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Mutational Targets (mutational + target)
Selected AbstractsJust how does the cII selection system work in MutaÔMouse?ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2001Roy R. Swiger Abstract The lambda CII protein is an essential component in the lytic vs. lysogeny decision a bacteriophage makes upon infection of a host at low temperatures. The protein interacts with numerous phage promoters modulating the expression of the CI repressor, thus providing the mechanism for lysogenization soon after infection. The Big Blue® and MutaÔMouse are two widely used in vivo mutational model systems. The assays rely on retrievable lambda-based transgenes housing mutational targets (lacI or lacZ, respectively). The transgenes provide an elegant vehicle for the quantification of mutations sustained in virtually any tissue of the rodent. The use of the bacteriophage cII locus as an alternative, or additional mutational target for use with the Big Blue® rodent system was first reported by Jakubczak et al. ([1996]: Proc Natl Acad Sci USA 93:9073,9078). More recently, this selection assay has been applied successfully to the MutaÔMouse (Swiger et al. [1999]: Environ Mol Mutagen 33:201,207). The use of an Hfl bacterial strain and low temperature allows the determination of mutations sustained at the cII locus in either system, with high fidelity. The cII selection assay in the Big Blue® relies on the presence of the lambda repressor protein CI. In contrast, the recombinant construct used to make the MutaÔMouse transgene lacks functional CI protein. Nevertheless, we report an excellent system for quantifying mutations at the cII locus in MutaÔMouse. Just how does cII selection work in the MutaÔMouse? Written in the context of lambda recombinant genetics, this paper explores the question further. Environ. Mol. Mutagen. 37:290,296, 2001 © 2001 Wiley-Liss, Inc. [source] MULTIVARIATE QUANTITATIVE GENETICS AND THE LEK PARADOX: GENETIC VARIANCE IN MALE SEXUALLY SELECTED TRAITS OF DROSOPHILA SERRATA UNDER FIELD CONDITIONSEVOLUTION, Issue 12 2004Emma Hine Abstract Single male sexually selected traits have been found to exhibit substantial genetic variance, even though natural and sexual selection are predicted to deplete genetic variance in these traits. We tested whether genetic variance in multiple male display traits of Drosophila serrata was maintained under field conditions. A breeding design involving 300 field-reared males and their laboratory-reared offspring allowed the estimation of the genetic variance-covariance matrix for six male cuticular hydrocarbons (CHCs) under field conditions. Despite individual CHCs displaying substantial genetic variance under field conditions, the vast majority of genetic variance in CHCs was not closely associated with the direction of sexual selection measured on field phenotypes. Relative concentrations of three CHCs correlated positively with body size in the field, but not under laboratory conditions, suggesting condition-dependent expression of CHCs under field conditions. Therefore condition dependence may not maintain genetic variance in preferred combinations of male CHCs under field conditions, suggesting that the large mutational target supplied by the evolution of condition dependence may not provide a solution to the lek paradox in this species. Sustained sexual selection may be adequate to deplete genetic variance in the direction of selection, perhaps as a consequence of the low rate of favorable mutations expected in multiple trait systems. [source] Just how does the cII selection system work in MutaÔMouse?ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2001Roy R. Swiger Abstract The lambda CII protein is an essential component in the lytic vs. lysogeny decision a bacteriophage makes upon infection of a host at low temperatures. The protein interacts with numerous phage promoters modulating the expression of the CI repressor, thus providing the mechanism for lysogenization soon after infection. The Big Blue® and MutaÔMouse are two widely used in vivo mutational model systems. The assays rely on retrievable lambda-based transgenes housing mutational targets (lacI or lacZ, respectively). The transgenes provide an elegant vehicle for the quantification of mutations sustained in virtually any tissue of the rodent. The use of the bacteriophage cII locus as an alternative, or additional mutational target for use with the Big Blue® rodent system was first reported by Jakubczak et al. ([1996]: Proc Natl Acad Sci USA 93:9073,9078). More recently, this selection assay has been applied successfully to the MutaÔMouse (Swiger et al. [1999]: Environ Mol Mutagen 33:201,207). The use of an Hfl bacterial strain and low temperature allows the determination of mutations sustained at the cII locus in either system, with high fidelity. The cII selection assay in the Big Blue® relies on the presence of the lambda repressor protein CI. In contrast, the recombinant construct used to make the MutaÔMouse transgene lacks functional CI protein. Nevertheless, we report an excellent system for quantifying mutations at the cII locus in MutaÔMouse. Just how does cII selection work in the MutaÔMouse? Written in the context of lambda recombinant genetics, this paper explores the question further. Environ. Mol. Mutagen. 37:290,296, 2001 © 2001 Wiley-Liss, Inc. [source] Novel regions of acquired uniparental disomy discovered in acute myeloid leukemiaGENES, CHROMOSOMES AND CANCER, Issue 9 2008Manu Gupta The acquisition of uniparental disomy (aUPD) in acute myeloid leukemia (AML) results in homozygosity for known gene mutations. Uncovering novel regions of aUPD has the potential to identify previously unknown mutational targets. We therefore aimed to develop a map of the regions of aUPD in AML. Here, we have analyzed a large set of diagnostic AML samples (n = 454) from young adults (age: 15,55 years) using genotype arrays. Acquired UPD was found in 17% of the samples with a nonrandom distribution particularly affecting chromosome arms 13q, 11p, and 11q. Novel recurrent regions of aUPD were uncovered at 2p, 17p, 2q, 17q, 1p, and Xq. Overall, aUPDs were observed across all cytogenetic risk groups, although samples with aUPD13q (5.4% of samples) belonged exclusively to the intermediate-risk group as defined by cytogenetics. All cases with a high FLT3 -ITD level, measured previously, had aUPD13q covering the FLT3 gene. Significantly, none of the samples with FLT3 -ITD - /FLT3 -TKD+ mutation exhibited aUPD13q. Of the 119 aUPDs observed, the majority (87%) were due to mitotic recombination while only 13% were due to nondisjunction. This study demonstrates aUPD is a frequent and significant finding in AML and pinpoints regions that may contain novel mutational targets. © 2008 Wiley-Liss, Inc. [source] Mutations in the ataxia telangiectasia and rad3-related,checkpoint kinase 1 DNA damage response axis in colon cancersGENES, CHROMOSOMES AND CANCER, Issue 12 2007Kriste A. Lewis In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase 1 (CHEK1) resulting in cell cycle arrest and subsequent DNA repair. ATR and CHEK1 contain mononucleotide microsatellite repeat regions, which are mutational targets in tumors with defective mismatch repair (MMR). This study examined the frequency of such mutations in colon cancers and their impact on biologic behavior. Screening for ATR mutations in 48 tumors was performed using denaturing high-performance liquid chromatography (DHPLC) and confirmed with sequencing analysis. The CHEK1 exon 7 A(9) region was sequenced in 20 of the 27 (74%) tumors with high frequency of microsatellite instability (MSI-H). Univariate and multivariate analyses were used to examine associations with clinical outcomes. Frequent mutations in MSI-H colon cancers were identified within the ATR (37%)/CHEK1(5%) damage response pathway. Stage and MSI status both independently predicted overall survival (OS) and disease-free survival (DFS). ATR status was not associated with stage, but was associated with a trend toward improved DFS: 0/9 cancers recurred in MSI-H cases harboring ATR mutations vs. 4/18 recurrences in MSI-H cases without ATR mutations. This suggests that ATR mutations may affect clinical behavior and response to therapy in MSI-H colon cancers. © 2007 Wiley-Liss, Inc. [source] | ||||||||||