Calibration of Multiple Poliovirus Molecular Clocks Covering an Extended Evolutionary Range▿ †

PubMed Central

Jorba, Jaume; Campagnoli, Ray; De, Lina; Kew, Olen

2008-01-01

We have calibrated five different molecular clocks for circulating poliovirus based upon the rates of fixation of total substitutions (Kt), synonymous substitutions (Ks), synonymous transitions (As), synonymous transversions (Bs), and nonsynonymous substitutions (Ka) into the P1/capsid region (2,643 nucleotides). Rates were determined over a 10-year period by analysis of sequences of 31 wild poliovirus type 1 isolates representing a well-defined phylogeny derived from a common imported ancestor. Similar rates were obtained by linear regression, the maximum likelihood/single-rate dated-tip method, and Bayesian inference. The very rapid Kt [(1.03 ± 0.10) × 10−2 substitutions/site/year] and Ks [(1.00 ± 0.08) × 10−2] clocks were driven primarily by the As clock [(0.96 ± 0.09) × 10−2], the Bs clock was ∼10-fold slower [(0.10 ± 0.03) × 10−2], and the more stochastic Ka clock was ∼30-fold slower [(0.03 ± 0.01) × 10−2]. Nonsynonymous substitutions at all P1/capsid sites, including the neutralizing antigenic sites, appeared to be constrained by purifying selection. Simulation of the evolution of third-codon positions suggested that saturation of synonymous transitions would be evident at 10 years and complete at ∼65 years of independent transmission. Saturation of synonymous transversions was predicted to be minimal at 20 years and incomplete at 100 years. The rapid evolution of the Kt, Ks, and As clocks can be used to estimate the dates of divergence of closely related viruses, whereas the slower Bs and Ka clocks may be used to explore deeper evolutionary relationships within and across poliovirus genotypes. PMID:18287242

Bayesian view of single-qubit clocks, and an energy versus accuracy tradeoff

NASA Astrophysics Data System (ADS)

Gopalkrishnan, Manoj; Kandula, Varshith; Sriram, Praveen; Deshpande, Abhishek; Muralidharan, Bhaskaran

2017-09-01

We bring a Bayesian approach to the analysis of clocks. Using exponential distributions as priors for clocks, we analyze how well one can keep time with a single qubit freely precessing under a magnetic field. We find that, at least with a single qubit, quantum mechanics does not allow exact timekeeping, in contrast to classical mechanics, which does. We find the design of the single-qubit clock that leads to maximum accuracy. Further, we find an energy versus accuracy tradeoff—the energy cost is at least kBT times the improvement in accuracy as measured by the entropy reduction in going from the prior distribution to the posterior distribution. We propose a physical realization of the single-qubit clock using charge transport across a capacitively coupled quantum dot.

The relative ages of ectomycorrhizal mushrooms and their plant hosts estimated using Bayesian relaxed molecular clock analyses

PubMed Central

Hibbett, David S; Matheny, P Brandon

2009-01-01

Background Ectomycorrhizae (ECM) are symbioses formed by polyphyletic assemblages of fungi (mostly Agaricomycetes) and plants (mostly Pinaceae and angiosperms in the rosid clade). Efforts to reconstruct the evolution of the ECM habit in Agaricomycetes have yielded vastly different results, ranging from scenarios with many relatively recent origins of the symbiosis and no reversals to the free-living condition; a single ancient origin of ECM and many subsequent transitions to the free-living condition; or multiple gains and losses of the association. To test the plausibility of these scenarios, we performed Bayesian relaxed molecular clock analyses including fungi, plants, and other eukaryotes, based on the principle that a symbiosis cannot evolve prior to the origin of both partners. As we were primarily interested in the relative ages of the plants and fungi, we did not attempt to calibrate the molecular clock using the very limited fossil record of Agaricomycetes. Results Topologically constrained and unconstrained analyses suggest that the root node of the Agaricomycetes is much older than either the rosids or Pinaceae. The Agaricomycetidae, a large clade containing the Agaricales and Boletales (collectively representing 70% of Agaricomycetes), is also significantly older than the rosids. The relative age of Agaricomycetidae and Pinaceae, however, is sensitive to tree topology, and the inclusion or exclusion of the gnetophyte Welwitschia mirabilis. Conclusion The ancestor of the Agaricomycetes could not have been an ECM species because it existed long before any of its potential hosts. Within more derived clades of Agaricomycetes, there have been at least eight independent origins of ECM associations involving angiosperms, and at least six to eight origins of associations with gymnosperms. The first ECM symbioses may have involved Pinaceae, which are older than rosids, but several major clades of Agaricomycetes, such as the Boletales and Russulales, are young enough to have been plesiomorphically associated with either rosids or Pinaceae, suggesting that some contemporary ECM partnerships could be of very ancient origin. PMID:19284559

Evolution and dispersal of St. Louis encephalitis virus in the Americas.

PubMed

Auguste, Albert J; Pybus, Oliver G; Carrington, Christine V F

2009-07-01

Using a Bayesian coalescent approach on a dataset of 73 envelope gene sequences we estimated substitution rates and dates of divergence for St. Louis encephalitis virus (SLEV) in the Americas. We found significant rate heterogeneity among lineages, such that "relaxed" molecular clock models were much better supported than a strict molecular clock. The mean substitution rate estimated for all SLEV was 4.1x10(-4)substitutions/site/year (95% HPD 2.5-5.7)-higher than previous estimates that relied on the less well-suited strict clock. Mean substitution rates for individual lineages varied from 3.7x10(-4) to 7.2x10(-4)substitutions/site/year. For the first time we also assessed the magnitude and direction of viral gene flow within the Americas. The overall direction of gene flow during the period represented by the phylogeny is from South to North, and the region between 15 degrees N and 30 degrees N latitude appears to be the major source of virus for the rest of North America, which is consistent with migratory birds returning to their northern breeding grounds having acquired infection while wintering in the region of the Gulf of Mexico.

Estimation of divergence times in litostomatean ciliates (Ciliophora: Intramacronucleata), using Bayesian relaxed clock and 18S rRNA gene.

PubMed

Vďačný, Peter

2015-08-01

The class Litostomatea comprises a diverse assemblage of free-living and endosymbiotic ciliates. To understand diversification dynamic of litostomateans, divergence times of their main groups were estimated with the Bayesian molecular dating, a technique allowing relaxation of molecular clock and incorporation of flexible calibration points. The class Litostomatea very likely emerged during the Cryogenian around 680 Mya. The origin of the subclass Rhynchostomatia is dated to about 415 Mya, while that of the subclass Haptoria to about 654 Mya. The order Pleurostomatida, emerging about 556 Mya, was recognized as the oldest group within the subclass Haptoria. The order Spathidiida appeared in the Paleozoic about 442 Mya. The three remaining haptorian orders evolved in the Paleozoic/Mesozoic periods: Didiniida about 419 Mya, Lacrymariida about 269 Mya, and Haptorida about 194 Mya. The subclass Trichostomatia originated from a spathidiid ancestor in the Mesozoic about 260 Mya. A further goal of this study was to investigate the impact of various settings on posterior divergence time estimates. The root placement and tree topology as well as the priors of the rate-drift model, birth-death process and nucleotide substitution rate, had no significant effect on calculation of posterior divergence time estimates. However, removal of calibration points could significantly change time estimates at some nodes. Copyright © 2015 Elsevier GmbH. All rights reserved.

FLOWERING LOCUS C Mediates Natural Variation in the High-Temperature Response of the Arabidopsis Circadian Clock[W

PubMed Central

Edwards, Kieron D.; Anderson, Paul E.; Hall, Anthony; Salathia, Neeraj S.; Locke, James C.W.; Lynn, James R.; Straume, Martin; Smith, James Q.; Millar, Andrew J.

2006-01-01

Temperature compensation contributes to the accuracy of biological timing by preventing circadian rhythms from running more quickly at high than at low temperatures. We previously identified quantitative trait loci (QTL) with temperature-specific effects on the circadian rhythm of leaf movement, including a QTL linked to the transcription factor FLOWERING LOCUS C (FLC). We have now analyzed FLC alleles in near-isogenic lines and induced mutants to eliminate other candidate genes. We showed that FLC lengthened the circadian period specifically at 27°C, contributing to temperature compensation of the circadian clock. Known upstream regulators of FLC expression in flowering time pathways similarly controlled its circadian effect. We sought to identify downstream targets of FLC regulation in the molecular mechanism of the circadian clock using genome-wide analysis to identify FLC-responsive genes and 3503 transcripts controlled by the circadian clock. A Bayesian clustering method based on Fourier coefficients allowed us to discriminate putative regulatory genes. Among rhythmic FLC-responsive genes, transcripts of the transcription factor LUX ARRHYTHMO (LUX) correlated in peak abundance with the circadian period in flc mutants. Mathematical modeling indicated that the modest change in peak LUX RNA abundance was sufficient to cause the period change due to FLC, providing a molecular target for the crosstalk between flowering time pathways and circadian regulation. PMID:16473970

Phylodynamics of classical swine fever virus with emphasis on Ecuadorian strains.

PubMed

Garrido Haro, A D; Barrera Valle, M; Acosta, A; J Flores, F

2018-06-01

Classic swine fever virus (CSFV) is a Pestivirus from the Flaviviridae family that affects pigs worldwide and is endemic in several Latin American countries. However, there are still some countries in the region, including Ecuador, for which CSFV molecular information is lacking. To better understand the epidemiology of CSFV in the Americas, sequences from CSFVs from Ecuador were generated and a phylodynamic analysis of the virus was performed. Sequences for the full-length glycoprotein E2 gene of twenty field isolates were obtained and, along with sequences from strains previously described in the Americas and from the most representative strains worldwide, were used to analyse the phylodynamics of the virus. Bayesian methods were used to test several molecular clock and demographic models. A calibrated ultrametric tree and a Bayesian skyline were constructed, and codons associated with positive selection involving immune scape were detected. The best model according to Bayes factors was the strict molecular clock and Bayesian skyline model, which shows that CSFV has an evolution rate of 3.2 × 10 -4 substitutions per site per year. The model estimates the origin of CSFV in the mid-1500s. There is a strong spatial structure for CSFV in the Americas, indicating that the virus is moving mainly through neighbouring countries. The genetic diversity of CSFV has increased constantly since its appearance, with a slight decrease in mid-twentieth century, which coincides, with eradication campaigns in North America. Even though there is no evidence of strong directional evolution of the E2 gene in CSFV, codons 713, 761, 762 and 975 appear to be selected positively and could be related to virulence or pathogenesis. These results reveal how CSFV has spread and evolved since it first appeared in the Americas and provide important information for attaining the goal of eradication of this virus in Latin America. © 2018 Blackwell Verlag GmbH.

Estimating evolutionary rates using time-structured data: a general comparison of phylogenetic methods.

