somewhat diluted during evolution. Interestingly, chicken RAP was found to correlate positively with the expression levels in somatic cells of the larger splice variant of the eight-cysteine repeat receptor, but not with those of the smaller variant, expressed only in germ cells. This is compatible with the possibility that RAP may play a role in receptor biology that could be complementing its function in assisting folding. Chicken RAP in crude extracts of the stable expressor COS cells is able to bind to LDLR relatives in ligand blots without requirement for prior purification of the ligand. Thus, in conjunction with the avian model of massive lipid transport to germ cells, these cells provide a novel comparative system amenable to investigation of the biological functions of RAP.
Amino Acid Sequence↗
Evolution of antibody variable region structure during the immune response.
The results reviewed above reveal that during the anti-Ars immune response of strain A mice a somatic process that results in the evolution of V region structure occurs. This process involves both the selection of V regions encoded by particular gene segment combinations as well as the selection of structural variants of these V regions produced by somatic mutation as the immune response progresses. As a result, both quantitative and qualitative changes in the V region population initially elicited by immunization take place. The structural and functional character of the immune V region repertoire appears to be largely determined by this process of "somatic evolution" occurring in the primary response.
Animals↗
Disappearance of the protein of a somatic mutation: a possible example of stem cell inactivation.
The low concentration of the hemoglobin variant, Hb Vicksburg (leucine-beta-75 deleted), and a profound deficit of its mRNA led us to postulate that a beta(+)-thalassemia mutation existed in cis to the coding region mutation, suppressing its synthesis. We examined blood from this patient 6, 8, and 10 yr after our initial studies, using methods of analysis unavailable initially. We found 1) mutations causing beta(+)-(-88 C----T) and beta 0-(849 A----G) thalassemia; 2) that the proportion of Hb Vicksburg in erythrocytes fell over time, from 8 to 4%, and ultimately disappeared; and 3) that the mutation causing Hb Vicksburg was not detectable in genomic DNA isolated from blood leukocytes when this variant was present in hemolysate. We postulate that Hb Vicksburg arose from a somatic mutation of a beta(+)-thalassemia gene in an erythroid-committed stem cell. Its gradual disappearance suggests the cycling of stem cells, with inactivation of different clones over time.
Adolescent↗
Somatic cell hybridization studies on the genetic regulation and allelic mutations in metachromatic leukodystrophy.
Metachromatic leukodystrophy is a hereditary neurodegenerative disease associated with deficient arylsulfatase A activity. Clinical variants differ in onset times and severity of the disease but each breeds true within families. Somatic cell hybridization techniques were used to clarify the genetic relationship among these mutants. Hybrid clones isolated with a nonselective method from fusing fibroblasts of an infantile and a juvenile variant did not show complementation of arylsulfatase A activity. Hence, these clinical variants are allelic mutants. Previous somatic cell hybridization studies suggested that "arylsulfatase A-deficiency" is a dominant phenotype, in contrast to its apparent recessive mode of inheritance. To resolve this discrepancy, hybrid clones from fusing normal and arylsulfatase A-deficient fibroblasts were isolated nonselectively. They continued to express arylsulfatase A activity. Hence, even in vitro, "arylsulfatase A-deficiency" remains as a recessive phenotype.
Adult↗
Somatic linker histones cause loss of mesodermal competence in Xenopus.
In Xenopus, cells from the animal hemisphere are competent to form mesodermal tissues from the morula through to the blastula stage. Loss of mesodermal competence at early gastrula is programmed cell-autonomously, and occurs even in single cells at the appropriate stage. To determine the mechanism by which this occurs, we have been investigating a concomitant, global change in expression of H1 linker histone subtypes. H1 histones are usually considered to be general repressors of transcription, but in Xenopus they are increasingly thought to have selective functions in transcriptional regulation. Xenopus eggs and embryos at stages before the midblastula transition are deficient in histone H1 protein, but contain an oocyte-specific variant called histone B4 or H1M. After the midblastula transition, histone B4 is progressively substituted by three somatic histone H1 variants, and replacement is complete by early neurula. Here we report that accumulation of somatic H1 protein is rate limiting for the loss of mesodermal competence. This involves selective transcriptional silencing of regulatory genes required for mesodermal differentiation pathways, like muscle, by somatic, but not maternal, H1 protein.
Activins↗
"Cold" single-strand conformational variants for mutation analysis of the RET protooncogene.
