(1/2256) Modelling developmental instability as the joint action of noise and stability: a Bayesian approach.
BACKGROUND: Fluctuating asymmetry is assumed to measure individual and population level developmental stability. The latter may in turn show an association with stress, which can be observed through asymmetry-stress correlations. However, the recent literature does not support an ubiquitous relationship. Very little is known why some studies show relatively strong associations while others completely fail to find such a correlation. We propose a new Bayesian statistical framework to examine these associations RESULTS: We are considering developmental stability - i.e. the individual buffering capacity - as the biologically relevant trait and show that (i) little variation in developmental stability can explain observed variation in fluctuating asymmetry when the distribution of developmental stability is highly skewed, and (ii) that a previously developed tool (i.e. the hypothetical repeatability of fluctuating asymmetry) contains only limited information about variation in developmental stability, which stands in sharp contrast to the earlier established close association between the repeatability and developmental instability. CONCLUSION: We provide tools to generate valuable information about the distribution of between-individual variation in developmental stability. A simple linear transformation of a previous model lead to completely different conclusions. Thus, theoretical modelling of asymmetry and stability appears to be very sensitive to the scale of inference. More research is urgently needed to get better insights in the developmental mechanisms of noise and stability. In spite of the fact that the model is likely to represent an oversimplification of reality, the accumulation of new insights could be incorporated in the Bayesian statistical approach to obtain more reliable estimation. (+info)
(2/2256) Comparative genomics of microbial pathogens and symbionts.
We are interested in quantifying the contribution of gene acquisition, loss, expansion and rearrangements to the evolution of microbial genomes. Here, we discuss factors influencing microbial genome divergence based on pair-wise genome comparisons of closely related strains and species with different lifestyles. A particular focus is on intracellular pathogens and symbionts of the genera Rickettsia, Bartonella and BUCHNERA: Extensive gene loss and restricted access to phage and plasmid pools may provide an explanation for why single host pathogens are normally less successful than multihost pathogens. We note that species-specific genes tend to be shorter than orthologous genes, suggesting that a fraction of these may represent fossil-orfs, as also supported by multiple sequence alignments among species. The results of our genome comparisons are placed in the context of phylogenomic analyses of alpha and gamma proteobacteria. We highlight artefacts caused by different rates and patterns of mutations, suggesting that atypical phylogenetic placements can not a priori be taken as evidence for horizontal gene transfer events. The flexibility in genome structure among free-living microbes contrasts with the extreme stability observed for the small genomes of aphid endosymbionts, in which no rearrangements or inflow of genetic material have occurred during the past 50 millions years (1). Taken together, the results suggest that genomic stability correlate with the content of repeated sequences and mobile genetic elements, and thereby indirectly with bacterial lifestyles. (+info)
(3/2256) Increased cell proliferation is associated with genomic instability: elevated micronuclei frequencies in estradiol-treated human ovarian cancer cells.
Estrogen-related cancers are often associated with the hormone's tumor promoting activity. Recently, estradiol has also been demonstrated to induce gene mutations in the physiological concentration range. Mitotic disturbances are found at higher concentrations. In the present study we demonstrate data suggesting an additional mechanism for the induction of genetic damage, i.e. chromosomal breakage. Estrogen receptor-positive (BG-1) and -negative (UCI) human ovarian cancer cell lines were investigated for micronucleus formation after treatment with estradiol. BG-1 cells but not UCI cells showed an increase in micronucleus formation which correlated with the estradiol-induced cell proliferation. The specific estradiol receptor antagonist hydroxytamoxifen suppressed the formation of micronuclei in BG-1 cells. Increased micronucleus frequencies were also seen after normalization of the data to the number of cell divisions. Kinetochore analysis revealed a difference between micronuclei induced by picomolar concentrations of estradiol (kinetochore-negative) and micromolar concentrations (predominantly kinetochore-positive) leading to mitotic disturbances. In accordance with this finding, analysis of the cell cycle revealed decreased cell numbers in G(2)/M phase after treatment with picomolar concentrations, usually not found after mitotic disturbances. We hypothesize that hormone-specific forcing of responsive cells through the cell cycle leads to an override of checkpoints operating under homeostatic control of the cell cycle, resulting in genomic instability. (+info)
(4/2256) Variation in the extent of microsatellite instability in human cell lines with defects in different mismatch repair genes.
Mismatch repair deficiency results in the elevation of mutation rates in tumors, which is especially pronounced in simple repeat sequences (microsatellites). We have investigated the relationship between microsatellite mutagenesis and certain combinations of mutations in mismatch repair genes, using a frameshift reversion assay to determine the spontaneous mutation rates of a dinucleotide microsatellite in two cancer cell lines, HCT116, which has defects in hMLH1 and hMSH3, and HEC-1-A, which has defects in hPMS2 and hMSH6. We found a 10-fold difference in mutation rates between these two cell lines. In addition, a mutant hPMS2 allele, PMS134, which has been reported to have a dominant negative effect, was expressed in mismatch repair-proficient telomerase-immortalized hTERT-1604 fibroblasts and mutation rates were determined. Expression of PMS134 did not elevate mutation rates in hTERT-1604. Combined, these results suggest that mutations in different mismatch repair genes can lead to varying degrees of microsatellite instability. It is also likely that there is heterogeneity in the mutations that are acquired in the absence of mismatch repair, such that some mismatch repair-defective cancer cells also contain mutations in other genes coding for proteins involved in the maintenance of genetic stability. (+info)
(5/2256) Gain of chromosome 8q23-24 is a predictive marker for lymph node positivity in colorectal cancer.