PubMed

Duchêne, Sebastián; Geoghegan, Jemma L; Holmes, Edward C; Ho, Simon Y W

2016-11-15

In rapidly evolving pathogens, including viruses and some bacteria, genetic change can accumulate over short time-frames. Accordingly, their sampling times can be used to calibrate molecular clocks, allowing estimation of evolutionary rates. Methods for estimating rates from time-structured data vary in how they treat phylogenetic uncertainty and rate variation among lineages. We compiled 81 virus data sets and estimated nucleotide substitution rates using root-to-tip regression, least-squares dating and Bayesian inference. Although estimates from these three methods were often congruent, this largely relied on the choice of clock model. In particular, relaxed-clock models tended to produce higher rate estimates than methods that assume constant rates. Discrepancies in rate estimates were also associated with high among-lineage rate variation, and phylogenetic and temporal clustering. These results provide insights into the factors that affect the reliability of rate estimates from time-structured sequence data, emphasizing the importance of clock-model testing. sduchene@unimelb.edu.au or garzonsebastian@hotmail.comSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Search for transient ultralight dark matter signatures with networks of precision measurement devices using a Bayesian statistics method

NASA Astrophysics Data System (ADS)

Roberts, B. M.; Blewitt, G.; Dailey, C.; Derevianko, A.

2018-04-01

We analyze the prospects of employing a distributed global network of precision measurement devices as a dark matter and exotic physics observatory. In particular, we consider the atomic clocks of the global positioning system (GPS), consisting of a constellation of 32 medium-Earth orbit satellites equipped with either Cs or Rb microwave clocks and a number of Earth-based receiver stations, some of which employ highly-stable H-maser atomic clocks. High-accuracy timing data is available for almost two decades. By analyzing the satellite and terrestrial atomic clock data, it is possible to search for transient signatures of exotic physics, such as "clumpy" dark matter and dark energy, effectively transforming the GPS constellation into a 50 000 km aperture sensor array. Here we characterize the noise of the GPS satellite atomic clocks, describe the search method based on Bayesian statistics, and test the method using simulated clock data. We present the projected discovery reach using our method, and demonstrate that it can surpass the existing constrains by several order of magnitude for certain models. Our method is not limited in scope to GPS or atomic clock networks, and can also be applied to other networks of precision measurement devices.

Flatfish monophyly refereed by the relationship of Psettodes in Carangimorphariae.

PubMed

Shi, Wei; Chen, Shixi; Kong, Xiaoyu; Si, Lizhen; Gong, Li; Zhang, Yanchun; Yu, Hui

2018-05-25

The monophyly of flatfishes has not been supported in many molecular phylogenetic studies. The monophyly of Pleuronectoidei, which comprises all but one family of flatfishes, is broadly supported. However, the Psettodoidei, comprising the single family Psettodidae, is often found to be most closely related to other carangimorphs based on substantial sequencing efforts and diversely analytical methods. In this study, we examined why this particular result is often obtained. The mitogenomes of five flatfishes were determined. Select mitogenomes of representative carangimorph species were further employed for phylogenetic and molecular clock analyses. Our phylogenetic results do not fully support Psettodes as a sister group to pleuronectoids or other carangimorphs. And results also supported the evidence of long-branch attraction between Psettodes and the adjacent clades. Two chronograms, derived from Bayesian relaxed-clock methods, suggest that over a short period in the early Paleocene, a series of important evolutionary events occurred in carangimorphs. Based on insights provided by the molecular clock, we propose the following evolutionary explanation for the difficulty in determining the phylogenetic position of Psettodes: The initial diversification of Psettodes was very close in time to the initial diversification of carangimorphs, and the primary diversification time of pleuronectoids, the other suborder of flatfishes, occurred later than that of some percomorph taxa. Additionally, the clade of Psettodes is long and naked branch, which supports the uncertainty of its phylogenetic placement. Finally, we confirmed the monophyly of flatfishes, which was accepted by most ichthyologists.

Short communication: phylodynamics analysis of the human immunodeficiency virus type 1 envelope gene in mother and child pairs.

PubMed

Santos, Luciane Amorim; Gray, Rebecca R; Monteiro-Cunha, Joana Paixão; Strazza, Evandra; Kashima, Simone; Santos, Edson de Souza; Araújo, Thessika Hialla Almeida; Gonçalves, Marilda de Souza; Salemi, Marco; Alcantara, Luiz Carlos Junior

2015-09-01

Characterizing the impact of HIV transmission routes on viral genetic diversity can improve the understanding of the mechanisms of virus evolution and adaptation. HIV vertical transmission can occur in utero, during delivery, or while breastfeeding. The present study investigated the phylodynamics of the HIV-1 env gene in mother-to-child transmission by analyzing one chronically infected pair from Brazil and three acutely infected pairs from Zambia, with three to five time points. Sequences from 25 clones from each sample were obtained and aligned using Clustal X. ML trees were constructed in PhyML using the best evolutionary model. Bayesian analyses testing the relaxed and strict molecular clock were performed using BEAST and a Bayesian Skyline Plot (BSP) was construed. The genetic variability of previously described epitopes was investigated and compared between each individual time point and between mother and child sequences. The relaxed molecular clock was the best-fitted model for all datasets. The tree topologies did not show differentiation in the evolutionary dynamics of the virus circulating in the mother from the viral population in the child. In the BSP, the effective population size was more constant in time in the chronically infected patients while in the acute patients it was possible to detect bottlenecks. The genetic variability within viral epitopes recognized by the human immune system was considerably higher among the chronically infected pair in comparison with acutely infected pairs. These results contribute to a better understanding of HIV-1 evolutionary dynamics in mother-to-child transmission.

Molecular cogs of the insect circadian clock.

PubMed

Shirasu, Naoto; Shimohigashi, Yasuyuki; Tominaga, Yoshiya; Shimohigashi, Miki

2003-08-01

During the last five years, enormous progress has been made in understanding the molecular basis of circadian systems, mainly by molecular genetic studies using the mouse and fly. Extensive evidence has revealed that the core clock machinery involves "clock genes" and "clock proteins" functioning as molecular cogs. These participate in transcriptional/translational feedback loops and many homologous clock-components in the fruit fly Drosophila are also expressed in mammalian clock tissues with circadian rhythms. Thus, the mechanisms of the central clock seem to be conserved across animal kingdom. However, some recent studies imply that the present widely accepted molecular models of circadian clocks may not always be supported by the experimental evidence.

Host jumps shaped the diversity of extant rust fungi (Pucciniales).

PubMed

McTaggart, Alistair R; Shivas, Roger G; van der Nest, Magriet A; Roux, Jolanda; Wingfield, Brenda D; Wingfield, Michael J

2016-02-01

The aim of this study was to determine the evolutionary time line for rust fungi and date key speciation events using a molecular clock. Evidence is provided that supports a contemporary view for a recent origin of rust fungi, with a common ancestor on a flowering plant. Divergence times for > 20 genera of rust fungi were studied with Bayesian evolutionary analyses. A relaxed molecular clock was applied to ribosomal and mitochondrial genes, calibrated against estimated divergence times for the hosts of rust fungi, such as Acacia (Fabaceae), angiosperms and the cupressophytes. Results showed that rust fungi shared a most recent common ancestor with a mean age between 113 and 115 million yr. This dates rust fungi to the Cretaceous period, which is much younger than previous estimations. Host jumps, whether taxonomically large or between host genera in the same family, most probably shaped the diversity of rust genera. Likewise, species diversified by host shifts (through coevolution) or via subsequent host jumps. This is in contrast to strict coevolution with their hosts. Puccinia psidii was recovered in Sphaerophragmiaceae, a family distinct from Raveneliaceae, which were regarded as confamilial in previous studies. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Bayesian historical earthquake relocation: an example from the 1909 Taipei earthquake

USGS Publications Warehouse

Minson, Sarah E.; Lee, William H.K.

2014-01-01

Locating earthquakes from the beginning of the modern instrumental period is complicated by the fact that there are few good-quality seismograms and what traveltimes do exist may be corrupted by both large phase-pick errors and clock errors. Here, we outline a Bayesian approach to simultaneous inference of not only the hypocentre location but also the clock errors at each station and the origin time of the earthquake. This methodology improves the solution for the source location and also provides an uncertainty analysis on all of the parameters included in the inversion. As an example, we applied this Bayesian approach to the well-studied 1909 Mw 7 Taipei earthquake. While our epicentre location and origin time for the 1909 Taipei earthquake are consistent with earlier studies, our focal depth is significantly shallower suggesting a higher seismic hazard to the populous Taipei metropolitan area than previously supposed.

Species delimitation of the Hyphydrus ovatus complex in western Palaearctic with an update of species distributions (Coleoptera, Dytiscidae)

PubMed Central

Bergsten, Johannes; Weingartner, Elisabeth; Hájek, Jiří

2017-01-01

Abstract The species status of Hyphydrus anatolicus Guignot, 1957 and H. sanctus Sharp, 1882, previously often confused with the widespread H. ovatus (Linnaeus, 1760), are tested with molecular and morphological characters. Cytochrome c oxidase subunit 1 (CO1) was sequenced for 32 specimens of all three species. Gene-trees were inferred with parsimony, time-free bayesian and strict clock bayesian analyses. The GMYC model was used to estimate species limits. All three species were reciprocally monophyletic with CO1 and highly supported. The GMYC species delimitation analysis unequivocally delimited the three species with no other than the three species solution included in the confidence interval. A likelihood ratio test rejected the one-species null model. Important morphological characters distinguishing the species are provided and illustrated. New distributional data are given for the following species: Hyphydrus anatolicus from Slovakia and Ukraine, and H. aubei Ganglbauer, 1891, and H. sanctus from Turkey. PMID:28769697

Searching for efficient Markov chain Monte Carlo proposal kernels

PubMed Central

Yang, Ziheng; Rodríguez, Carlos E.

2013-01-01

Markov chain Monte Carlo (MCMC) or the Metropolis–Hastings algorithm is a simulation algorithm that has made modern Bayesian statistical inference possible. Nevertheless, the efficiency of different Metropolis–Hastings proposal kernels has rarely been studied except for the Gaussian proposal. Here we propose a unique class of Bactrian kernels, which avoid proposing values that are very close to the current value, and compare their efficiency with a number of proposals for simulating different target distributions, with efficiency measured by the asymptotic variance of a parameter estimate. The uniform kernel is found to be more efficient than the Gaussian kernel, whereas the Bactrian kernel is even better. When optimal scales are used for both, the Bactrian kernel is at least 50% more efficient than the Gaussian. Implementation in a Bayesian program for molecular clock dating confirms the general applicability of our results to generic MCMC algorithms. Our results refute a previous claim that all proposals had nearly identical performance and will prompt further research into efficient MCMC proposals. PMID:24218600

Circadian molecular clock in lung pathophysiology

PubMed Central

Sundar, Isaac K.; Yao, Hongwei; Sellix, Michael T.

2015-01-01

Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

The Drosophila Clock Neuron Network Features Diverse Coupling Modes and Requires Network-wide Coherence for Robust Circadian Rhythms.

