428 research outputs found
Effects of Epistasis and Pleiotropy on Fitness Landscapes
The factors that influence genetic architecture shape the structure of the
fitness landscape, and therefore play a large role in the evolutionary
dynamics. Here the NK model is used to investigate how epistasis and pleiotropy
-- key components of genetic architecture -- affect the structure of the
fitness landscape, and how they affect the ability of evolving populations to
adapt despite the difficulty of crossing valleys present in rugged landscapes.
Populations are seen to make use of epistatic interactions and pleiotropy to
attain higher fitness, and are not inhibited by the fact that valleys have to
be crossed to reach peaks of higher fitness.Comment: 10 pages, 6 figures. To appear in "Origin of Life and Evolutionary
Mechanisms" (P. Pontarotti, ed.). Evolutionary Biology: 16th Meeting 2012,
Springer-Verla
Formation of regulatory modules by local sequence duplication
Turnover of regulatory sequence and function is an important part of
molecular evolution. But what are the modes of sequence evolution leading to
rapid formation and loss of regulatory sites? Here, we show that a large
fraction of neighboring transcription factor binding sites in the fly genome
have formed from a common sequence origin by local duplications. This mode of
evolution is found to produce regulatory information: duplications can seed new
sites in the neighborhood of existing sites. Duplicate seeds evolve
subsequently by point mutations, often towards binding a different factor than
their ancestral neighbor sites. These results are based on a statistical
analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome,
and a comparison set of intergenic regulatory sequence in Saccharomyces
cerevisiae. In fly regulatory modules, pairs of binding sites show
significantly enhanced sequence similarity up to distances of about 50 bp. We
analyze these data in terms of an evolutionary model with two distinct modes of
site formation: (i) evolution from independent sequence origin and (ii)
divergent evolution following duplication of a common ancestor sequence. Our
results suggest that pervasive formation of binding sites by local sequence
duplications distinguishes the complex regulatory architecture of higher
eukaryotes from the simpler architecture of unicellular organisms
Numerical Estimation of the Asymptotic Behaviour of Solid Partitions of an Integer
The number of solid partitions of a positive integer is an unsolved problem
in combinatorial number theory. In this paper, solid partitions are studied
numerically by the method of exact enumeration for integers up to 50 and by
Monte Carlo simulations using Wang-Landau sampling method for integers up to
8000. It is shown that, for large n, ln[p(n)]/n^(3/4) = 1.79 \pm 0.01, where
p(n) is the number of solid partitions of the integer n. This result strongly
suggests that the MacMahon conjecture for solid partitions, though not exact,
could still give the correct leading asymptotic behaviour.Comment: 6 pages, 4 figures, revtex
Akalasia
Vertaisarvioitu.Akalasia on harvinainen ruokatorven sairaus, joka aiheuttaa ruokatorven alasulkijan relaksaatiohäiriön ja runko-osan motiliteettihäiriön. Nämä johtavat ruuan nielemisvaikeuteen, käänteisvirtaukseen, rintakipuihin ja joskus painon vähenemiseen. Diagnoosiin päästään tarkkuusmanometrialla. Parantavaa hoitoa ei ole, mutta oireita voidaan lievittää löystyttämällä ruokatorven alasulkijaa joko endoskooppisella pallolaajennnuksella tai leikkaamalla sulkijalihas poikki joko laparoskopiassa (Heller-Dorin leikkaus) tai endoskopiassa (peroraalinen endoskooppinen myotomia, POEM). Monisairaiden potilaiden hoidossa voidaan joskus turvautua farmakologisiin hoitokeinoihin eli suun kautta otettaviin nitraatteihin tai kalsiumin estäjiin taikka botuliinitoksiiniruiskeisiin, mutta niiden teho on rajallinen. Pieni osa potilaista päätyy ruokatorviresektioon taudin edettyä.Peer reviewe
Early age exposure to moisture damage and systemic inflammation at the age of 6 years
Cross-sectional studies have shown that exposure to indoor
moisture damage and mold may be associated with subclinical
inflammation. Our aim was to determine whether early age
exposure to moisture damage or mold is prospectively associated
with subclinical systemic inflammation or with immune
responsiveness in later childhood. Home inspections were
performed in children's homes in the first year of life. At age
6 years, subclinical systemic inflammation was measured by serum
C-reactive protein(CRP) and blood leucocytes and immune
responsiveness by ex vivo production of interleukin
1-beta(IL-1beta), IL-6 and tumor necrosis
factor-alpha(TNF-alpha) in whole blood cultures without
stimulation or after 24h stimulation with phorbol 12-myristate
13-acetate and ionomycin(PI), lipopolysaccharide(LPS) or
peptidoglycan(PPG) in 251 to 270 children. Moisture damage in
child's main living areas in infancy was not significantly
associated with elevated levels of CRP or leucocytes at 6 years.
In contrast, there was some suggestion for an effect on immune
responsiveness, as moisture damage with visible mold was
positively associated with LPS-stimulated production of
TNF-alpha and minor moisture damage was inversely associated
with PI-stimulated IL-1beta. While early life exposure to mold
damage may have some influence on later immune responsiveness,
it does not seem to increase subclinical systemic inflammation
in later life. This article is protected by copyright. All
rights reserved
Monotonicity of Fitness Landscapes and Mutation Rate Control
A common view in evolutionary biology is that mutation rates are minimised.