PURPOSE: The prognosis of patients with colorectal cancer is largely determined by tumor stage. In this respect, colorectal cancers with lymph node metastases indicate a worse prognosis versus lymph node-negative tumors. Accordingly, there is considerable clinical interest in understanding the genetic mechanisms underlying metastasis formation. Furthermore, sensitive and specific biomarkers are needed to predict the metastatic phenotype at the time of diagnosis. EXPERIMENTAL DESIGN: Fifty colorectal cancers with or without lymph node metastases were assessed for genomic imbalances by comparative genomic hybridization. Particular interest was focused on whether specific chromosomal alterations exist in primary tumors that might be indicative and specific for the metastatic phenotype. RESULTS: The analysis revealed that lymph node-positive colorectal cancers show a higher degree of chromosomal instability than lymph node-negative cancers (average number of chromosomal copy alterations, 9.8 versus 7.5). Chromosomal alterations commonly described in colorectal cancers such as gain of 20q or loss of 18q21 were not different. However, the gain of chromosomal region 8q23-24 was seen in the vast majority of lymph node-positive cancers, whereas it was rather rare in lymph node-negative carcinomas (P = 0.0016). CONCLUSIONS: These data suggest that genes located at 8q23-24 might favor the development of lymphatic metastases in colorectal cancers. Additionally, the gain of this region could be used to predict the metastatic potential of primary colorectal cancers. (+info)
(6/2256) Positive and negative roles of homologous recombination in the maintenance of genome stability in Saccharomyces cerevisiae.
In previous studies of the loss of heterozygosity (LOH), we analyzed a hemizygous URA3 marker on chromosome III in S. cerevisiae and showed that homologous recombination is involved in processes that lead to LOH in multiple ways, including allelic recombination, chromosome size alterations, and chromosome loss. To investigate the role of homologous recombination more precisely, we examined LOH events in rad50 Delta, rad51 Delta, rad52 Delta, rad50 Delta rad52 Delta, and rad51 Delta rad52 Delta mutants. As compared to Rad(+) cells, the frequency of LOH was significantly increased in all mutants, and most events were chromosome loss. Other LOH events were differentially affected in each mutant: the frequencies of all types of recombination were decreased in rad52 mutants and enhanced in rad50 mutants. The rad51 mutation increased the frequency of ectopic but not allelic recombination. Both the rad52 and rad51 mutations increased the frequency of intragenic point mutations approximately 25-fold, suggesting that alternative mutagenic pathways partially substitute for homologous recombination. Overall, these results indicate that all of the genes are required for chromosome maintenance and that they most likely function in homologous recombination between sister chromatids. In contrast, other recombination pathways can occur at a substantial level even in the absence of one of the genes and contribute to generating various chromosome rearrangements. (+info)
(7/2256) Single-nucleotide polymorphisms of the Trypanosoma cruzi MSH2 gene support the existence of three phylogenetic lineages presenting differences in mismatch-repair efficiency.
We have identified single-nucleotide polymorphisms (SNPs) in the mismatch-repair gene TcMSH2 from Trypanosoma cruzi. Phylogenetic inferences based on the SNPs, confirmed by RFLP analysis of 32 strains, showed three distinct haplogroups, denominated A, B, and C. Haplogroups A and C presented strong identity with the previously described T. cruzi lineages I and II, respectively. A third haplogroup (B) was composed of strains presenting hybrid characteristics. All strains from a haplogroup encoded the same specific protein isoform, called, respectively, TcMHS2a, TcMHS2b, and TcMHS2c. The classification into haplogroups A, B, and C correlated with variation in the efficiency of mismatch repair in these cells. When microsatellite loci of strains representative of each haplogroup were analyzed after being cultured in the presence of hydrogen peroxide, new microsatellite alleles were definitely seen in haplogroups B and C, while no evidence of microsatellite instability was found in haplogroup A. Also, cells from haplogroups B and C were considerably more resistant to cisplatin treatment, a characteristic known to be conferred by deficiency of mismatch repair in eukaryotic cells. Altogether, our data suggest that strains belonging to haplogroups B and C may have decreased mismatch-repair ability when compared with strains assigned to the haplogroup A lineage. (+info)
(8/2256) Ensuring the stability of the genome: DNA damage checkpoints.
The cellular response to DNA damage is vital for the cell"s ability to maintain genomic integrity. Checkpoint signalling pathways, which induce a cell cycle arrest in response to DNA damage, are an essential component of this process. This is reflected by the functional conservation of these pathways in all eukaryotes from yeast to mammalian cells. This review will examine the cellular response to DNA damage throughout the cell cycle. A key component of the DNA damage response is checkpoint signalling, which monitors the state of the genome prior to DNA replication (G1/S) and chromosome segregation (G2/M). Checkpoint signalling in model systems including mice, Xenopus laevis, Drosophila melanogaster, and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe have been useful in elucidating these pathways in mammalian cells. An examination of this research, with emphasis on the function of checkpoint proteins, their relationship to DNA repair, and their involvement in oncogenesis is undertaken here. (+info)