PubMed

Yao, Zepeng; Bennett, Amelia J; Clem, Jenna L; Shafer, Orie T

2016-12-13

In animals, networks of clock neurons containing molecular clocks orchestrate daily rhythms in physiology and behavior. However, how various types of clock neurons communicate and coordinate with one another to produce coherent circadian rhythms is not well understood. Here, we investigate clock neuron coupling in the brain of Drosophila and demonstrate that the fly's various groups of clock neurons display unique and complex coupling relationships to core pacemaker neurons. Furthermore, we find that coordinated free-running rhythms require molecular clock synchrony not only within the well-characterized lateral clock neuron classes but also between lateral clock neurons and dorsal clock neurons. These results uncover unexpected patterns of coupling in the clock neuron network and reveal that robust free-running behavioral rhythms require a coherence of molecular oscillations across most of the fly's clock neuron network. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Evaluating the Impact of Genomic Data and Priors on Bayesian Estimates of the Angiosperm Evolutionary Timescale.

PubMed

Foster, Charles S P; Sauquet, Hervê; van der Merwe, Marlien; McPherson, Hannah; Rossetto, Maurizio; Ho, Simon Y W

2017-05-01

The evolutionary timescale of angiosperms has long been a key question in biology. Molecular estimates of this timescale have shown considerable variation, being influenced by differences in taxon sampling, gene sampling, fossil calibrations, evolutionary models, and choices of priors. Here, we analyze a data set comprising 76 protein-coding genes from the chloroplast genomes of 195 taxa spanning 86 families, including novel genome sequences for 11 taxa, to evaluate the impact of models, priors, and gene sampling on Bayesian estimates of the angiosperm evolutionary timescale. Using a Bayesian relaxed molecular-clock method, with a core set of 35 minimum and two maximum fossil constraints, we estimated that crown angiosperms arose 221 (251-192) Ma during the Triassic. Based on a range of additional sensitivity and subsampling analyses, we found that our date estimates were generally robust to large changes in the parameters of the birth-death tree prior and of the model of rate variation across branches. We found an exception to this when we implemented fossil calibrations in the form of highly informative gamma priors rather than as uniform priors on node ages. Under all other calibration schemes, including trials of seven maximum age constraints, we consistently found that the earliest divergences of angiosperm clades substantially predate the oldest fossils that can be assigned unequivocally to their crown group. Overall, our results and experiments with genome-scale data suggest that reliable estimates of the angiosperm crown age will require increased taxon sampling, significant methodological changes, and new information from the fossil record. [Angiospermae, chloroplast, genome, molecular dating, Triassic.]. © The Author(s) 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Molecular clock of HIV-1 envelope genes under early immune selection

DOE PAGES

Park, Sung Yong; Love, Tanzy M. T.; Perelson, Alan S.; ...

2016-06-01

Here, the molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1’s early evolution in the presence of immune selection has not yet been fully examined.

Molecular clock of HIV-1 envelope genes under early immune selection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Sung Yong; Love, Tanzy M. T.; Perelson, Alan S.

Here, the molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1’s early evolution in the presence of immune selection has not yet been fully examined.

A total-evidence approach to dating with fossils, applied to the early radiation of the hymenoptera.

PubMed

Ronquist, Fredrik; Klopfstein, Seraina; Vilhelmsen, Lars; Schulmeister, Susanne; Murray, Debra L; Rasnitsyn, Alexandr P

2012-12-01

Phylogenies are usually dated by calibrating interior nodes against the fossil record. This relies on indirect methods that, in the worst case, misrepresent the fossil information. Here, we contrast such node dating with an approach that includes fossils along with the extant taxa in a Bayesian total-evidence analysis. As a test case, we focus on the early radiation of the Hymenoptera, mostly documented by poorly preserved impression fossils that are difficult to place phylogenetically. Specifically, we compare node dating using nine calibration points derived from the fossil record with total-evidence dating based on 343 morphological characters scored for 45 fossil (4--20 complete) and 68 extant taxa. In both cases we use molecular data from seven markers (∼5 kb) for the extant taxa. Because it is difficult to model speciation, extinction, sampling, and fossil preservation realistically, we develop a simple uniform prior for clock trees with fossils, and we use relaxed clock models to accommodate rate variation across the tree. Despite considerable uncertainty in the placement of most fossils, we find that they contribute significantly to the estimation of divergence times in the total-evidence analysis. In particular, the posterior distributions on divergence times are less sensitive to prior assumptions and tend to be more precise than in node dating. The total-evidence analysis also shows that four of the seven Hymenoptera calibration points used in node dating are likely to be based on erroneous or doubtful assumptions about the fossil placement. With respect to the early radiation of Hymenoptera, our results suggest that the crown group dates back to the Carboniferous, ∼309 Ma (95% interval: 291--347 Ma), and diversified into major extant lineages much earlier than previously thought, well before the Triassic. [Bayesian inference; fossil dating; morphological evolution; relaxed clock; statistical phylogenetics.].

A Total-Evidence Approach to Dating with Fossils, Applied to the Early Radiation of the Hymenoptera

PubMed Central

Ronquist, Fredrik; Klopfstein, Seraina; Vilhelmsen, Lars; Schulmeister, Susanne; Murray, Debra L.; Rasnitsyn, Alexandr P.

2012-01-01

Abstract Phylogenies are usually dated by calibrating interior nodes against the fossil record. This relies on indirect methods that, in the worst case, misrepresent the fossil information. Here, we contrast such node dating with an approach that includes fossils along with the extant taxa in a Bayesian total-evidence analysis. As a test case, we focus on the early radiation of the Hymenoptera, mostly documented by poorly preserved impression fossils that are difficult to place phylogenetically. Specifically, we compare node dating using nine calibration points derived from the fossil record with total-evidence dating based on 343 morphological characters scored for 45 fossil (4--20 complete) and 68 extant taxa. In both cases we use molecular data from seven markers (∼5 kb) for the extant taxa. Because it is difficult to model speciation, extinction, sampling, and fossil preservation realistically, we develop a simple uniform prior for clock trees with fossils, and we use relaxed clock models to accommodate rate variation across the tree. Despite considerable uncertainty in the placement of most fossils, we find that they contribute significantly to the estimation of divergence times in the total-evidence analysis. In particular, the posterior distributions on divergence times are less sensitive to prior assumptions and tend to be more precise than in node dating. The total-evidence analysis also shows that four of the seven Hymenoptera calibration points used in node dating are likely to be based on erroneous or doubtful assumptions about the fossil placement. With respect to the early radiation of Hymenoptera, our results suggest that the crown group dates back to the Carboniferous, ∼309 Ma (95% interval: 291--347 Ma), and diversified into major extant lineages much earlier than previously thought, well before the Triassic. [Bayesian inference; fossil dating; morphological evolution; relaxed clock; statistical phylogenetics.] PMID:22723471

Circadian Rhythms, the Molecular Clock, and Skeletal Muscle

PubMed Central

Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A.

2015-01-01

Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1−/− and ClockΔ19 mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle. PMID:21621073

Molecular Systematics of the Cape Parrot (Poicephalus robustus): Implications for Taxonomy and Conservation

PubMed Central

Coetzer, Willem G.; Downs, Colleen T.; Perrin, Mike R.; Willows-Munro, Sandi

2015-01-01

The taxonomic position of the Cape Parrot (Poicephalus robustus robustus) has been the focus of much debate. A number of authors suggest that the Cape Parrot should be viewed as a distinct species separate from the other two P. robustus subspecies (P. r. fuscicollis and P. r. suahelicus). These recommendations were based on morphological, ecological, and behavioural assessments. In this study we investigated the validity of these recommendations using multilocus DNA analyses. We genotyped 138 specimens from five Poicephalus species (P. cryptoxanthus, P. gulielmi, P. meyeri, P. robustus, and P. rueppellii) using 11 microsatellite loci. Additionally, two mitochondrial (cytochrome oxidase I gene and 16S ribosomal RNA) and one nuclear intron (intron 7 of the β-fibrinogen gene) markers were amplified and sequenced. Bayesian clustering analysis and pairwise FST analysis of microsatellite data identified P. r. robustus as genetically distinct from the other P. robustus subspecies. Phylogenetic and molecular clock analyses on sequence data also supported the microsatellite analyses, placing P. r. robustus in a distinct clade separate from the other P. robustus subspecies. Molecular clock analysis places the most recent common ancestor between P. r. robustus and P. r. fuscicollis / P. r. suahelicus at 2.13 to 2.67 million years ago. Our results all support previous recommendations to elevate the Cape Parrot to species level. This will facilitate better planning and implementation of international and local conservation management strategies for the Cape Parrot. PMID:26267261

Theoretical Foundation of the RelTime Method for Estimating Divergence Times from Variable Evolutionary Rates

PubMed Central

Tamura, Koichiro; Tao, Qiqing; Kumar, Sudhir

2018-01-01

Abstract RelTime estimates divergence times by relaxing the assumption of a strict molecular clock in a phylogeny. It shows excellent performance in estimating divergence times for both simulated and empirical molecular sequence data sets in which evolutionary rates varied extensively throughout the tree. RelTime is computationally efficient and scales well with increasing size of data sets. Until now, however, RelTime has not had a formal mathematical foundation. Here, we show that the basis of the RelTime approach is a relative rate framework (RRF) that combines comparisons of evolutionary rates in sister lineages with the principle of minimum rate change between evolutionary lineages and their respective descendants. We present analytical solutions for estimating relative lineage rates and divergence times under RRF. We also discuss the relationship of RRF with other approaches, including the Bayesian framework. We conclude that RelTime will be useful for phylogenies with branch lengths derived not only from molecular data, but also morphological and biochemical traits. PMID:29893954

Molecular targets for small-molecule modulators of circadian clocks

PubMed Central

He, Baokun; Chen, Zheng

2016-01-01

Background Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. Methods Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. Results Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. Conclusion Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases. PMID:26750111

Phylogenetic Status and Timescale for the Diversification of Steno and Sotalia Dolphins

PubMed Central

Cunha, Haydée A.; Moraes, Lucas C.; Medeiros, Bruna V.; Lailson-Brito, José; da Silva, Vera M. F.; Solé-Cava, Antonio M.; Schrago, Carlos G.

2011-01-01

Molecular data have provided many insights into cetacean evolution but some unsettled issues still remain. We estimated the topology and timing of cetacean evolutionary relationships using Bayesian and maximum likelihood analyses of complete mitochondrial genomes. In order to clarify the phylogenetic placement of Sotalia and Steno within the Delphinidae, we sequenced three new delphinid mitogenomes. Our analyses support three delphinid clades: one joining Steno and Sotalia (supporting the revised subfamily Stenoninae); another placing Sousa within the Delphininae; and a third, the Globicephalinae, which includes Globicephala, Feresa, Pseudorca, Peponocephala and Grampus. We also conclude that Orcinus does not belong in the Globicephalinae, but Orcaella may be part of that subfamily. Divergence dates were estimated using the relaxed molecular clock calibrated with fossil data. We hypothesise that the timing of separation of the marine and Amazonian Sotalia species (2.3 Ma) coincided with the establishment of the modern Amazon River basin. PMID:22163290

Phylogenetic status and timescale for the diversification of Steno and Sotalia dolphins.