However, studies in combinatorial optimisation and search have shown a clear
advantage of using variable mutation rates as a control parameter to optimise
the performance of evolutionary algorithms. Much biological theory in this area
is based on Ronald Fisher's work, who used Euclidean geometry to study the
relation between mutation size and expected fitness of the offspring in
infinite phenotypic spaces. Here we reconsider this theory based on the
alternative geometry of discrete and finite spaces of DNA sequences. First, we
consider the geometric case of fitness being isomorphic to distance from an
optimum, and show how problems of optimal mutation rate control can be solved
exactly or approximately depending on additional constraints of the problem.
Then we consider the general case of fitness communicating only partial
information about the distance. We define weak monotonicity of fitness
landscapes and prove that this property holds in all landscapes that are
continuous and open at the optimum. This theoretical result motivates our
hypothesis that optimal mutation rate functions in such landscapes will
increase when fitness decreases in some neighbourhood of an optimum, resembling
the control functions derived in the geometric case. We test this hypothesis
experimentally by analysing approximately optimal mutation rate control
functions in 115 complete landscapes of binding scores between DNA sequences
and transcription factors. Our findings support the hypothesis and find that
the increase of mutation rate is more rapid in landscapes that are less
monotonic (more rugged). We discuss the relevance of these findings to living
organisms
Predicting evolution and visualizing high-dimensional fitness landscapes
The tempo and mode of an adaptive process is strongly determined by the
structure of the fitness landscape that underlies it. In order to be able to
predict evolutionary outcomes (even on the short term), we must know more about
the nature of realistic fitness landscapes than we do today. For example, in
order to know whether evolution is predominantly taking paths that move upwards
in fitness and along neutral ridges, or else entails a significant number of
valley crossings, we need to be able to visualize these landscapes: we must
determine whether there are peaks in the landscape, where these peaks are
located with respect to one another, and whether evolutionary paths can connect
them. This is a difficult task because genetic fitness landscapes (as opposed
to those based on traits) are high-dimensional, and tools for visualizing such
landscapes are lacking. In this contribution, we focus on the predictability of
evolution on rugged genetic fitness landscapes, and determine that peaks in
such landscapes are highly clustered: high peaks are predominantly close to
other high peaks. As a consequence, the valleys separating such peaks are
shallow and narrow, such that evolutionary trajectories towards the highest
peak in the landscape can be achieved via a series of valley crossingsComment: 12 pages, 7 figures. To appear in "Recent Advances in the Theory and
Application of Fitness Landscapes" (A. Engelbrecht and H. Richter, eds.).
Springer Series in Emergence, Complexity, and Computation, 201
Artificial drainage of peatlands: hydrological and hydrochemical process and wetland restoration
Peatlands have been subject to artificial drainage for centuries. This drainage has been in response to agricultural demand, forestry, horticultural and energy properties of peat and alleviation of flood risk. However, the are several environmental problems associated with drainage of peatlands. This paper describes the nature of these problems and examines the evidence for changes in hydrological and hydrochemical processes associated with these changes. Traditional black-box water balance approaches demonstrate little about wetland dynamics and therefore the science of catchment response to peat drainage is poorly understood. It is crucial that a more process-based approach be adopted within peatland ecosystems. The environmental problems associated with peat drainage have led, in part, to a recent reversal in attitudes to peatlands and we have seen a move towards wetland restoration. However, a detailed understanding of hydrological, hydrochemical and ecological process-interactions will be fundamental if we are to adequately restore degraded peatlands, preserve those that are still intact and understand the impacts of such management actions at the catchment scale
High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.Peer reviewe
Genotype to phenotype mapping and the fitness landscape of the E. coli lac promoter
Genotype-to-phenotype maps and the related fitness landscapes that include
epistatic interactions are difficult to measure because of their high
dimensional structure. Here we construct such a map using the recently
collected corpora of high-throughput sequence data from the 75 base pairs long
mutagenized E. coli lac promoter region, where each sequence is associated with
its phenotype, the induced transcriptional activity measured by a fluorescent
reporter. We find that the additive (non-epistatic) contributions of individual
mutations account for about two-thirds of the explainable phenotype variance,
while pairwise epistasis explains about 7% of the variance for the full
mutagenized sequence and about 15% for the subsequence associated with protein
binding sites. Surprisingly, there is no evidence for third order epistatic
contributions, and our inferred fitness landscape is essentially single peaked,
with a small amount of antagonistic epistasis. There is a significant selective
pressure on the wild type, which we deduce to be multi-objective optimal for
gene expression in environments with different nutrient sources. We identify
transcription factor (CRP) and RNA polymerase binding sites in the promotor
region and their interactions without difficult optimization steps. In
particular, we observe evidence for previously unexplored genetic regulatory
mechanisms, possibly kinetic in nature. We conclude with a cautionary note that
inferred properties of fitness landscapes may be severely influenced by biases
in the sequence data
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