673 research outputs found
Superhelical Duplex Destabilization and the Recombination Position Effect
The susceptibility to recombination of a plasmid inserted into a chromosome
varies with its genomic position. This recombination position effect is known to
correlate with the average G+C content of the flanking sequences. Here we
propose that this effect could be mediated by changes in the susceptibility to
superhelical duplex destabilization that would occur. We use standard
nonparametric statistical tests, regression analysis and principal component
analysis to identify statistically significant differences in the
destabilization profiles calculated for the plasmid in different contexts, and
correlate the results with their measured recombination rates. We show that the
flanking sequences significantly affect the free energy of denaturation at
specific sites interior to the plasmid. These changes correlate well with
experimentally measured variations of the recombination rates within the
plasmid. This correlation of recombination rate with superhelical
destabilization properties of the inserted plasmid DNA is stronger than that
with average G+C content of the flanking sequences. This model suggests a
possible mechanism by which flanking sequence base composition, which is not
itself a context-dependent attribute, can affect recombination rates at
positions within the plasmid
A stitch in time: Efficient computation of genomic DNA melting bubbles
Background: It is of biological interest to make genome-wide predictions of
the locations of DNA melting bubbles using statistical mechanics models.
Computationally, this poses the challenge that a generic search through all
combinations of bubble starts and ends is quadratic.
Results: An efficient algorithm is described, which shows that the time
complexity of the task is O(NlogN) rather than quadratic. The algorithm
exploits that bubble lengths may be limited, but without a prior assumption of
a maximal bubble length. No approximations, such as windowing, have been
introduced to reduce the time complexity. More than just finding the bubbles,
the algorithm produces a stitch profile, which is a probabilistic graphical
model of bubbles and helical regions. The algorithm applies a probability peak
finding method based on a hierarchical analysis of the energy barriers in the
Poland-Scheraga model.
Conclusions: Exact and fast computation of genomic stitch profiles is thus
feasible. Sequences of several megabases have been computed, only limited by
computer memory. Possible applications are the genome-wide comparisons of
bubbles with promotors, TSS, viral integration sites, and other melting-related
regions.Comment: 16 pages, 10 figure
Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA
We develop a statistical mechanical model to analyze the competitive behavior of transitions to multiple alternate conformations in a negatively supercoiled DNA molecule of kilobase length and specified base sequence. Since DNA superhelicity topologically couples together the transition behaviors of all base pairs, a unified model is required to analyze all the transitions to which the DNA sequence is susceptible. Here we present a first model of this type. Our numerical approach generalizes the strategy of previously developed algorithms, which studied superhelical transitions to a single alternate conformation. We apply our multi-state model to study the competition between strand separation and B-Z transitions in superhelical DNA. We show this competition to be highly sensitive to temperature and to the imposed level of supercoiling. Comparison of our results with experimental data shows that, when the energetics appropriate to the experimental conditions are used, the competition between these two transitions is accurately captured by our algorithm. We analyze the superhelical competition between B-Z transitions and denaturation around the c-myc oncogene, where both transitions are known to occur when this gene is transcribing. We apply our model to explore the correlation between stress-induced transitions and transcriptional activity in various organisms. In higher eukaryotes we find a strong enhancement of Z-forming regions immediately 5′ to their transcription start sites (TSS), and a depletion of strand separating sites in a broad region around the TSS. The opposite patterns occur around transcript end locations. We also show that susceptibility to each type of transition is different in eukaryotes and prokaryotes. By analyzing a set of untranscribed pseudogenes we show that the Z-susceptibility just downstream of the TSS is not preserved, suggesting it may be under selection pressure
Contribution of a mutational hot spot to hemoglobin adaptation in high-altitude Andean house wrens
A key question in evolutionary genetics is why certain mutations or certain types of mutation make disproportionate contributions to adaptive phenotypic evolution. In principle, the preferential fixation of particular mutations could stem directly from variation in the underlying rate of mutation to function-altering alleles. However, the influence of mutation bias on the genetic architecture of phenotypic evolution is difficult to evaluate because data on rates of mutation to function-altering alleles are seldom available. Here, we report the discovery that a single point mutation at a highly mutable site in the βA-globin gene has contributed to an evolutionary change in hemoglobin (Hb) function in high-altitude Andean house wrens (Troglodytes aedon). Results of experiments on native Hb variants and engineered, recombinant Hb mutants demonstrate that a nonsynonymous mutation at a CpG dinucleotide in the βA-globin gene is responsible for an evolved difference in Hb–O2 affinity between high- and low-altitude house wren populations. Moreover, patterns of genomic differentiation between high- and low-altitude populations suggest that altitudinal differentiation in allele frequencies at the causal amino acid polymorphism reflects a history of spatially varying selection. The experimental results highlight the influence of mutation rate on the genetic basis of phenotypic evolution by demonstrating that a large-effect allele at a highly mutable CpG site has promoted physiological differentiation in blood O2 transport capacity between house wren populations that are native to different elevations
