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PubMed1988

Structure and expression of rodent genes encoding the testis-specific cytochrome c. Differences in gene structure and evolution between somatic and testicular variants.

Mammalian testis contains two forms of cytochrome c, one identical to the form found in somatic tissues and a second that is expressed in a stage-specific manner during spermatogenic differentiation. We have isolated both rat and mouse cDNA clones and the rat gene encoding the testis-specific cytochrome c and determined their DNA sequences. The testicular variant displays a number of notable differences with its somatic counterpart. 1) In contrast to the multipseudogene family derived from mammalian somatic cytochrome c genes, the testis gene is single-copy in genomic DNA with no detectable pseudogenes. 2) The rat testis gene is approximately 7 kilobases (kb) long with three introns totaling nearly 6.5 kb whereas the two introns dividing the 2.1-kb somatic gene occupy only 0.9 kb. Introns differ in position as well as size. 3) The testicular variant has a longer 5'-untranslated leader (230 versus 70 base pairs for the somatic gene) with an upstream open reading frame of 129 base pairs beginning with an AUG in a favorable translational context. 4) A single polyadenylation site in the testicular mRNA (approximately 900 nucleotides) contrasts with the three functionally equivalent sites observed in rat somatic messages. 5) Finally, rat and mouse testis cytochromes c differ at 4 amino acid residues as opposed to the complete sequence identity found in the somatic proteins suggesting a shorter unit evolutionary period for these molecules. These observations are consistent with a duplication of an ancestral cytochrome c gene leading to the emergence of novel structural features and regulatory properties likely associated with the striking tissue specificity of the testicular cytochrome c.

Amino Acid Sequence↗
PubMed1986

Analysis of somatic cell H-2 variants to define the structural requirements for class I antigen expression.

We have taken the approach of producing somatic cell variants with altered H-2 products to study the structural requirements for cell surface expression of class I histocompatibility molecules. H-2 antigen variants generated by chemical mutagenesis of a cell line expressing the H-2b haplotype were first selected with alloantisera for their loss of H-2Kb expression, and then were analyzed by radioimmunoassay for the appearance of intracellular Kb antigen. For one such variant (69.9.15), whereas the H-2Kb antigen was absent from the cell surface as assayed by antibody-mediated complement-dependent cytotoxicity, an H-2Kb molecule was detected within the cell lysate as confirmed by direct immune precipitation with Kb-specific monoclonal antibodies. The product had an altered antigenic phenotype, since it reacted with only two anti-Kb monoclonal antibodies (Y-3 and EH-144) and not with a third (5F1.2). Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis identified the beta 2 microglobulin-associated, intracellular H-2Kb heavy chain to be slightly smaller in Mr than the H-2Kb of the parental cell line. Hybridization analysis revealed the Kb gene from the variant to be without gross alterations, and furthermore, identified a Kb mRNA species that was identical in size to wild-type Kb mRNA. Because complementation was not observed after somatic cell fusion of variant cells with BALB/c splenocytes, it appeared that the alteration in Kb expression was due to a cis-acting defect. In addition, DNA-mediated gene transfer of the wild-type Kb gene into the variant cell line resulted in expression of the Kb antigen on the cell surface, thus confirming that the defect in expression of the mutant Kb product was not due to other factors in the 69.9.15 cell line. Such findings are consistent with the conclusion that stable H-2Kb surface-negative somatic variants can arise due to limited alterations in the Kb gene, resulting in the synthesis of a class I molecule that is expressed only as an intracellular product.

Animals↗
PubMed1981

Somatically generated mouse myeloma variants synthesizing IgA half-molecules.

Whereas mouse myelomas that secrete IgA half-molecules have been shown to arise in vivo, their origin has not been definitely established. We show that somatic variants secreting phenotypically similar molecules can arise directly from the normal IgA-secreting myelomas S107 and W3082. In addition to being improperly assembled, the variant proteins have distinct carboxy-terminal deletions and an aberrant heavy-light chain disulfide bond. For at least one of the variants, variable region serology and affinity for hapten are both unaffected by these changes. Southern and Northern blot analyses indicate normal size DNA restriction fragments and mRNA, suggesting premature termination as the mechanism of deletion. These results are discussed in relation to possible mutational hot spots and long-range interdomain interactions.

