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PubMed2005

No Evidence for BRAF as a melanoma/nevus susceptibility gene.

Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.

Alleles↗
PubMed2026

Beyond Exons: Linking Noncoding Heritability and Polygenicity across Complex Human Traits and Disorders.

The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across exonic, intronic, and intergenic regions for 34 traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons explain a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of a broader set of functional annotations reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less polygenic traits show stronger contributions in promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, pointing to a shift from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects as a key determinant of differences in polygenicity across traits.

Journal Article↗
PubMed1990

Human chromosome 5 complements the DNA double-strand break-repair deficiency and gamma-ray sensitivity of the XR-1 hamster variant.

XR-1 is a Chinese hamster ovary (CHO) cell mutant which is unusually sensitive to killing by gamma rays in the G1 portion of the cell cycle but has nearly normal resistance to gamma-ray damage in late S phase. The cell-cycle sensitivity correlates with the mutant's inability to repair DNA double-strand breaks (DSBs) produced by ionizing radiation and restriction enzymes. We have previously shown in somatic cell hybrids of XR-1 cells and human fibroblasts that the XR-1 mutation is a recessive mutation. In this study, using somatic cell hybrids formed between XR-1 and human fibroblasts, we map the human complementing gene to chromosome 5 by chromosome-segregation analysis. This gene biochemically restores the hamster defect to wild-type levels of gamma-ray and bleomycin resistance as well as restoring its proficiency to repair DNA DSBs, suggesting that a single gene is responsible for the XR-1 phenotype. We have tentatively assigned the name XRCC4 (X-ray-complementing Chinese hamster gene 4) to this human gene until its biochemical function in repair is discovered.

Animals↗
PubMed1998

Increased somatic recombination in methylation tolerant human cells with defective DNA mismatch repair.

We have studied whether spontaneous intrachromosomal recombination is altered in methylation tolerant human cells with a defect in mismatch repair. Somatic recombination was analysed in HeLaMR cells containing the vector pTPSN, which carries two copies of the gene for hygromycin resistance. The hygromycin genes are both inactivated by an inserted HindIII linker but hygromycin-resistant clones can arise by recombination. The spontaneous rate of recombination in a clone of HeLaMR cells containing a single integrated copy of pTPSN (HeLaG1) was 3.1x10(-6)/cell per generation. Two methylation tolerant variants from HeLaG1 cells (clone 12 and clone 15) were isolated by exposure to MNNG. Clone 12 cells exhibited a 16-fold increase in spontaneous mutation rate at the HPRT gene and extensive microsatellite instability at both mono- and dinucleotide repeats. Microsatellite instability limited to mononucleotide repeats was found in clone 15, whereas the mutation rate at HPRT was not significantly affected. A mismatch binding defect in extracts of clone 15 could be complemented by exogenous GTBP but not by purified hMSH2 protein. These data suggest that clone 15 is defective in GTBP. Extracts of clone 12 were unable to correct a single C:T mispair and complementation by extracts of human colorectal carcinoma cells with known deficiencies in mismatch repair indicated a defect in hMutLalpha. Western blotting with antibodies against different human mismatch repair proteins showed that clone 12 cells did not express hPMS2 protein, but expression of hMLH1, hMSH2 and GTBP appeared normal. The spontaneous recombination rate of clone 12 was 19-fold higher than the parental HeLaG1 cells, whereas no increase was observed in clone 15. Analysis of individual recombinants showed that hygromycin resistance arose exclusively by gene conversion. Our data indicate that mismatch correction regulates somatic recombination in human cells.

Base Sequence↗
PubMed1995

Dominant mutations confer resistance to the immunosuppressant, rapamycin, in variants of a T cell lymphoma.