PubMed

Cunha, Haydée A; Moraes, Lucas C; Medeiros, Bruna V; Lailson-Brito, José; da Silva, Vera M F; Solé-Cava, Antonio M; Schrago, Carlos G

2011-01-01

Molecular data have provided many insights into cetacean evolution but some unsettled issues still remain. We estimated the topology and timing of cetacean evolutionary relationships using bayesian and maximum likelihood analyses of complete mitochondrial genomes. In order to clarify the phylogenetic placement of Sotalia and Steno within the Delphinidae, we sequenced three new delphinid mitogenomes. Our analyses support three delphinid clades: one joining Steno and Sotalia (supporting the revised subfamily Stenoninae); another placing Sousa within the Delphininae; and a third, the Globicephalinae, which includes Globicephala, Feresa, Pseudorca, Peponocephala and Grampus. We also conclude that Orcinus does not belong in the Globicephalinae, but Orcaella may be part of that subfamily. Divergence dates were estimated using the relaxed molecular clock calibrated with fossil data. We hypothesise that the timing of separation of the marine and Amazonian Sotalia species (2.3 Ma) coincided with the establishment of the modern Amazon River basin.

Bayesian phylogenetic estimation of fossil ages.

PubMed

Drummond, Alexei J; Stadler, Tanja

2016-07-19

Recent advances have allowed for both morphological fossil evidence and molecular sequences to be integrated into a single combined inference of divergence dates under the rule of Bayesian probability. In particular, the fossilized birth-death tree prior and the Lewis-Mk model of discrete morphological evolution allow for the estimation of both divergence times and phylogenetic relationships between fossil and extant taxa. We exploit this statistical framework to investigate the internal consistency of these models by producing phylogenetic estimates of the age of each fossil in turn, within two rich and well-characterized datasets of fossil and extant species (penguins and canids). We find that the estimation accuracy of fossil ages is generally high with credible intervals seldom excluding the true age and median relative error in the two datasets of 5.7% and 13.2%, respectively. The median relative standard error (RSD) was 9.2% and 7.2%, respectively, suggesting good precision, although with some outliers. In fact, in the two datasets we analyse, the phylogenetic estimate of fossil age is on average less than 2 Myr from the mid-point age of the geological strata from which it was excavated. The high level of internal consistency found in our analyses suggests that the Bayesian statistical model employed is an adequate fit for both the geological and morphological data, and provides evidence from real data that the framework used can accurately model the evolution of discrete morphological traits coded from fossil and extant taxa. We anticipate that this approach will have diverse applications beyond divergence time dating, including dating fossils that are temporally unconstrained, testing of the 'morphological clock', and for uncovering potential model misspecification and/or data errors when controversial phylogenetic hypotheses are obtained based on combined divergence dating analyses.This article is part of the themed issue 'Dating species divergences using rocks and clocks'. © 2016 The Authors.

"Molecular Clock" Analogs: A Relative Rates Exercise

ERIC Educational Resources Information Center

Wares, John P.

2008-01-01

Although molecular clock theory is a commonly discussed facet of evolutionary biology, undergraduates are rarely presented with the underlying information of how this theory is examined relative to empirical data. Here a simple contextual exercise is presented that not only provides insight into molecular clocks, but is also a useful exercise for…

Phylogeny and divergence of the pinnipeds (Carnivora: Mammalia) assessed using a multigene dataset

PubMed Central

Higdon, Jeff W; Bininda-Emonds, Olaf RP; Beck, Robin MD; Ferguson, Steven H

2007-01-01

Background Phylogenetic comparative methods are often improved by complete phylogenies with meaningful branch lengths (e.g., divergence dates). This study presents a dated molecular supertree for all 34 world pinniped species derived from a weighted matrix representation with parsimony (MRP) supertree analysis of 50 gene trees, each determined under a maximum likelihood (ML) framework. Divergence times were determined by mapping the same sequence data (plus two additional genes) on to the supertree topology and calibrating the ML branch lengths against a range of fossil calibrations. We assessed the sensitivity of our supertree topology in two ways: 1) a second supertree with all mtDNA genes combined into a single source tree, and 2) likelihood-based supermatrix analyses. Divergence dates were also calculated using a Bayesian relaxed molecular clock with rate autocorrelation to test the sensitivity of our supertree results further. Results The resulting phylogenies all agreed broadly with recent molecular studies, in particular supporting the monophyly of Phocidae, Otariidae, and the two phocid subfamilies, as well as an Odobenidae + Otariidae sister relationship; areas of disagreement were limited to four more poorly supported regions. Neither the supertree nor supermatrix analyses supported the monophyly of the two traditional otariid subfamilies, supporting suggestions for the need for taxonomic revision in this group. Phocid relationships were similar to other recent studies and deeper branches were generally well-resolved. Halichoerus grypus was nested within a paraphyletic Pusa, although relationships within Phocina tend to be poorly supported. Divergence date estimates for the supertree were in good agreement with other studies and the available fossil record; however, the Bayesian relaxed molecular clock divergence date estimates were significantly older. Conclusion Our results join other recent studies and highlight the need for a re-evaluation of pinniped taxonomy, especially as regards the subfamilial classification of otariids and the generic nomenclature of Phocina. Even with the recent publication of new sequence data, the available genetic sequence information for several species, particularly those in Arctocephalus, remains very limited, especially for nuclear markers. However, resolution of parts of the tree will probably remain difficult, even with additional data, due to apparent rapid radiations. Our study addresses the lack of a recent pinniped phylogeny that includes all species and robust divergence dates for all nodes, and will therefore prove indispensable to comparative and macroevolutionary studies of this group of carnivores. PMID:17996107

Transcriptional oscillation of canonical clock genes in mouse peripheral tissues

PubMed Central

Yamamoto, Takuro; Nakahata, Yasukazu; Soma, Haruhiko; Akashi, Makoto; Mamine, Takayoshi; Takumi, Toru

2004-01-01

Background The circadian rhythm of about 24 hours is a fundamental physiological function observed in almost all organisms from prokaryotes to humans. Identification of clock genes has allowed us to study the molecular bases for circadian behaviors and temporal physiological processes such as hormonal secretion, and has prompted the idea that molecular clocks reside not only in a central pacemaker, the suprachiasmatic nuclei (SCN) of hypothalamus in mammals, but also in peripheral tissues, even in immortalized cells. Furthermore, previous molecular dissection revealed that the mechanism of circadian oscillation at a molecular level is based on transcriptional regulation of clock and clock-controlled genes. Results We systematically analyzed the mRNA expression of clock and clock-controlled genes in mouse peripheral tissues. Eight genes (mBmal1, mNpas2, mRev-erbα, mDbp, mRev-erbβ, mPer3, mPer1 and mPer2; given in the temporal order of the rhythm peak) showed robust circadian expressions of mRNAs in all tissues except testis, suggesting that these genes are core molecules of the molecular biological clock. The bioinformatics analysis revealed that these genes have one or a combination of 3 transcriptional elements (RORE, DBPE, and E-box), which are conserved among human, mouse, and rat genome sequences, and indicated that these 3 elements may be responsible for the biological timing of expression of canonical clock genes. Conclusions The observation of oscillatory profiles of canonical clock genes is not only useful for physiological and pathological examination of the circadian clock in various organs but also important for systematic understanding of transcriptional regulation on a genome-wide basis. Our finding of the oscillatory expression of canonical clock genes with a temporal order provides us an interesting hypothesis, that cyclic timing of all clock and clock-controlled genes may be dependent on several transcriptional elements including 3 known elements, E-box, RORE, and DBPE. PMID:15473909

Early sex-specific modulation of the molecular clock in trauma.

PubMed

Mehraj, Vikram; Wiramus, Sandrine; Capo, Christian; Leone, Marc; Mege, Jean-Louis; Textoris, Julien

2014-01-01

Immune system biology and most physiologic functions are tightly linked to circadian rhythms. Time of day-dependent variations in many biologic parameters also play a fundamental role in the disease process. We previously showed that the genes encoding the peripheral molecular clock were modulated in a sex-dependent manner in Q fever. Here, we examined severe trauma patients at admission to the intensive care unit. Using quantitative real-time polymerase chain reaction, the whole-blood expression of the molecular clock components ARNTL, CLOCK, and PER2 was assessed in male and female trauma patients. Healthy volunteers of both sexes were used as controls. We observed a significant overexpression of both ARNTL and CLOCK in male trauma patients. We report, for the first time, the sex-related modulation of the molecular clock genes in the blood following severe trauma. These results emphasize the role of circadian rhythms in the immune response in trauma patients. Epidemiologic study, level IV.

Circadian clocks in the cnidaria: environmental entrainment, molecular regulation, and organismal outputs.

PubMed

Reitzel, Adam M; Tarrant, Ann M; Levy, Oren

2013-07-01

The circadian clock is a molecular network that translates predictable environmental signals, such as light levels, into organismal responses, including behavior and physiology. Regular oscillations of the molecular components of the clock enable individuals to anticipate regularly fluctuating environmental conditions. Cnidarians play important roles in benthic and pelagic marine environments and also occupy a key evolutionary position as the likely sister group to the bilaterians. Together, these attributes make members of this phylum attractive as models for testing hypotheses on roles for circadian clocks in regulating behavior, physiology, and reproduction as well as those regarding the deep evolutionary conservation of circadian regulatory pathways in animal evolution. Here, we review and synthesize the field of cnidarian circadian biology by discussing the diverse effects of daily light cycles on cnidarians, summarizing the molecular evidence for the conservation of a bilaterian-like circadian clock in anthozoan cnidarians, and presenting new empirical data supporting the presence of a conserved feed-forward loop in the starlet sea anemone, Nematostella vectensis. Furthermore, we discuss critical gaps in our current knowledge about the cnidarian clock, including the functions directly regulated by the clock and the precise molecular interactions that drive the oscillating gene-expression patterns. We conclude that the field of cnidarian circadian biology is moving rapidly toward linking molecular mechanisms with physiology and behavior.