Animals↗
PubMed2000

Hormone status selects for spontaneous somatic androgen receptor variants that demonstrate specific ligand and cofactor dependent activities in autochthonous prostate cancer.

We have used the autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate the relationship between somatic mutation in the androgen receptor (AR) and the emergence of androgen-independent prostate cancer. Here we report the identification, isolation, and characterization of distinct classes of AR variants from spontaneous prostate tumors in the TRAMP model. Using cDNA cloning, single stranded conformation polymorphism and sequencing strategies, 15 unique somatic mutations in the AR were identified in prostate tumors obtained from eight TRAMP mice between 24 and 29 weeks of age. At least one mutation was isolated from each mouse. All mutations were single base substitutions, 10 were missense and 5 were silent. Nine mutations in the AR were identified in tumors of four mice that were castrated at 12 weeks of age. Interestingly, the majority of mutations (seven out of nine, 78%) identified in the androgen-independent tumors colocalized in the AR transactivation domain. The remaining mutations colocalized in the AR ligand binding domain. In general, the AR variants demonstrated promoter-, cell-, and cofactor-specific activities in response to various hormones. All AR variants isolated in this study maintained strong sensitivity for androgens, and four AR variants isolated from castrated mice demonstrated increased activities in the absence of ligand. The K638M and F677S variants demonstrated increased activities in response to androgen, and K638M also demonstrated increased response to estradiol. In the presence of AR coactivator ARA70 the E231G variant demonstrated increased activity in response to both androgen and estradiol. However, in the presence of AR coactivator ARA160 the E231G variant was selectively responsive to androgen. Collectively these analyses not only indicate that somatic mutations in the AR gene occur spontaneously in TRAMP tumors but also how changes in the hormonal environment may drive the selection of spontaneous somatic mutations that provide a growth advantage.

Animals↗
PubMed1983

Somatic H-2Kk variants reveal nonidentity of serological and cytotoxic T cell-defined Kk determinants.

The relationship of serologically defined determinants to determinants recognized by cytotoxic T cells on molecules encoded by the Kk gene of the murine major histocompatibility complex (H-2) has been analyzed. For this purpose we used three somatic variants of a Kk-expressing lymphoma line lacking individual determinants of the Kk molecule, as defined by monoclonal antibodies (mAb), as target cells for Kk-specific alloreactive and Kk-restricted cytotoxic T lymphocytes (CTL) cloned by limiting dilution. Neither alloreactive nor fluorescein isothiocyanate, influenza- or Newcastle disease virus-specific Kk-restricted CTL clones were found to distinguish between variants and wild type cells, indicating that the serologically defined determinants lost by the variants were not essential for antigen recognition of CTL with these specificities. On the other hand, two of the variants lacking either one of a pair of serological determinants were discriminated from Kk wild type cells by about 40% of Kk-restricted, trinitrophenol (TNP)-specific CTL clones. The third variant, lacking both of the determinants, however, was lysed by all CTL clones to the same extent as wild type cells. From these results we conclude that the determinants restricting the TNP-specific CTL were also not identical with those defined by mAb. In experiments performed to optimize the conditions for the limiting dilution analysis we found that the specificity of the CTL stimulation was strongly dependent on the concentration of T cell growth factor (interleukin 2) in the cultures during CTL stimulation. High concentrations of IL2 resulted in a drastic increase in the frequency of CTL clones. Part of these clones, however, were found not to be specific for antigens present on the stimulator cells.

Animals↗
PubMed1977

Tumor-associated antigens in H-2 hemizygous isoantigenic variants of a somatic cell hybrid, derived from the fusion of a 3-methylcholanthrene-induced sarcoma and a mammary carcinoma.