Rapamycin (RAP) disrupts signaling events implicated in cytokine-dependent proliferation of lymphocytes and other cells. This action is known to involve the formation of molecular complexes between the drug and intracellular binding proteins, termed FKBPs. However, the biochemical target(s) for the effector RAP-FKBP complexes remain uncharacterized. As an approach to explore the mechanism of action of RAP, we have isolated three independent sets of somatic mutants of the YAC-1 murine T cell line with markedly reduced sensitivity to the drug's inhibitory effects on proliferation and on IL-1-induced IFN-gamma production. These mutants were still fully sensitive to FK-506, an immunosuppressant structurally related to RAP whose mode of action also involves an interaction with FKBPs. Furthermore, the 12-kDa FKBP, FKBP12, was detectable in immunoblots from cytosolic extracts and eluates from RAP-affinity matrix in the mutants as in wild-type cells, suggesting that the resistance to RAP in the mutants is not due to a lack of FKBP12 expression. Cell fusion experiments were conducted to further define the nature of the alterations imparting RAP resistance in these mutants. Clones deficient in either thymidine kinase or hypoxanthine-guanine phosphoribosyltransferase, suitable as fusion partners for aminopterin-based selection of hybrids were generated from the wild-type or mutant lines. In most instances, the hybrids derived from the fusion between RAP-sensitive clones and RAP-resistant clones exhibited a RAP-resistant phenotype. Similar results were obtained with hybrids between RAP-resistant YAC-1 clones and the RAP-sensitive EL-4 cell line. Therefore, the mutations that confer resistance to RAP in the present system are dominant. Altogether, our observations are consistent with a model where pharmacologically relevant targets for the RAP-FKBP complex, rather than FKBP, might be altered in the mutants such that the inactivation of these targets by the effector complex is prevented.

Animals↗
PubMed2005

PIK3CA mutations in advanced ovarian carcinomas.

PIK3CA belongs to the phosphatidylinositol 3-kinases (PI3Ks) family, which play an important role in proliferation, adherence, transformation and cell survival through the PI3K/AKT signaling pathway. Somatic activating mutations of this gene have recently been detected in several types of cancers. In the present study, 109 advanced ovarian carcinomas were analyzed for PIK3CA mutations in exon 9 and exon 20 by direct sequencing. Activating missense mutations were observed in 4 of the 109 tumors in addition to one variant leading no change of the PIK3CA protein. Two of the cases with mutations were mucinous and clear cell tumors, suggesting that PIK3CA mutations are more common in these rare histological types.

Adenocarcinoma, Clear Cell↗
PubMed2004

Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA.

We obtained 7,566 peripheral blood mononuclear cell (PBMC) samples from 2,332 individuals and screened them for human herpesvirus infection. We identified five individuals who persistently harbored high copy numbers of human herpesvirus 6 (HHV-6) DNA in their PBMCs. HHV-6 DNA was also detected in other somatic tissues of these individuals. Five additional cases were identified among their family members. For two of these families, chromosomally integrated HHV-6 DNA (CIHHV-6) was detected in the PBMCs by fluorescence in situ hybridization. The prevalence of CIHHV-6 among all the subjects was 0.21%. The HHV-6 DNA was variant B in four families and variant A in one family. Antibodies to immediate early antigen and glycoprotein B were detected in 57 and 14% of individuals with CIHHV-6 and in 0 and 60% of healthy volunteers without CIHHV-6, respectively. HHV-6 could not be isolated from PBMCs with CIHHV-6. These cases shared no clinical features, and included three healthy individuals. Our data suggest that CIHHV-6 is rare but detectable in the general population and that hereditary transmission is one of the routes of HHV-6 transmission.

Antibodies, Viral↗
PubMed2026

Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders.

The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across 74 functional annotations covering exonic, intronic, and intergenic regions for 34 complex traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons account for a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less-polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of the broader set of functional annotations also reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less-polygenic traits show stronger contributions from promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, shifting from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects.

MiXeR↗
PubMed1991

Antigenic shifts in serotype determinants of Campylobacter coli are accompanied by changes in the chromosomal DNA restriction endonuclease digestion pattern.

Changes in somatic (O) lipopolysaccharide (LPS) antigenic specificities of Campylobacter coli serostrains were observed after continuous laboratory subculture. Two serostrains (C. coli O34 and C. coli O48) lost O specificity and did not react with homologous or any of the available heterologous antisera. The C. coli serostrain for serogroup O5, after subculture, yielded a variant that had acquired a new specificity which was detectable with a heterologous antiserum. In a repeat experiment with the original isolate of the O5 strain, a second variant was obtained which had not only acquired the same new determinant but had, unlike the first variant, lost reactivity with the homologous antiserum. Immunoblot experiments with homologous and heterologous antisera indicated that changes in antigenic specificity were associated with the O side chains of the LPS molecules. Results of restriction endonuclease analysis of chromosomal DNA of the variants and their parents revealed minor differences in restriction patterns which suggested that C. coli is capable of undergoing genomic re-arrangements that lead to changes in LPS specificity and structure.