Identification of the Molecular Clockwork of the Oyster Crassostrea gigas

PubMed Central

Perrigault, Mickael; Tran, Damien

2017-01-01

Molecular clock system constitutes the origin of biological rhythms that allow organisms to anticipate cyclic environmental changes and adapt their behavior and physiology. Components of the molecular clock are largely conserved across a broad range of species but appreciable diversity in clock structure and function is also present especially in invertebrates. The present work aimed at identify and characterize molecular clockwork components in relationship with the monitoring of valve activity behavior in the oyster Crassostrea gigas. Results provided the characterization of most of canonical clock gene including clock, bmal/cycle, period, timeless, vertebrate-type cry, rev-erb, ror as well as other members of the cryptochrome/photolyase family (plant-like cry, 6–4 photolyase). Analyses of transcriptional variations of clock candidates in oysters exposed to light / dark regime and to constant darkness led to the generation of a putative and original clockwork model in C. gigas, intermediate of described systems in vertebrates and insects. This study is the first characterization of a mollusk clockwork. It constitutes essential bases to understand interactions of the different components of the molecular clock in C. gigas as well as the global mechanisms associated to the generation and the synchronization of biological rhythms in oysters. PMID:28072861

Bayesian Morphological Clock Methods Resurrect Placoderm Monophyly and Reveal Rapid Early Evolution in Jawed Vertebrates.

PubMed

King, Benedict; Qiao, Tuo; Lee, Michael S Y; Zhu, Min; Long, John A

2017-07-01

The phylogeny of early gnathostomes provides an important framework for understanding one of the most significant evolutionary events, the origin and diversification of jawed vertebrates. A series of recent cladistic analyses have suggested that the placoderms, an extinct group of armoured fish, form a paraphyletic group basal to all other jawed vertebrates. We revised and expanded this morphological data set, most notably by sampling autapomorphies in a similar way to parsimony-informative traits, thus ensuring this data (unlike most existing morphological data sets) satisfied an important assumption of Bayesian tip-dated morphological clock approaches. We also found problems with characters supporting placoderm paraphyly, including character correlation and incorrect codings. Analysis of this data set reveals that paraphyly and monophyly of core placoderms (excluding maxillate forms) are essentially equally parsimonious. The two alternative topologies have different root positions for the jawed vertebrates but are otherwise similar. However, analysis using tip-dated clock methods reveals strong support for placoderm monophyly, due to this analysis favoring trees with more balanced rates of evolution. Furthermore, enforcing placoderm paraphyly results in higher levels and unusual patterns of rate heterogeneity among branches, similar to that generated from simulated trees reconstructed with incorrect root positions. These simulations also show that Bayesian tip-dated clock methods outperform parsimony when the outgroup is largely uninformative (e.g., due to inapplicable characters), as might be the case here. The analysis also reveals that gnathostomes underwent a rapid burst of evolution during the Silurian period which declined during the Early Devonian. This rapid evolution during a period with few articulated fossils might partly explain the difficulty in ascertaining the root position of jawed vertebrates. © The Author(s) 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A Screening of UNF Targets Identifies Rnb, a Novel Regulator of Drosophila Circadian Rhythms.

PubMed

Kozlov, Anatoly; Jaumouillé, Edouard; Machado Almeida, Pedro; Koch, Rafael; Rodriguez, Joseph; Abruzzi, Katharine C; Nagoshi, Emi

2017-07-12

Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled ( unf ) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period ( per ) (Jaumouillé et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837 , which we termed R and B ( Rnb ), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit. SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics distinguishing the s-LNvs, the master pacemaker of the locomotor rhythms, from other clock neuron subtypes. We demonstrated that a newly identified gene Rnb is an s-LNv-specific regulator of the molecular clock and essential for the generation of circadian locomotor behavior. Our results provide additional evidence to the emerging view that the differential regulation of the molecular clocks underlies the functional differences among the pacemaker neuron subgroups. Copyright © 2017 the authors 0270-6474/17/376673-13$15.00/0.

Paleogene Radiation of a Plant Pathogenic Mushroom

PubMed Central

Coetzee, Martin P. A.; Bloomer, Paulette; Wingfield, Michael J.; Wingfield, Brenda D.

2011-01-01

Background The global movement and speciation of fungal plant pathogens is important, especially because of the economic losses they cause and the ease with which they are able to spread across large areas. Understanding the biogeography and origin of these plant pathogens can provide insights regarding their dispersal and current day distribution. We tested the hypothesis of a Gondwanan origin of the plant pathogenic mushroom genus Armillaria and the currently accepted premise that vicariance accounts for the extant distribution of the species. Methods The phylogeny of a selection of Armillaria species was reconstructed based on Maximum Parsimony (MP), Maximum Likelihood (ML) and Bayesian Inference (BI). A timeline was then placed on the divergence of lineages using a Bayesian relaxed molecular clock approach. Results Phylogenetic analyses of sequenced data for three combined nuclear regions provided strong support for three major geographically defined clades: Holarctic, South American-Australasian and African. Molecular dating placed the initial radiation of the genus at 54 million years ago within the Early Paleogene, postdating the tectonic break-up of Gondwana. Conclusions The distribution of extant Armillaria species is the result of ancient long-distance dispersal rather than vicariance due to continental drift. As these finding are contrary to most prior vicariance hypotheses for fungi, our results highlight the important role of long-distance dispersal in the radiation of fungal pathogens from the Southern Hemisphere. PMID:22216099

Circadian Clocks in the Cnidaria: Environmental Entrainment, Molecular Regulation, and Organismal Outputs

PubMed Central

Reitzel, Adam M.; Tarrant, Ann M.; Levy, Oren

2013-01-01

The circadian clock is a molecular network that translates predictable environmental signals, such as light levels, into organismal responses, including behavior and physiology. Regular oscillations of the molecular components of the clock enable individuals to anticipate regularly fluctuating environmental conditions. Cnidarians play important roles in benthic and pelagic marine environments and also occupy a key evolutionary position as the likely sister group to the bilaterians. Together, these attributes make members of this phylum attractive as models for testing hypotheses on roles for circadian clocks in regulating behavior, physiology, and reproduction as well as those regarding the deep evolutionary conservation of circadian regulatory pathways in animal evolution. Here, we review and synthesize the field of cnidarian circadian biology by discussing the diverse effects of daily light cycles on cnidarians, summarizing the molecular evidence for the conservation of a bilaterian-like circadian clock in anthozoan cnidarians, and presenting new empirical data supporting the presence of a conserved feed-forward loop in the starlet sea anemone, Nematostella vectensis. Furthermore, we discuss critical gaps in our current knowledge about the cnidarian clock, including the functions directly regulated by the clock and the precise molecular interactions that drive the oscillating gene-expression patterns. We conclude that the field of cnidarian circadian biology is moving rapidly toward linking molecular mechanisms with physiology and behavior. PMID:23620252

Eocene diversification of crown group rails (Aves: Gruiformes: Rallidae).

PubMed

García-R, Juan C; Gibb, Gillian C; Trewick, Steve A

2014-01-01

Central to our understanding of the timing of bird evolution is debate about an apparent conflict between fossil and molecular data. A deep age for higher level taxa within Neoaves is evident from molecular analyses but much remains to be learned about the age of diversification in modern bird families and their evolutionary ecology. In order to better understand the timing and pattern of diversification within the family Rallidae we used a relaxed molecular clock, fossil calibrations, and complete mitochondrial genomes from a range of rallid species analysed in a Bayesian framework. The estimated time of origin of Rallidae is Eocene, about 40.5 Mya, with evidence of intrafamiliar diversification from the Late Eocene to the Miocene. This timing is older than previously suggested for crown group Rallidae, but fossil calibrations, extent of taxon sampling and substantial sequence data give it credence. We note that fossils of Eocene age tentatively assigned to Rallidae are consistent with our findings. Compared to available studies of other bird lineages, the rail clade is old and supports an inference of deep ancestry of ground-dwelling habits among Neoaves.

Molecular phylogenetic analysis of nuclear genes suggests a Cenozoic over-water dispersal origin for the Cuban solenodon.

PubMed

Sato, Jun J; Ohdachi, Satoshi D; Echenique-Diaz, Lazaro M; Borroto-Páez, Rafael; Begué-Quiala, Gerardo; Delgado-Labañino, Jorge L; Gámez-Díez, Jorgelino; Alvarez-Lemus, José; Nguyen, Son Truong; Yamaguchi, Nobuyuki; Kita, Masaki

2016-08-08

The Cuban solenodon (Solenodon cubanus) is one of the most enigmatic mammals and is an extremely rare species with a distribution limited to a small part of the island of Cuba. Despite its rarity, in 2012 seven individuals of S. cubanus were captured and sampled successfully for DNA analysis, providing new insights into the evolutionary origin of this species and into the origins of the Caribbean fauna, which remain controversial. We conducted molecular phylogenetic analyses of five nuclear genes (Apob, Atp7a, Bdnf, Brca1 and Rag1; total, 4,602 bp) from 35 species of the mammalian order Eulipotyphla. Based on Bayesian relaxed molecular clock analyses, the family Solenodontidae diverged from other eulipotyphlan in the Paleocene, after the bolide impact on the Yucatan Peninsula, and S. cubanus diverged from the Hispaniolan solenodon (S. paradoxus) in the Early Pliocene. The strikingly recent divergence time estimates suggest that S. cubanus and its ancestral lineage originated via over-water dispersal rather than vicariance events, as had previously been hypothesised.

Molecular phylogenetic analysis of nuclear genes suggests a Cenozoic over-water dispersal origin for the Cuban solenodon

PubMed Central

Sato, Jun J.; Ohdachi, Satoshi D.; Echenique-Diaz, Lazaro M.; Borroto-Páez, Rafael; Begué-Quiala, Gerardo; Delgado-Labañino, Jorge L.; Gámez-Díez, Jorgelino; Alvarez-Lemus, José; Nguyen, Son Truong; Yamaguchi, Nobuyuki; Kita, Masaki

2016-01-01

The Cuban solenodon (Solenodon cubanus) is one of the most enigmatic mammals and is an extremely rare species with a distribution limited to a small part of the island of Cuba. Despite its rarity, in 2012 seven individuals of S. cubanus were captured and sampled successfully for DNA analysis, providing new insights into the evolutionary origin of this species and into the origins of the Caribbean fauna, which remain controversial. We conducted molecular phylogenetic analyses of five nuclear genes (Apob, Atp7a, Bdnf, Brca1 and Rag1; total, 4,602 bp) from 35 species of the mammalian order Eulipotyphla. Based on Bayesian relaxed molecular clock analyses, the family Solenodontidae diverged from other eulipotyphlan in the Paleocene, after the bolide impact on the Yucatan Peninsula, and S. cubanus diverged from the Hispaniolan solenodon (S. paradoxus) in the Early Pliocene. The strikingly recent divergence time estimates suggest that S. cubanus and its ancestral lineage originated via over-water dispersal rather than vicariance events, as had previously been hypothesised. PMID:27498968

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks.

PubMed

de Assis, Leonardo Vinícius Monteiro; Moraes, Maria Nathália; Magalhães-Marques, Keila Karoline; Kinker, Gabriela Sarti; da Silveira Cruz-Machado, Sanseray; Castrucci, Ana Maria de Lauro

2018-04-03

The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME) and macro-environments (TMaE) in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis), and the suprachiasmatic nucleus (SCN) were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism's biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target.