Conformations of Linear DNA
We examine the conformations of a model for under- and overwound DNA. The
molecule is represented as a cylindrically symmetric elastic string subjected
to a stretching force and to constraints corresponding to a specification of
the link number. We derive a fundamental relation between the Euler angles that
describe the curve and the topological linking number. Analytical expressions
for the spatial configurations of the molecule in the infinite- length limit
were obtained. A unique configuraion minimizes the energy for a given set of
physical conditions. An elastic model incorporating thermal fluctuations
provides excellent agreement with experimental results on the plectonemic
transition.Comment: 5 pages, RevTeX; 6 postscript figure
Mesoscopic models for DNA stretching under force: new results and comparison to experiments
Single molecule experiments on B-DNA stretching have revealed one or two
structural transitions, when increasing the external force. They are
characterized by a sudden increase of DNA contour length and a decrease of the
bending rigidity. It has been proposed that the first transition, at forces of
60--80 pN, is a transition from B to S-DNA, viewed as a stretched duplex DNA,
while the second one, at stronger forces, is a strand peeling resulting in
single stranded DNAs (ssDNA), similar to thermal denaturation. But due to
experimental conditions these two transitions can overlap, for instance for
poly(dA-dT). We derive analytical formula using a coupled discrete worm like
chain-Ising model. Our model takes into account bending rigidity, discreteness
of the chain, linear and non-linear (for ssDNA) bond stretching. In the limit
of zero force, this model simplifies into a coupled model already developed by
us for studying thermal DNA melting, establishing a connexion with previous
fitting parameter values for denaturation profiles. We find that: (i) ssDNA is
fitted, using an analytical formula, over a nanoNewton range with only three
free parameters, the contour length, the bending modulus and the monomer size;
(ii) a surprisingly good fit on this force range is possible only by choosing a
monomer size of 0.2 nm, almost 4 times smaller than the ssDNA nucleobase
length; (iii) mesoscopic models are not able to fit B to ssDNA (or S to ss)
transitions; (iv) an analytical formula for fitting B to S transitions is
derived in the strong force approximation and for long DNAs, which is in
excellent agreement with exact transfer matrix calculations; (v) this formula
fits perfectly well poly(dG-dC) and -DNA force-extension curves with
consistent parameter values; (vi) a coherent picture, where S to ssDNA
transitions are much more sensitive to base-pair sequence than the B to S one,
emerges.Comment: 14 pages, 9 figure
Salerno's model of DNA reanalysed: could solitons have biological significance?
We investigate the sequence-dependent behaviour of localised excitations in a
toy, nonlinear model of DNA base-pair opening originally proposed by Salerno.
Specifically we ask whether ``breather'' solitons could play a role in the
facilitated location of promoters by RNA polymerase. In an effective potential
formalism, we find excellent correlation between potential minima and {\em
Escherichia coli} promoter recognition sites in the T7 bacteriophage genome.
Evidence for a similar relationship between phage promoters and downstream
coding regions is found and alternative reasons for links between AT richness
and transcriptionally-significant sites are discussed. Consideration of the
soliton energy of translocation provides a novel dynamical picture of sliding:
steep potential gradients correspond to deterministic motion, while ``flat''
regions, corresponding to homogeneous AT or GC content, are governed by random,
thermal motion. Finally we demonstrate an interesting equivalence between
planar, breather solitons and the helical motion of a sliding protein
``particle'' about a bent DNA axis.Comment: Latex file 20 pages, 5 figures. Manuscript of paper to appear in J.
Biol. Phys., accepted 02/09/0
Dynamics of liquid 4He in Vycor
We have measured the dynamic structure factor of liquid 4He in Vycor using
neutron inelastic scattering. Well-defined phonon-roton (p-r) excitations are
observed in the superfluid phase for all wave vectors 0.3 < Q < 2.15. The p-r
energies and lifetimes at low temperature (T = 0.5 K) and their temperature
dependence are the same as in bulk liquid 4He. However, the weight of the
single p-r component does not scale with the superfluid fraction (SF) as it
does in the bulk. In particular, we observe a p-r excitation between T_c =
1.952 K, where SF = 0, and T_(lambda)=2.172 K of the bulk. This suggests, if
the p-r excitation intensity scales with the Bose condensate, that there is a
separation of the Bose-Einstein condensation temperature and the superfluid
transition temperature T_c of 4He in Vycor. We also observe a two-dimensional
layer mode near the roton wave vector. Its dispersion is consistent with
specific heat and SF measurements and with layer modes observed on graphite
surfaces.Comment: 3 pages, 4 figure
Ornithological expeditions to Sarawak, Malaysian Borneo, 2007-2017
Louisiana State University, the University of Kansas, and the Universiti Malaysia Sarawak undertook collaborative research on the evolution and ecology of Bornean birds starting in 2005. This collaboration included a series of expeditions from 2007–2017 to collect and study birds at \u3e30 sites in Sarawak, Malaysian Borneo. Here we provide information on the study-sites and summarize the main discoveries resulting from the collaboration
Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.
Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes
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