Animals↗
PubMed2005

Selection on increased intrinsic growth rates in coho salmon, Oncorhynchus kisutch.

Substantial evidence from the animal kingdom shows that there is a trade-off between benefits and costs associated with rapid somatic growth. One would therefore expect growth rates under natural conditions to be close to an evolutionary optimum. Nevertheless, natural selection in many salmonid species appears to be toward larger size and earlier emergence from spawning redds, indicating a potential for increased growth rate to evolve. We tested how selection for genetic variants (growth hormone transgenic coho salmon, Oncorhynchus kisutch, with more than doubled daily growth rate potential relative to wild genotypes) depended on predator timing and food abundance during the early period of life (fry stage). In artificial redds, fry of the fast-growing genotypes showed a highly significant developmental shift, emerging from gravel nests approximately two weeks sooner, but with an 18.6% reduced survival, relative to wild-genotype fry. In seminatural streams, fry of the fast-growing genotypes suffered higher predation than those of wild genotypes when predators were present at the time of fry emergence, but this difference was less pronounced when food was scarce. In streams where predators were introduced after emergence, fry survived equally well regardless of food availability. Surviving fry grew faster in habitats provided with more food, and fast-growing genotypes also grew faster than wild genotypes when predators arrived late and food was abundant. Fewer fish migrated downstream past a waterfall when food availability was high and in the presence of predators, and wild-genotype fry were more likely to migrate than fry of the fast-growing genotypes. After being returned to the experimental streams after migration, fast-growing genotypes survived equally well as those of the same genotypes that did not migrate, whereas migrating wild genotypes experienced higher mortality relative to those of the same genotypes that did not migrate. Comparisons of growth rates between siblings retained under hatchery conditions and those from habitats with the fastest growth in the experimental stream revealed that growth rates were similar for wild genotypes in both environments, whereas the fast-growing genotypes in the streams only realized 90% of their growth potential. The present study has shown that a major shift in developmental timing can alter critical early stages affecting survival and can have a significant effect on fitness. Furthermore, ecological conditions such as food abundance and predation pressure can strongly influence the potential for fast-growing variants to survive under natural conditions. The large-scale removal of many predatory species around the world may augment the evolution of increased intrinsic growth rates in some taxa.

Age Factors↗
PubMed1993

[Behavioral and developmental manifestations: disorders or normal variations?].

Most developmental and behavioural disturbances paediatricians are faced with are not due to organic lesions of the central nervous system. They occur at a distinct age and are of limited duration, reflecting a strong maturational nature. The disturbances can be related to the following three factors. (1) Extreme behaviour within normal variability; the variant may consist of an extreme manifestation of a certain behaviour (e.g. excessive crying during the first 3 months of life) or of a maturational delay (e.g. primary nocturnal enuresis). (2) Lack of fit between child and environment (e. g. a child sleeps less than his/her parents expect). (3) Impaired psychic and/or somatic well-being of the child (e. g. following the loss of one parent). Since any one developmental and behavioural disturbances may be caused by different endogenous and exogenous factors, careful investigation is required to determine what appropriate educational, medical and social measures are appropriate.

Child↗
PubMed1999

Alternative splicing and hypermutation of a nonproductively rearranged TCR alpha-chain in a T cell hybridoma.

Like Ig genes, TCR genes are formed by somatic rearrangements of noncontiguous genomic V, J, and C regions. Unlike Ig genes, somatic hypermutation of TCR V regions is an infrequent event. We describe the occurrence of spontaneous hypermutation in a nonproductively rearranged TCR alpha-chain gene in a clonal T cell hybridoma that had lost its productively rearranged alpha-chain. The mutating hybridoma was eventually supplanted in culture by a nonmutating variant that had restored an open reading frame in the nonproductively rearranged TCR alpha-chain through the use of cryptic splice sites in the V alpha region. Evidence is presented for the presence of cDNA reverse transcripts of the TCR alpha-chain within the hybridoma, suggesting a role for reverse transcriptase in the generation of mutations.

