Distinct changes of genomic biases in nucleotide substitution at the time of mammalian radiation

Differences in the regional substitution patterns in the human genome created patterns of large-scale variation of base composition known as genomic isochores. To gain insight into the origin of the genomic isochores we develop a maximum likelihood approach to determine the history of substitution patterns in the human genome. This approach utilizes the vast amount of repetitive sequence deposited in the human genome over the past ~250 MYR. Using this approach we estimate the frequencies of seven types of substitutions: the four transversions, two transitions, and the methyl-assisted transition of cytosine in CpG. Comparing substitutional patterns in repetitive elements of various ages, we reconstruct the history of the base-substitutional process in the different isochores for the past 250 Myr. At around 90 Myr ago (around the time of the mammalian radiation), we find an abrupt 4- to 8-fold increase of the cytosine transition rate in CpG pairs compared to that of the reptilian ancestor. Further analysis of nucleotide substitutions in regions with different GC-content reveals concurrent changes in the substitutional patterns. While the substitutional pattern was dependent on the regional GC-content in such ways that it preserved the regional GC-content before the mammalian radiation, it lost this dependence afterwards. The substitutional pattern changed from an isochore-preserving to an isochore-degrading one. We conclude that isochores have been established before the radiation of the eutherian mammals and have been subject to the process of homogenization since then

Substantial regional variation in substitution rates in the human genome: importance of GC content, gene density and telomere-specific effects

This study presents the first global, 1 Mbp level analysis of patterns of nucleotide substitutions along the human lineage. The study is based on the analysis of a large amount of repetitive elements deposited into the human genome since the mammalian radiation, yielding a number of results that would have been difficult to obtain using the more conventional comparative method of analysis. This analysis revealed substantial and consistent variability of rates of substitution, with the variability ranging up to 2-fold among different regions. The rates of substitutions of C or G nucleotides with A or T nucleotides vary much more sharply than the reverse rates suggesting that much of that variation is due to differences in mutation rates rather than in the probabilities of fixation of C/G vs. A/T nucleotides across the genome. For all types of substitution we observe substantially more hotspots than coldspots, with hotspots showing substantial clustering over tens of Mbp's. Our analysis revealed that GC-content of surrounding sequences is the best predictor of the rates of substitution. The pattern of substitution appears very different near telomeres compared to the rest of the genome and cannot be explained by the genome-wide correlations of the substitution rates with GC content or exon density. The telomere pattern of substitution is consistent with natural selection or biased gene conversion acting to increase the GC-content of the sequences that are within 10-15 Mbp away from the telomere.Comment: 35 pages, 6 figure

Spontaneous Breaking of Translational Invariance in One-Dimensional Stationary States on a Ring

We consider a model in which positive and negative particles diffuse in an asymmetric, CP-invariant way on a ring. The positive particles hop clockwise, the negative counterclockwise and oppositely-charged adjacent particles may swap positions. Monte-Carlo simulations and analytic calculations suggest that the model has three phases; a "pure" phase in which one has three pinned blocks of only positive, negative particles and vacancies, and in which translational invariance is spontaneously broken, a "mixed" phase with a non-vanishing current in which the three blocks are positive, negative and neutral, and a disordered phase without blocks.Comment: 7 pages, LaTeX, needs epsf.st

Yang-Lee Theory for a Nonequilibrium Phase Transition

To analyze phase transitions in a nonequilibrium system we study its grand canonical partition function as a function of complex fugacity. Real and positive roots of the partition function mark phase transitions. This behavior, first found by Yang and Lee under general conditions for equilibrium systems, can also be applied to nonequilibrium phase transitions. We consider a one-dimensional diffusion model with periodic boundary conditions. Depending on the diffusion rates, we find real and positive roots and can distinguish two regions of analyticity, which can identified with two different phases. In a region of the parameter space both of these phases coexist. The condensation point can be computed with high accuracy.Comment: 4 pages, accepted for publication in Phys.Rev.Let

CorGen—measuring and generating long-range correlations for DNA sequence analysis

CorGen is a web server that measures long-range correlations in the base composition of DNA and generates random sequences with the same correlation parameters. Long-range correlations are characterized by a power-law decay of the auto correlation function of the GC-content. The widespread presence of such correlations in eukaryotic genomes calls for their incorporation into accurate null models of eukaryotic DNA in computational biology. For example, the score statistics of sequence alignment and the performance of motif finding algorithms are significantly affected by the presence of genomic long-range correlations. We use an expansion-randomization dynamics to efficiently generate the correlated random sequences. The server is available a

Emotional and rational disease acceptance in patients with depression and alcohol addiction

<p>Abstract</p> <p>Background</p> <p>The concept of a rational respectively emotional acceptance of disease is highly valued in the treatment of patients with depression or addiction. Due to the importance of this concept for the long-term course of disease, there is a strong interest to develop a tool to identify the levels and factors of acceptance. We thus intended to test an instrument designed to assess the level of positive psychological wellbeing and coping, particularly emotional disease acceptance and life satisfaction</p> <p>Methods</p> <p>In an anonymous cross-sectional survey enrolling 115 patients (51% female, 49% male; mean age 47.6 ± 10.0 years) with depression and/or alcohol addiction, the ERDA questionnaire was tested.</p> <p>Results</p> <p>Factor analysis of the 29-item construct (Cronbach's alpha = 0.933) revealed a 4-factor solution, which explained 59.4% of variance: (1) Positive Life Construction, Contentedness and Well-Being; (2) Conscious Dealing with Illness; (3) Rejection of an Irrational Dealing with Disease; (4) Disease Acceptance. Two factors could be ascribed to a rational, and two to an emotional acceptance. All factors correlated negatively with Depression and Escape, while several aspects of Life Satisfaction" (i.e. myself, overall life, where I live, and future prospects) correlated positively. The highest factor scores were found for the rational acceptance styles (i.e. Conscious Dealing with Illness; Disease Acceptance). Emotional acceptance styles were not valued in a state of depression. Escape from illness was the strongest predictor for several acceptance aspects, while life satisfaction was the most relevant predictor for "Positive Life Construction, Contentedness and Well-Being".</p> <p>Conclusion</p> <p>The ERDA questionnaire was found to be a reliable and valid assessment of disease acceptance strategies in patients with depressive disorders and drug abuses. The results indicate the preferential use of rational acceptance styles even in depression. Disease acceptance should not be regarded as a coping style with an attitude of fatalistic resignation, but as a complex and active process of dealing with a chronic disease. One may assume that an emotional acceptance of disease will result in a therapeutic coping process associated with higher level of life satisfaction and overall quality of life.</p