BACKGROUND: RET protooncogene mutation analysis is a routinely performed predictive DNA test in kindreds affected by multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC), and is a valuable diagnostic tool in newly diagnosed cases of medullary thyroid carcinoma (MTC). METHODS: We tested the suitability of the recently introduced "cold" single-strand conformational variant (SSCV) technique, which promises rapid, simple, nonradioactive detection of sequence variants in the identification of germline and somatic RET mutations. A total of 11 different mutations in exon 10 (codons 609, 611, 618, and 620) and 6 mutations in exon 11 (codon 634) were studied. RESULTS: Conditions were optimized so that conformational variants were demonstrated for all mutations examined in a single setting for exons 10 and 11. A novel six base pair (bp) inframe deletion between cysteines 630 and 634 was detected in a sporadic MTC. This adds to the evidence that not only cysteine deletions and substitutions but also changes in the spacing between cysteine residues have a pathogenic effect. CONCLUSIONS: Our results indicate that the cold SSCV method offers the advantages of simplicity, time savings, and nonradioactive detection for screening for RET sequence variants in hereditary and sporadic MTCs.
Amino Acid Sequence↗
Presence of a bi-directional S phase-specific transcription regulatory element in the promoter shared by testis-specific TH2A and TH2B histone genes.
During mammalian spermatogenesis, somatic histones are replaced by testis-specific variants. The synthesis of the variants occurs primarily in the germ cells undergoing meiosis in the absence of DNA replication. We have cloned the genes encoding rat somatic and testis-specific H2A (TH2A) histones. The two genes share 300 bp of 5' upstream region with respective H2B genes: somatic H2A with somatic H2B and testis-specific TH2A with testis-specific TH2B gene. The deduced amino acid sequences show that H2A and TH2A histones have eight amino acid differences in the first half of the molecules and three consecutive changes in the C-terminal region. TH2A gene is expressed only in testis. Although synthesis of TH2A and TH2B histones is independent of DNA replication and insensitive to inhibitors of DNA synthesis in testis, the regulatory region shared by the two genes contain a bi-directional S phase-specific transcription regulatory element. In addition, TH2A gene, like TH2B gene, contains the consensus sequence element in the 3' non-coding region which is involved in the S phase-specific stabilization of histone mRNA.
Amino Acid Sequence↗
A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells.
We have identified and characterized two mutually exclusive nuclear proteins that interact with a single crucial element of the albumin promoter. One, albumin proximal factor (APF), is found only in liver or differentiated hepatoma cells and is probably identical to the liver-specific factor named HNF1, alpha 1TFB, or HP1-binding protein. The other, variant albumin proximal factor (vAPF), is present in dedifferentiated hepatoma cells as well as in somatic cell hybrids that show extinction of the expression of liver-specific proteins, including albumin. Reversion to the hepatic phenotype of either a dedifferentiated variant or an extinguished somatic hybrid clone is accompanied by loss of vAPF and reappearance of APF. These two proteins differ in their thermostability and in their molecular weight, while displaying identical sequence specificities. Both proteins interact with a homologous motif present in promoter regions of several other liver-specific genes. In vitro transcription assays, using a rat liver nuclear extract, indicate that the binding of APF to its target sequence is required for albumin transcription. These results suggest that a modification in the primary structure of a transcription factor is correlated with the differentiated state of the hepatic cell.
Albumins↗
The gene for a variant form of the polyadenylation protein CstF-64 is on chromosome 19 and is expressed in pachytene spermatocytes in mice.
Many mRNAs in male germ cells lack the canonical AAUAAA but are normally polyadenylated (Wallace, A. M., Dass, B., Ravnik, S. E., Tonk, V., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., and MacDonald, C. C. (1999) Proc. Natl. Acad Sci. U. S. A. 96, 6763-6768). Previously, we demonstrated the presence of two distinct forms of the M(r) 64,000 protein of the cleavage stimulation factor (CstF-64) in mouse male germ cells and in brain, a somatic M(r) 64,000 form and a variant M(r) 70,000 form. The variant form was specific to meiotic and postmeiotic germ cells. We localized the gene for the somatic CstF-64 to the X chromosome, which would be inactivated during male meiosis. This suggested that the variant CstF-64 was an autosomal homolog activated during that time. We have named the variant form "tau CstF-64," and we describe here the cloning and characterization of the mouse tauCstF-64 cDNA, which maps to chromosome 19. The mouse tauCstF-64 protein fits the criteria of the variant CstF-64, including antibody reactivity, size, germ cell expression, and a common proteolytic digest pattern with tauCstF-64 from testis. Features of mtauCstF-64 that might allow it to promote the germ cell pattern of polyadenylation include a Pro --> Ser substitution in the RNA-binding domain and significant changes in the region that interacts with CstF-77.
Amino Acid Sequence↗