Alternative Splicing↗
PubMed2002

High sensitivity of detection of TP53 somatic mutations by fluorescence-assisted mismatch analysis.

We analyzed exons 5-9 of the TP53 gene in 41 breast cancers using direct sequencing, PCR-SSCP (single-strand conformation polymorphism), and fluorescence-assisted mismatch analysis (FAMA), to test the level of specificity and sensitivity of each method. A major issue for the correct detection of TP53 somatic mutations in primary tumors is often represented by the large amount of normal DNA, which can cause excessive dilution of the mutant allele, with consequent possible false-negative results. High sensitivity upon dilution of the mutant allele has been demonstrated for FAMA, a method based on the chemical cleavage of a mismatch within heteroduplex DNA molecules. Exons 5-9 of the TP53 gene were analyzed by FAMA using only two long bifluorescent fragments. Differences in sensitivity, accuracy, and specificity were observed among the above-mentioned procedures. Thirteen of the 41 samples (31.7%) revealed TP53 genetic alterations by automated sequencing, 19 samples (46.3%) were positive for SSCP, whereas 14 samples (34%) showed variants detectable by FAMA. Seven samples were positive in SSCP, but negative in both FAMA and sequencing assays; however, 2 SSCP-negative samples revealed evident signals by FAMA, indicating the presence of TP53 mutations. One of the latter samples showed the alteration by sequence analysis, whereas the other failed to reveal the mutation signal even by sequencing, as a consequence of the very small amount of the mutant allele resulting from the excess of contaminating normal DNA. Our results show that FAMA may represent a suitable and accurate assay for the routine diagnosis of TP53 somatic mutations in DNAs from solid tumor biopsies.

Base Pair Mismatch↗
PubMed1994

Somatic mutations at T-cell antigen receptor and glycophorin A loci in pediatric leukemia patients following chemotherapy: comparison with HPRT locus mutation.

Frequencies of somatic mutations in pediatric patients with leukemia were evaluated following intensive treatment at three different loci: the hypoxanthine-guanine phosphoribosyl transferase (HPRT), T-cell antigen receptor (TCR), and glycophorin A (GPA) gene. Thirty-two children with acute lymphoblastic leukemia (ALL), nine children with acute myelogenous leukemia (AML), and 20 age-matched healthy controls were included in the study of mutant frequencies (Mfs) at the HPRT and TCR loci. Among these patients and controls, individuals with heterozygous MN blood type, i.e., 14 children with ALL, three children with AML, and nine healthy controls, served for the further assessment of variant frequency (Vf) at the GPA locus. In ALL patients, geometric mean Mfs and Vfs at these loci were significantly higher than in healthy controls. The high Mf value at the HPRT locus persisted for up to 8 years after the end of chemotherapy. On the other hand, the Mf values at the TCR locus and Vf values at the GPA locus declined gradually with time. In AML patients, on the other hand, the geometric mean Mf only at the TCR locus was significantly higher than in the controls, albeit to a lesser degree than in ALL patients. These data suggest that anti-cancer therapy induces somatic mutations at various loci and that ALL patients are more susceptible to mutagenic intervention than are AML patients.

Adolescent↗
PubMed1982

Isolation and characterization of peanut agglutinin-resistant embryonal carcinoma cell-surface variants.