To check the suggestion that 3-methylcholanthrene-induced, sarcoma-associated, tumor-specific transplantation antigens (TSTA) could be modified H-2 antigens, reciprocal isoantigenic variants derived from TA3Ha/MSWBS hybrid cells were examined. This hybrid was produced by the fusion of the TA3Ha ascites carcinoma (H-2a) and the 3-methylcholanthrene-induced MSWBS ascites sarcoma (H-2s). MSWBS expresses a strong TSTA capable of inducing a rejection reaction in the syngeneic A.SW host. The genetic determinants of the H-2 complex are known to be localized on chromosome No. 17. TA3Ha contributes two normal, telocentric chromosomes No. 17 to the hybrid. In contrast, both chromosomes No. 17 of MSWBS are localized on readily identifiable translocations (17/1 and 17/M1). We have previously shown that the chromosomes No. 17 of one parental strain or the other (but not both) can be eliminated from the hybrid upon selective passage in the opposite parental strain. The present studies showed that the two strain A-compatible variants that have lost the sarcoma-derived 17-chromosomes still contained the same TSTA as the two reciprocal strain A.SW-compatible variants that have lost the mammary carcinoma-derived H-2 chromosomes. These findings argue against the possibility that methylcholanthrene-induced TSTA is a modified form of H-2 or that its structural determinants(s) is localized on chromosome 17.

Animals↗
PubMed1986

Sequence of the amino terminal half of rat testis-specific histone variant H1t.

H1t is a testis-specific H1 histone variant that appears during the meiotic phase of spermatogenesis in mammals. The sequence of the first 108 residues of rat H1t have been determined and compared to boar H1t and also to a consensus sequence characteristic of standard somatic H1 variants. The two versions of H1t share a common pattern of divergence from the standard somatic consensus. For example, they both share many substitutions within the H1 globular region (residues 40-110), a portion of the molecule that is virtually invariant among the common somatic variants. Within the entire region sequenced, there are 28 shared locations where both forms of H1t differ from the somatic consensus. However, identical substitutions occur at only 15 of these sites, and each protein also differs from the consensus at five (boar) or ten (rat) additional locations that are not shared. These results establish that H1t from diverse sources shows a characteristic pattern of divergence from the sequence of standard somatic H1 proteins. However, it is also clear that there is great tolerance for species-specific variation within this H1 class.

Amino Acid Sequence↗
PubMed1990

A carrot cell variant temperature sensitive for somatic embryogenesis reveals a defect in the glycosylation of extracellular proteins.

The temperature-sensitive carrot cell variant ts11c, arrested in somatic embryogenesis after the globular stage, was characterized. The sensitivity to a shift from 24 degrees C (permissive temperature) to 32 degrees C (non-permissive temperature) is greatest at the globular stage of embryogenesis, while cells proliferating in unorganized fashion and plantlets are not affected. Embryogenesis in ts11c is also arrested at the permissive temperature by replacement of conditioned culture medium with fresh medium. The timing of sensitivity of ts11c to medium replacement coincides with the sensitivity to temperature shift. Both sensitivities are recessive in somatic hybrids between ts11c and wild-type cells. Extracellular glycoproteins synthesized by ts11c at the non-permissive temperature contain much less fucose than those synthesized by the wild type. The glycoproteins synthesized by the variant under non-permissive conditions do not accumulate at the periphery of the embryo, as their wild-type counterparts do, but instead show a diffuse distribution throughout the embryo. The defect in ts11c can be fully complemented by the addition of extracellular wild-type proteins. A revertant of ts11c was isolated that simultaneously reacquired temperature insensitivity and normal glycosylation ability. Collectively, these observations indicate that ts11c is not able to perform proper glycosylation at the non-permissive temperature and suggest that the activity of certain extracellular proteins, essential for the transition of globular to heart stage somatic embryos, depends on the correct modification of their oligosaccharide side-chains.

Biological Transport↗
PubMed2001

Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype.

Hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP) is characterized by a remarkable genomic instability at simple repeated sequences. The genomic instability is often caused by germline and somatic mutations in DNA mismatch repair (MMR) genes hMSH2 and hMLH1. The MMP can be also caused by epigenetic inactivation of hMLH1. The MMP generates many somatic frameshift mutations in genes containing mononucleotide repeats. We previously reported that in MMP tumors the hMSH6 and hMSH3 MMR genes often carry frameshift mutations in their (C)(8) and (A)(8) tracks, respectively. We proposed that these 'secondary mutator mutations' contribute to a gradual manifestation of the MMP. Here we report the detection of other frameshift, nonsense, and missense mutations in these genes in colon and gastric cancers of the MMP. A germline frameshift mutation was found in hMSH6 in a colon tumor harboring another somatic frameshift mutation. Several germline sequence variants and somatic missense mutations at conserved residues were detected in hMSH6 and only one was detected in hMSH3. Of the three hMSH6 germline variants in conserved residues, one coexisted with a somatic mutation at the (C)(8) track and another had a somatic missense mutation. We suggest that some of these germline and somatic missense variants are pathogenic. While biallelic hMSH6 and hMSH3 frameshift mutations were found in some tumors, many tumors seemed to contain only monoallelic mutations. In some tumors, these somatic monoallelic frameshift mutations at the (C)(8) and (A)(8) tracks were found to coexist with other somatic mutations in the other allele, supporting their functionality during tumorigenesis. However, the low incidence of these additional somatic mutations in hMSH6 and hMSH3 leaves many tumors with only monoallelic mutations. The impact of the frameshift mutations in gene expression was studied by comparative analysis of RNA and protein expression in different tumor cell clones with different genotypes. The results show that the hMSH6 (C)(8) frameshift mutation abolishes protein expression, ruling out a dominant negative effect by a truncated protein. We suggest the functionality of these secondary monoallelic mutator mutations in the context of an accumulative haploinsufficiency model.

Amino Acid Sequence↗
PubMed2025

Comparative Analysis of Somatic and Germline Polymerase Proofreading Deficiencies in Cancer: Molecular and Clinical Implications.

Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of POLE and POLD1 impair proofreading, causing hypermutated tumors. Despite shared mutational features that make these tumors highly immunogenic, molecular and clinical distinctions between POLE and POLD1 mutations and between somatic and germline variants remain incompletely understood. We compared the molecular and clinical characteristics of POLE and POLD1 ED PVs (n = 31), assessing their location, pathogenicity, clinical phenotypes, mismatch repair (MMR) status, tumor mutational burden, and signatures. We analyzed 360 proofreading-deficient tumors (source: The Cancer Genome Atlas [TCGA] and Catalogue Of Somatic Mutations In Cancer [COSMIC]) and 70 families (249 individuals) with polymerase proofreading-associated polyposis. All germline and somatic PVs had high AlphaMissense scores (0.87-1) and clustered within or near Exo motifs. Recurrent, nonfounder germline PVs, POLE L424V and POLD1 S478N, showed low/modest REVEL scores. Somatic variants occurred mainly in endometrial cancers (75% of proofreading-deficient TCGA cancers), whereas colorectal cancer predominated in polymerase proofreading-associated polyposis (56% of carriers). Cancer risks and tumor spectra differed between POLE and POLD1 PV carriers. Aggressive hereditary phenotypes were linked to either specific POLE PVs (eg, S297F, V411L, P436R, M444K, A456P, and S461T) or the co-occurrence of germline ED PVs with germline MMR gene PVs. Distinct hypermutator profiles were confirmed for polymerase ε and polymerase δ proofreading deficiencies via unique mutational signatures (Polymerase ε: SBS10a/b, SBS28; Polymerase δ: SBS10c/d). Tumors with combined proofreading and MMR deficiencies had significantly higher tumor mutational burden and a shift in the associated mutational spectra. Unlike POLE, POLD1 ED PVs exhibited haplosufficiency, typically requiring a somatic second hit (eg, loss of heterozygosity) or MMR deficiency to drive hypermutation. In conclusion, differences between POLE and POLD1 and between somatic and germline mutations influence clinical presentation, mutagenic potential, and reliance on cooperating defects in tumorigenesis. These insights advance the understanding of proofreading-deficient cancers, with implications for diagnostics, genetic counseling, and precision oncology.