Species Radiation of Carabid Beetles (Broscini: Mecodema) in New Zealand

PubMed Central

Goldberg, Julia; Knapp, Michael; Emberson, Rowan M.; Townsend, J. Ian; Trewick, Steven A.

2014-01-01

New Zealand biodiversity has often been viewed as Gondwanan in origin and age, but it is increasingly apparent from molecular studies that diversification, and in many cases origination of lineages, postdate the break-up of Gondwanaland. Relatively few studies of New Zealand animal species radiations have as yet been reported, and here we consider the species-rich genus of carabid beetles, Mecodema. Constrained stratigraphic information (emergence of the Chatham Islands) and a substitution rate for Coleoptera were separately used to calibrate Bayesian relaxed molecular clock date estimates for diversification of Mecodema. The inferred timings indicate radiation of these beetles no earlier than the mid-Miocene with most divergences being younger, dating to the Plio-Pleistocene. A shallow age for the radiation along with a complex spatial distribution of these taxa involving many instances of sympatry implicates recent ecological speciation rather than a simplistic allopatric model. This emphasises the youthful and dynamic nature of New Zealand evolution that will be further elucidated with detailed ecological and population genetic analyses. PMID:24465949

A Multilocus Molecular Phylogeny of the Parrots (Psittaciformes): Support for a Gondwanan Origin during the Cretaceous

PubMed Central

Schirtzinger, Erin E.; Matsumoto, Tania; Eberhard, Jessica R.; Graves, Gary R.; Sanchez, Juan J.; Capelli, Sara; Müller, Heinrich; Scharpegge, Julia; Chambers, Geoffrey K.; Fleischer, Robert C.

2008-01-01

The question of when modern birds (Neornithes) first diversified has generated much debate among avian systematists. Fossil evidence generally supports a Tertiary diversification, whereas estimates based on molecular dating favor an earlier diversification in the Cretaceous period. In this study, we used an alternate approach, the inference of historical biogeographic patterns, to test the hypothesis that the initial radiation of the Order Psittaciformes (the parrots and cockatoos) originated on the Gondwana supercontinent during the Cretaceous. We utilized broad taxonomic sampling (representatives of 69 of the 82 extant genera and 8 outgroup taxa) and multilocus molecular character sampling (3,941 bp from mitochondrial DNA (mtDNA) genes cytochrome oxidase I and NADH dehydrogenase 2 and nuclear introns of rhodopsin intron 1, tropomyosin alpha-subunit intron 5, and transforming growth factor ß-2) to generate phylogenetic hypotheses for the Psittaciformes. Analyses of the combined character partitions using maximum parsimony, maximum likelihood, and Bayesian criteria produced well-resolved and topologically similar trees in which the New Zealand taxa Strigops and Nestor (Psittacidae) were sister to all other psittaciforms and the cockatoo clade (Cacatuidae) was sister to a clade containing all remaining parrots (Psittacidae). Within this large clade of Psittacidae, some traditionally recognized tribes and subfamilies were monophyletic (e.g., Arini, Psittacini, and Loriinae), whereas several others were polyphyletic (e.g., Cyclopsittacini, Platycercini, Psittaculini, and Psittacinae). Ancestral area reconstructions using our Bayesian phylogenetic hypothesis and current distributions of genera supported the hypothesis of an Australasian origin for the Psittaciformes. Separate analyses of the timing of parrot diversification constructed with both Bayesian relaxed-clock and penalized likelihood approaches showed better agreement between geologic and diversification events in the chronograms based on a Cretaceous dating of the basal split within parrots than the chronograms based on a Tertiary dating of this split, although these data are more equivocal. Taken together, our results support a Cretaceous origin of Psittaciformes in Gondwana after the separation of Africa and the India/Madagascar block with subsequent diversification through both vicariance and dispersal. These well-resolved molecular phylogenies will be of value for comparative studies of behavior, ecology, and life history in parrots. PMID:18653733

Bowhead whale localization using time-difference-of-arrival data from asynchronous recorders.

PubMed

Warner, Graham A; Dosso, Stan E; Hannay, David E

2017-03-01

This paper estimates bowhead whale locations and uncertainties using nonlinear Bayesian inversion of the time-difference-of-arrival (TDOA) of low-frequency whale calls recorded on onmi-directional asynchronous recorders in the shallow waters of the northeastern Chukchi Sea, Alaska. A Y-shaped cluster of seven autonomous ocean-bottom hydrophones, separated by 0.5-9.2 km, was deployed for several months over which time their clocks drifted out of synchronization. Hundreds of recorded whale calls are manually associated between recorders. The TDOA between hydrophone pairs are calculated from filtered waveform cross correlations and depend on the whale locations, hydrophone locations, relative recorder clock offsets, and effective waveguide sound speed. A nonlinear Bayesian inversion estimates all of these parameters and their uncertainties as well as data error statistics. The problem is highly nonlinear and a linearized inversion did not produce physically realistic results. Whale location uncertainties from nonlinear inversion can be low enough to allow accurate tracking of migrating whales that vocalize repeatedly over several minutes. Estimates of clock drift rates are obtained from inversions of TDOA data over two weeks and agree with corresponding estimates obtained from long-time averaged ambient noise cross correlations. The inversion is suitable for application to large data sets of manually or automatically detected whale calls.

Optical Lattice Clocks with Weakly Bound Molecules.

PubMed

Borkowski, Mateusz

2018-02-23

Optical molecular clocks promise unparalleled sensitivity to the temporal variation of the electron-to-proton mass ratio and insight into possible new physics beyond the standard model. We propose to realize a molecular clock with bosonic ^{174}Yb_{2} molecules, where the forbidden ^{1}S_{0}→^{3}P_{0} clock transition would be induced magnetically. The use of a bosonic species avoids possible complications due to the hyperfine structure present in fermionic species. While direct clock line photoassociation would be challenging, weakly bound ground state molecules could be produced by stimulated Raman adiabatic passage and used instead. The recent scattering measurements [L. Franchi, et al. New J. Phys. 19, 103037 (2017)NJOPFM1367-263010.1088/1367-2630/aa8fb4] enable us to determine the positions of target ^{1}S_{0}+^{3}P_{0} vibrational levels and calculate the Franck-Condon factors for clock transitions between ground and excited molecular states. The resulting magnetically induced Rabi frequencies are similar to those for atoms hinting that an experimental realization is feasible. A successful observation could pave the way towards Hz-level molecular spectroscopy.

Optical Lattice Clocks with Weakly Bound Molecules

NASA Astrophysics Data System (ADS)

Borkowski, Mateusz

2018-02-01

Optical molecular clocks promise unparalleled sensitivity to the temporal variation of the electron-to-proton mass ratio and insight into possible new physics beyond the standard model. We propose to realize a molecular clock with bosonic 174Yb2 molecules, where the forbidden 1S0 →3P0 clock transition would be induced magnetically. The use of a bosonic species avoids possible complications due to the hyperfine structure present in fermionic species. While direct clock line photoassociation would be challenging, weakly bound ground state molecules could be produced by stimulated Raman adiabatic passage and used instead. The recent scattering measurements [L. Franchi, et al. New J. Phys. 19, 103037 (2017), 10.1088/1367-2630/aa8fb4] enable us to determine the positions of target 1S0 +3P0 vibrational levels and calculate the Franck-Condon factors for clock transitions between ground and excited molecular states. The resulting magnetically induced Rabi frequencies are similar to those for atoms hinting that an experimental realization is feasible. A successful observation could pave the way towards Hz-level molecular spectroscopy.

Anabolic Heterogeneity Following Resistance Training: A Role for Circadian Rhythm?

PubMed

Camera, Donny M

2018-01-01

It is now well established that resistance exercise stimulates muscle protein synthesis and promotes gains in muscle mass and strength. However, considerable variability exists following standardized resistance training programs in the magnitude of muscle cross-sectional area and strength responses from one individual to another. Several studies have recently posited that alterations in satellite cell population, myogenic gene expression and microRNAs may contribute to individual variability in anabolic adaptation. One emerging factor that may also explain the variability in responses to resistance exercise is circadian rhythms and underlying molecular clock signals. The molecular clock is found in most cells within the body, including skeletal muscle, and principally functions to optimize the timing of specific cellular events around a 24 h cycle. Accumulating evidence investigating the skeletal muscle molecular clock indicates that exercise-induced contraction and its timing may regulate gene expression and protein synthesis responses which, over time, can influence and modulate key physiological responses such as muscle hypertrophy and increased strength. Therefore, the circadian clock may play a key role in the heterogeneous anabolic responses with resistance exercise. The central aim of this Hypothesis and Theory is to discuss and propose the potential interplay between the circadian molecular clock and established molecular mechanisms mediating muscle anabolic responses with resistance training. This article begins with a current review of the mechanisms associated with the heterogeneity in muscle anabolism with resistance training before introducing the molecular pathways regulating circadian function in skeletal muscle. Recent work showing members of the core molecular clock system can regulate myogenic and translational signaling pathways is also discussed, forming the basis for a possible role of the circadian clock in the variable anabolic responses with resistance exercise.

Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior.

PubMed

Ben-Moshe Livne, Zohar; Alon, Shahar; Vallone, Daniela; Bayleyen, Yared; Tovin, Adi; Shainer, Inbal; Nisembaum, Laura G; Aviram, Idit; Smadja-Storz, Sima; Fuentes, Michael; Falcón, Jack; Eisenberg, Eli; Klein, David C; Burgess, Harold A; Foulkes, Nicholas S; Gothilf, Yoav

2016-11-01

The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior.

Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

PubMed Central

Alon, Shahar; Vallone, Daniela; Tovin, Adi; Shainer, Inbal; Nisembaum, Laura G.; Aviram, Idit; Smadja-Storz, Sima; Fuentes, Michael; Falcón, Jack; Eisenberg, Eli; Klein, David C.; Burgess, Harold A.; Foulkes, Nicholas S.; Gothilf, Yoav

2016-01-01

The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior. PMID:27870848

An expanding universe of circadian networks in higher plants.

PubMed

Pruneda-Paz, Jose L; Kay, Steve A

2010-05-01

Extensive circadian clock networks regulate almost every biological process in plants. Clock-controlled physiological responses are coupled with daily oscillations in environmental conditions resulting in enhanced fitness and growth vigor. Identification of core clock components and their associated molecular interactions has established the basic network architecture of plant clocks, which consists of multiple interlocked feedback loops. A hierarchical structure of transcriptional feedback overlaid with regulated protein turnover sets the pace of the clock and ultimately drives all clock-controlled processes. Although originally described as linear entities, increasing evidence suggests that many signaling pathways can act as both inputs and outputs within the overall network. Future studies will determine the molecular mechanisms involved in these complex regulatory loops. 2010 Elsevier Ltd. All rights reserved.

Treating fossils as terminal taxa in divergence time estimation reveals ancient vicariance patterns in the palpimanoid spiders.