The isolation and characterization of variant embryonal carcinoma (EC) cells possessing altered cell-surface structures is described. The lectin peanut agglutinin (PNA), which binds to EC cells but not their differentiated derivatives, was used to select the variants. Clones resistant to the cytotoxic effect of PNA were isolated at a frequency of 4 X 10(-5) following mutagenesis. The resistant phenotype was stable in the absence of selection in all eight clones tested. The increased frequency of resistant clones following mutagenesis and the stability of the phenotype suggests a mutational origin. Somatic cell hybrids constructed between wild-type cells and two different PNA-resistant cell lines were sensitive to PNA; this suggests that the resistant phenotype is recessive. Binding assays demonstrated that resistant cells exhibited a twofold to fourfold reduction in the total amount of PNA bound. Together with the recessive behavior of the phenotype, this suggests that resistant cells are deficient for PNA receptors. The PNA-resistant cells also showed reduced binding of monoclonal antibody against stage-specific embryonic antigen 1 (SSEA-1) in indirect cytotoxicity tests. All eight PNA-resistant lines isolated were tumorigenic in syngeneic mice and gave rise to well-differentiated teratocarcinomas. The PNA-resistant cells behaved like their wild-type parents in a cell recognition assay; when incubated in suspension with endodermal cells, they sorted out to form simple embryoid bodies (a core of EC cells surrounded by an endodermal rind). Thus, EC cells can form tumors, differentiate, and recognize differentiated cells in a sorting assay despite a reduction in expression of the embryo-specific cell surface structures (s) that bind PNA and anti-SSEA-1 antibody.

Animals↗
PubMed2003

Altered expression of the septin gene, SEPT9, in ovarian neoplasia.

The septin family of genes has been implicated in a variety of cellular processes including cytokinesis, membrane transport and fusion, exocytosis, and apoptosis. One member of the septin family maps to chromosome 17q25.3, a region commonly deleted in sporadic ovarian and breast tumours, and has also been identified as a fusion partner of MLL in acute myeloid leukaemias. The present study demonstrates that the pattern of expression of multiple splice variants of this septin gene is altered in ovarian tumours and cell lines. In particular, expression of the zeta transcript is detectable in the majority of tumours and cell lines, but not in a range of non-malignant adult and fetal tissues. Zeta expression is accompanied by loss of the ubiquitous beta transcript. Somatic mutations of the gene were not detected in ovarian tumours, but it was demonstrated that beta expression in tumour cell lines can be reactivated by 5-azacytidine treatment, suggesting a role for methylation in the control of expression of this gene.

Adult↗
PubMed1995

Mapping of the focal adhesion kinase (Fadk) gene to mouse chromosome 15 and human chromosome 8.

Focal adhesion kinase (pp125FAK or FAK) is a cytoplasmic protein-tyrosine kinase stimulated in response to cell interactions with extracellular matrix components and by exposure to a variety of agonists, including neuropeptides. FAK lacks Src-homology SH2 and SH3 domains, is highly conserved across species, and may represent the prototype for a tyrosine kinase family involved in novel signal transduction pathways. We have identified sequence variants in the 3' untranslated regions of the focal adhesion kinase gene in mice and used a PCR-based oligonucleotide hybridization assay to map the mouse gene (Fadk) to Chromosome (Chr) 15 distal to the myelocytomatosis protooncogene (Myc). The human homolog (PTK2) has been assigned to human Chr 8 on a panel of somatic hybrid cell lines. On the basis of synteny of mouse and human chromosomal maps, the position of the human PTK2 gene probably corresponds to human Chr 8q24-qter.

Animals↗
PubMed2005

ten-1, an essential gene for germ cell development, epidermal morphogenesis, gonad migration, and neuronal pathfinding in Caenorhabditis elegans.

ten-m (odz) is the only pair-rule gene discovered in Drosophila that encodes a transmembrane protein and not a transcription factor. The vertebrate Ten-m orthologues have been implicated in pattern formation and neuronal development. To investigate the role of this protein in development, we characterize here the structure and function of the Caenorhabditis elegans orthologue ten-1. We found that two promoters control the expression of two different ten-1 transcripts. This results in the expression of type II transmembrane protein variants differing in their intracellular domains. Both ten-1 transcripts show complex, but distinct, expression patterns during development and in the adult. Interference with Ten-1 expression by RNAi experiments leads to multiple phenotypes resulting in defects in hypodermal cell migration, neuronal migration, pathfinding and fasciculation, distal tip cell migration, the establishment of the somatic gonad, and gametogenesis. The RNAi phenotypes were confirmed by the analysis of a deletion mutant which revealed that Ten-1 is essential for somatic gonad formation. The intracellular domain of the long form was detected at the cell membrane and in the nucleus. We propose that Ten-1 acts as a receptor for morphogenetic cue(s) and directly signals to the nucleus by translocation of its intracellular domain to the nucleus following its proteolytic release from the cell membrane.

Animals↗