Humans↗
PubMed2006

Identification of somatic and germline mitochondrial DNA sequence variants in prostate cancer patients.

Prostate cancer (PCa) is the second most frequent cancer among men in the European Union and the most common in the United States. Older age and a positive family history of PCa are important risk factors, but little is known about the disease aetiology. Mitochondria are involved in essential cellular pathways, some of which have been associated with tumorigenesis. We analysed the presence of sequence variants, depletion and rearrangements in the mitochondrial DNA (mtDNA) of PCa patients. Sequencing of the D-loop and genes RNR1 and 2, ND3, ND4L and ND4, and long-range and real-time PCR techniques were carried out on 51 samples (41 from patients and 10 from controls). Normal, hyperplastic or tumour samples were obtained from 17 patients. Six patients' seminal vesicles were also investigated as an additional patient's control tissue (these structures seldom develop tumours). Neither depletion nor mtDNA rearrangements were detected. In contrast, 94 mtDNA sequence variants were identified, 9 previously unreported. The regions presenting more sequence variants were MT-DLOOP (52%), MT-RNR2 (14%) and MT-ND4 (13%). The patients' seminal vesicles studied showed the same set of variants as the corresponding prostate, suggesting either that the pathogenic role of these particular variants is minor or that they participate in the prostatic carcinogenesis in combination with other factors absent in seminal vesicles. Five patients (29.4%) harboured eight somatic changes in the mtDNA. One affects a conserved residue and three have not been previously described. The analysis of other genes in the mtDNA molecule might demonstrate an even higher incidence of mtDNA somatic variants in these PCa patients.

Aged↗
PubMed1976

X-chromosome inactivation and selection in somatic cells.

X-Chromosome inactivation leads to the formation of mosaic cell populations in the somatic cells of mammalian females. Cells have either a maternal or paternal X-chromosome active. If an individual is heterozygous for a cell autonomous X-linked trait, then a set of built-in cellular markers is provided for the investigation of various developmental phenomena, including selection. In the absence of somatic cell selection the tissues of an X-linked heterozygote should all be mosaic and should have a mosaic composition approaching 1:1. If somatic cell selection is occurring, it should be detectable by a significance shift from the random expected 1:1 mosaicism. The system is effective at detecting selection acting on X-linked loci and on newly arisen somatic autosomal variants, and several examples of somatic cell selection are described. However, it is concluded that somatic cell selection, as described above, is not a normal aspect of ontogeny.

Animals↗
PubMed2005

Testis-specific histone H3 expression in somatic cells.

Histone variants functionally differentiate individual nucleosomes and, hence, act as key regulators of chromatin structure and function. Large-scale proteomic projects are now valuable sources of histone-variant discovery, showing, in particular, that somatic mammalian cells express a larger panel of histone H3 variants than previously thought, including testis-specific variants and as yet uncharacterized species. These data also suggest a tight relationship between the complexity of histone-variant expression and physiopathological states of the cells.

Amino Acid Sequence↗
PubMed2001

Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas.

Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.

Adenoma↗
PubMed1982

Somatic cell parasitism and the evolution of somatic tissue compatibility.

Selection pressures proposed to account for the convergent evolution of self/not-self recognition systems in lower organisms include defense against microbial parasites and somatic cell variants. Direct support for the existence of somatic cell parasites in natural populations has been lacking. I here report the occurrence of a somatic cell parasite in the cellular slime mold Dictyostelium mucoroides and discuss the implications of this phenomenon to the evolution of mechanisms of somatic tissue compatibility.

Animals↗