PubMed

Wood, Hannah Marie; Matzke, Nicholas J; Gillespie, Rosemary G; Griswold, Charles E

2013-03-01

Incorporation of fossils into biogeographic studies can have a profound effect on the conclusions that result, particularly when fossil ranges are nonoverlapping with extant ranges. This is the case in archaeid spiders, where there are known fossils from the Northern Hemisphere, yet all living members are restricted to the Southern Hemisphere. To better understand the biogeographic patterns of archaeid spiders and their palpimanoid relatives, we estimate a dated phylogeny using a relaxed clock on a combined molecular and morphological data set. Dating information is compared with treating the archaeid fossil taxa as both node calibrations and as noncontemporaneous terminal tips, both with and without additional calibration points. Estimation of ancestral biogeographic ranges is then performed, using likelihood and Bayesian methods to take into account uncertainty in phylogeny and in dating. We find that treating the fossils as terminal tips within a Bayesian framework, as opposed to dating the phylogeny based only on molecular data with the dates coming from node calibrations, removes the subjectivity involved in assigning priors, which has not been possible with previous methods. Our analyses suggest that the diversification of the northern and southern archaeid lineages was congruent with the breakup of Pangaea into Laurasia and Gondwanaland. This analysis provides a rare example, and perhaps the most strongly supported, where a dated phylogeny confirms a biogeographical hypothesis based on vicariance due to the breakup of the ancient continental plates.

Parameter estimation for an immortal model of colonic stem cell division using approximate Bayesian computation.

PubMed

Walters, Kevin

2012-08-07

In this paper we use approximate Bayesian computation to estimate the parameters in an immortal model of colonic stem cell division. We base the inferences on the observed DNA methylation patterns of cells sampled from the human colon. Utilising DNA methylation patterns as a form of molecular clock is an emerging area of research and has been used in several studies investigating colonic stem cell turnover. There is much debate concerning the two competing models of stem cell turnover: the symmetric (immortal) and asymmetric models. Early simulation studies concluded that the observed methylation data were not consistent with the immortal model. A later modified version of the immortal model that included preferential strand segregation was subsequently shown to be consistent with the same methylation data. Most of this earlier work assumes site independent methylation models that do not take account of the known processivity of methyltransferases whilst other work does not take into account the methylation errors that occur in differentiated cells. This paper addresses both of these issues for the immortal model and demonstrates that approximate Bayesian computation provides accurate estimates of the parameters in this neighbour-dependent model of methylation error rates. The results indicate that if colonic stem cells divide asymmetrically then colon stem cell niches are maintained by more than 8 stem cells. Results also indicate the possibility of preferential strand segregation and provide clear evidence against a site-independent model for methylation errors. In addition, algebraic expressions for some of the summary statistics used in the approximate Bayesian computation (that allow for the additional variation arising from cell division in differentiated cells) are derived and their utility discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

Adrenal-dependent and -independent stress-induced Per1 mRNA in hypothalamic paraventricular nucleus and prefrontal cortex of male and female rats.

PubMed

Chun, Lauren E; Christensen, Jenny; Woodruff, Elizabeth R; Morton, Sarah J; Hinds, Laura R; Spencer, Robert L

2018-01-01

Oscillating clock gene expression gives rise to a molecular clock that is present not only in the body's master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), but also in extra-SCN brain regions. These extra-SCN molecular clocks depend on the SCN for entrainment to a light:dark cycle. The SCN has limited neural efferents, so it may entrain extra-SCN molecular clocks through its well-established circadian control of glucocorticoid hormone secretion. Glucocorticoids can regulate the normal rhythmic expression of clock genes in some extra-SCN tissues. Untimely stress-induced glucocorticoid secretion may compromise extra-SCN molecular clock function. We examined whether acute restraint stress during the rat's inactive phase can rapidly (within 30 min) alter clock gene (Per1, Per2, Bmal1) and cFos mRNA (in situ hybridization) in the SCN, hypothalamic paraventricular nucleus (PVN), and prefrontal cortex (PFC) of male and female rats (6 rats per treatment group). Restraint stress increased Per1 and cFos mRNA in the PVN and PFC of both sexes. Stress also increased cFos mRNA in the SCN of male rats, but not when subsequently tested during their active phase. We also examined in male rats whether endogenous glucocorticoids are necessary for stress-induced Per1 mRNA (6-7 rats per treatment group). Adrenalectomy attenuated stress-induced Per1 mRNA in the PVN and ventral orbital cortex, but not in the medial PFC. These data indicate that increased Per1 mRNA may be a means by which extra-SCN molecular clocks adapt to environmental stimuli (e.g. stress), and in the PFC this effect is largely independent of glucocorticoids.

Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis

PubMed Central

2014-01-01

Background The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level. Results We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5′ splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD. Conclusion Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock and environmental stress adaptation in plants. It is also envisioned that alternative splicing of the clock genes plays more complex roles than previously expected. PMID:24885185

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

PubMed Central

Lefta, Mellani; Zhang, Xiping; Bartos, Daniel; Feng, Han-Zhong; Zhao, Yihua; Patwardhan, Abhijit; Jin, Jian-Ping; Esser, Karyn A.; Delisle, Brian P.

2013-01-01

The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1−/−) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSΔBmal1−/− hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na+ channel (NaV1.5), was circadianly expressed in control mouse and rat hearts but not in iCSΔBmal1−/− hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSΔBmal1−/− hearts was associated with decreased levels of NaV1.5 and Na+ current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans. PMID:23364267

Electrical silencing of PDF neurons advances the phase of non-PDF clock neurons in Drosophila.

PubMed

Wu, Ying; Cao, Guan; Nitabach, Michael N

2008-04-01

Drosophila clock neurons exhibit self-sustaining cellular oscillations that rely in part on rhythmic transcriptional feedback loops. We have previously determined that electrical silencing of the pigment dispersing factor (PDF)-expressing lateral-ventral (LN(V)) pacemaker subset of fly clock neurons via expression of an inward-rectifier K(+) channel (Kir2.1) severely disrupts free-running rhythms of locomotor activity-most flies are arrhythmic and those that are not exhibit weak short-period rhythms-and abolishes LN(V) molecular oscillation in constant darkness. PDF is known to be an important LN(V) output signal. Here we examine the effects of electrical silencing of the LN(V) pacemakers on molecular rhythms in other, nonsilenced, subsets of clock neurons. In contrast to previously described cell-autonomous abolition of free-running molecular rhythms, we find that electrical silencing of the LN(V) pacemakers via Kir2.1 expression does not impair molecular rhythms in LN(D), DN1, and DN2 subsets of clock neurons. However, free-running molecular rhythms in these non-LN(V) clock neurons occur with advanced phase. Electrical silencing of LN(V)s phenocopies PDF null mutation (pdf (01) ) at both behavioral and molecular levels except for the complete abolition of free-running cellular oscillation in the LN(V)s themselves. LN(V) electrically silenced or pdf 01 flies exhibit weak free-running behavioral rhythms with short period, and the molecular oscillation in non-LN(V) neurons phase advances in constant darkness. That LN( V) electrical silencing leads to the same behavioral and non-LN( V) molecular phenotypes as pdf 01 suggests that persistence of LN(V) molecular oscillation in pdf 01 flies has no functional effect, either on behavioral rhythms or on non-LN(V) molecular rhythms. We thus conclude that functionally relevant signals from LN(V)s to non-LN(V) clock neurons and other downstream targets rely both on PDF signaling and LN(V) electrical activity, and that LN( V)s do not ordinarily send functionally relevant signals via PDF-independent mechanisms.

The central molecular clock is robust in the face of behavioural arrhythmia in a Drosophila model of Alzheimer's disease.

PubMed

Chen, Ko-Fan; Possidente, Bernard; Lomas, David A; Crowther, Damian C

2014-04-01

Circadian behavioural deficits, including sleep irregularity and restlessness in the evening, are a distressing early feature of Alzheimer's disease (AD). We have investigated these phenomena by studying the circadian behaviour of transgenic Drosophila expressing the amyloid beta peptide (Aβ). We find that Aβ expression results in an age-related loss of circadian behavioural rhythms despite ongoing normal molecular oscillations in the central clock neurons. Even in the absence of any behavioural correlate, the synchronised activity of the central clock remains protective, prolonging lifespan, in Aβ flies just as it does in control flies. Confocal microscopy and bioluminescence measurements point to processes downstream of the molecular clock as the main site of Aβ toxicity. In addition, there seems to be significant non-cell-autonomous Aβ toxicity resulting in morphological and probably functional signalling deficits in central clock neurons.

Molecular Regulation of Parturition: The Role of the Decidual Clock.

PubMed

Norwitz, Errol R; Bonney, Elizabeth A; Snegovskikh, Victoria V; Williams, Michelle A; Phillippe, Mark; Park, Joong Shin; Abrahams, Vikki M

2015-04-27

The timing of birth is a critical determinant of perinatal outcome. Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term and preterm remain unclear. It is likely that a "parturition cascade" exists that triggers labor at term, that preterm labor results from mechanisms that either prematurely stimulate or short-circuit this cascade, and that these mechanisms involve the activation of proinflammatory pathways within the uterus. It has long been postulated that the fetoplacental unit is in control of the timing of birth through a "placental clock." We suggest that it is not a placental clock that regulates the timing of birth, but rather a "decidual clock." Here, we review the evidence in support of the endometrium/decidua as the organ primarily responsible for the timing of birth and discuss the molecular mechanisms that prime this decidual clock. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Molecular Regulation of Parturition: The Role of the Decidual Clock

PubMed Central

Norwitz, Errol R.; Bonney, Elizabeth A.; Snegovskikh, Victoria V.; Williams, Michelle A.; Phillippe, Mark; Park, Joong Shin; Abrahams, Vikki M.

2015-01-01

The timing of birth is a critical determinant of perinatal outcome. Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term and preterm remain unclear. It is likely that a “parturition cascade” exists that triggers labor at term, that preterm labor results from mechanisms that either prematurely stimulate or short-circuit this cascade, and that these mechanisms involve the activation of proinflammatory pathways within the uterus. It has long been postulated that the fetoplacental unit is in control of the timing of birth through a “placental clock.” We suggest that it is not a placental clock that regulates the timing of birth, but rather a “decidual clock.” Here, we review the evidence in support of the endometrium/decidua as the organ primarily responsible for the timing of birth and discuss the molecular mechanisms that prime this decidual clock. PMID:25918180

The central molecular clock is robust in the face of behavioural arrhythmia in a Drosophila model of Alzheimer’s disease

PubMed Central

Chen, Ko-Fan; Possidente, Bernard; Lomas, David A.; Crowther, Damian C.

2014-01-01

Circadian behavioural deficits, including sleep irregularity and restlessness in the evening, are a distressing early feature of Alzheimer’s disease (AD). We have investigated these phenomena by studying the circadian behaviour of transgenic Drosophila expressing the amyloid beta peptide (Aβ). We find that Aβ expression results in an age-related loss of circadian behavioural rhythms despite ongoing normal molecular oscillations in the central clock neurons. Even in the absence of any behavioural correlate, the synchronised activity of the central clock remains protective, prolonging lifespan, in Aβ flies just as it does in control flies. Confocal microscopy and bioluminescence measurements point to processes downstream of the molecular clock as the main site of Aβ toxicity. In addition, there seems to be significant non-cell-autonomous Aβ toxicity resulting in morphological and probably functional signalling deficits in central clock neurons. PMID:24574361

Nucleotide sequences of immunoglobulin eta genes of chimpanzee and orangutan: DNA molecular clock and hominoid evolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakoyama, Y.; Hong, K.J.; Byun, S.M.

To determine the phylogenetic relationships among hominoids and the dates of their divergence, the complete nucleotide sequences of the constant region of the immunoglobulin eta-chain (C/sub eta1/) genes from chimpanzee and orangutan have been determined. These sequences were compared with the human eta-chain constant-region sequence. A molecular clock (silent molecular clock), measured by the degree of sequence divergence at the synonymous (silent) positions of protein-encoding regions, was introduced for the present study. From the comparison of nucleotide sequences of ..cap alpha../sub 1/-antitrypsin and ..beta..- and delta-globulin genes between humans and Old World monkeys, the silent molecular clock was calibrated: themore » mean evolutionary rate of silent substitution was determined to be 1.56 x 10/sup -9/ substitutions per site per year. Using the silent molecular clock, the mean divergence dates of chimpanzee and orangutan from the human lineage were estimated as 6.4 +/- 2.6 million years and 17.3 +/- 4.5 million years, respectively. It was also shown that the evolutionary rate of primate genes is considerably slower than those of other mammalian genes.« less

Chronobiology of crickets: a review.

PubMed

Tomioka, Kenji

2014-10-01

Crickets provide a good model for the study of mechanisms underlying circadian rhythms and photoperiodic responses. They show clear circadian rhythms in their overt behavior and the sensitivity of the visual system. Classical neurobiological studies revealed that a pair of optic lobes is the locus of the circadian clock controlling these rhythms and that the compound eye is the major photoreceptor necessary for synchronization to environmental light cycles. The two optic lobe clocks are mutually coupled through a neural pathway and the coupling regulates an output circadian waveform and a free-running period. Recent molecular studies revealed that the cricket's clock consists of cyclic expression of so-called clock genes and that the clock mechanism is featured by both Drosophila-like and mammalian-like traits. Molecular oscillation is also observed in some extra-optic lobe tissues and depends on the optic lobe clock in a tissue dependent manner. Interestingly, the clock is also involved in adaptation to seasonally changing environment. It fits its waveform to a given photoperiod and may be an indispensable part of a photoperiodic time-measurement mechanism. With adoption of modern molecular technologies, the cricket becomes a much more important and promising model animal for the study of circadian and photoperiodic biology.

Fifty-year old and still ticking.... an interview with Emile Zuckerkandl on the 50th anniversary of the molecular clock. Interview by Giacomo Bernardi.

PubMed

Zuckerkandl, Emile

2012-06-01

In 1962, a young post-doctoral fellow and a prominent Nobel Prize winner, Emile Zuckerkandl and Linus Pauling, published a seminal paper that described the relationship between the average number of aminoacid replacements and divergence time, known as the molecular clock (Zuckerkandl and Pauling 1962). Fifty years after the original publication, I was fortunate enough to interview Emile Zuckerkandl. We shared thoughts on his life and the historical events that led to the discovery of the molecular clock.

Watch-ing out for chick limb development.

PubMed

Pascoal, Susana; Palmeirim, Isabel

2007-09-01

Time control is a crucial issue during embryonic development. Nevertheless, little is known about how embryonic cells measure time. Until recently, the only molecular clock known to operate during vertebrate embryonic development was the somitogenesis clock, exclusively functioning in coordinating the precise timing of each new pair of somites formed from the presomitic mesoderm. We have recently evidenced that a similar molecular clock also underlies the timing at which autopod chondrogenic precursors are laid down to form a skeletal limb element. In addition, we herein suggest that the molecular clock is not the only parallelism that can be established between somitogenesis and limb-bud development. In an evolutionary perspective, we support the previously proposed idea that the molecular mechanisms involved in the segmentation of the body axis may have been partially reused in the mesoderm of the lateral plate, thereby allowing the emergence of paired appendages.

A supermatrix analysis of genomic, morphological, and paleontological data from crown Cetacea

PubMed Central

2011-01-01

Background Cetacea (dolphins, porpoises, and whales) is a clade of aquatic species that includes the most massive, deepest diving, and largest brained mammals. Understanding the temporal pattern of diversification in the group as well as the evolution of cetacean anatomy and behavior requires a robust and well-resolved phylogenetic hypothesis. Although a large body of molecular data has accumulated over the past 20 years, DNA sequences of cetaceans have not been directly integrated with the rich, cetacean fossil record to reconcile discrepancies among molecular and morphological characters. Results We combined new nuclear DNA sequences, including segments of six genes (~2800 basepairs) from the functionally extinct Yangtze River dolphin, with an expanded morphological matrix and published genomic data. Diverse analyses of these data resolved the relationships of 74 taxa that represent all extant families and 11 extinct families of Cetacea. The resulting supermatrix (61,155 characters) and its sub-partitions were analyzed using parsimony methods. Bayesian and maximum likelihood (ML) searches were conducted on the molecular partition, and a molecular scaffold obtained from these searches was used to constrain a parsimony search of the morphological partition. Based on analysis of the supermatrix and model-based analyses of the molecular partition, we found overwhelming support for 15 extant clades. When extinct taxa are included, we recovered trees that are significantly correlated with the fossil record. These trees were used to reconstruct the timing of cetacean diversification and the evolution of characters shared by "river dolphins," a non-monophyletic set of species according to all of our phylogenetic analyses. Conclusions The parsimony analysis of the supermatrix and the analysis of morphology constrained to fit the ML/Bayesian molecular tree yielded broadly congruent phylogenetic hypotheses. In trees from both analyses, all Oligocene taxa included in our study fell outside crown Mysticeti and crown Odontoceti, suggesting that these two clades radiated in the late Oligocene or later, contra some recent molecular clock studies. Our trees also imply that many character states shared by river dolphins evolved in their oceanic ancestors, contradicting the hypothesis that these characters are convergent adaptations to fluvial habitats. PMID:21518443

A supermatrix analysis of genomic, morphological, and paleontological data from crown Cetacea.

PubMed

Geisler, Jonathan H; McGowen, Michael R; Yang, Guang; Gatesy, John

2011-04-25

Cetacea (dolphins, porpoises, and whales) is a clade of aquatic species that includes the most massive, deepest diving, and largest brained mammals. Understanding the temporal pattern of diversification in the group as well as the evolution of cetacean anatomy and behavior requires a robust and well-resolved phylogenetic hypothesis. Although a large body of molecular data has accumulated over the past 20 years, DNA sequences of cetaceans have not been directly integrated with the rich, cetacean fossil record to reconcile discrepancies among molecular and morphological characters. We combined new nuclear DNA sequences, including segments of six genes (~2800 basepairs) from the functionally extinct Yangtze River dolphin, with an expanded morphological matrix and published genomic data. Diverse analyses of these data resolved the relationships of 74 taxa that represent all extant families and 11 extinct families of Cetacea. The resulting supermatrix (61,155 characters) and its sub-partitions were analyzed using parsimony methods. Bayesian and maximum likelihood (ML) searches were conducted on the molecular partition, and a molecular scaffold obtained from these searches was used to constrain a parsimony search of the morphological partition. Based on analysis of the supermatrix and model-based analyses of the molecular partition, we found overwhelming support for 15 extant clades. When extinct taxa are included, we recovered trees that are significantly correlated with the fossil record. These trees were used to reconstruct the timing of cetacean diversification and the evolution of characters shared by "river dolphins," a non-monophyletic set of species according to all of our phylogenetic analyses. The parsimony analysis of the supermatrix and the analysis of morphology constrained to fit the ML/Bayesian molecular tree yielded broadly congruent phylogenetic hypotheses. In trees from both analyses, all Oligocene taxa included in our study fell outside crown Mysticeti and crown Odontoceti, suggesting that these two clades radiated in the late Oligocene or later, contra some recent molecular clock studies. Our trees also imply that many character states shared by river dolphins evolved in their oceanic ancestors, contradicting the hypothesis that these characters are convergent adaptations to fluvial habitats.

Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior.

PubMed

Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

2014-03-01

Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(-) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(-) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per⁰¹ mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per⁰¹ flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output.

Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior

PubMed Central

Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

2014-01-01

Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(−) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(−) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per01 mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per01 flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output. PMID:24643294

Machine Learning Helps Identify CHRONO as a Circadian Clock Component

PubMed Central

Venkataraman, Anand; Ramanathan, Chidambaram; Kavakli, Ibrahim H.; Hughes, Michael E.; Baggs, Julie E.; Growe, Jacqueline; Liu, Andrew C.; Kim, Junhyong; Hogenesch, John B.

2014-01-01

Over the last decades, researchers have characterized a set of “clock genes” that drive daily rhythms in physiology and behavior. This arduous work has yielded results with far-reaching consequences in metabolic, psychiatric, and neoplastic disorders. Recent attempts to expand our understanding of circadian regulation have moved beyond the mutagenesis screens that identified the first clock components, employing higher throughput genomic and proteomic techniques. In order to further accelerate clock gene discovery, we utilized a computer-assisted approach to identify and prioritize candidate clock components. We used a simple form of probabilistic machine learning to integrate biologically relevant, genome-scale data and ranked genes on their similarity to known clock components. We then used a secondary experimental screen to characterize the top candidates. We found that several physically interact with known clock components in a mammalian two-hybrid screen and modulate in vitro cellular rhythms in an immortalized mouse fibroblast line (NIH 3T3). One candidate, Gene Model 129, interacts with BMAL1 and functionally represses the key driver of molecular rhythms, the BMAL1/CLOCK transcriptional complex. Given these results, we have renamed the gene CHRONO (computationally highlighted repressor of the network oscillator). Bi-molecular fluorescence complementation and co-immunoprecipitation demonstrate that CHRONO represses by abrogating the binding of BMAL1 to its transcriptional co-activator CBP. Most importantly, CHRONO knockout mice display a prolonged free-running circadian period similar to, or more drastic than, six other clock components. We conclude that CHRONO is a functional clock component providing a new layer of control on circadian molecular dynamics. PMID:24737000

Molecular epidemiology of Saint Louis encephalitis virus in the Brazilian Amazon: genetic divergence and dispersal.

PubMed

Rodrigues, Sueli G; Nunes, Márcio R T; Casseb, Samir M M; Prazeres, Assis S C; Rodrigues, Daniela S G; Silva, Mayra O; Cruz, Ana C R; Tavares-Neto, José C; Vasconcelos, Pedro F C

2010-10-01

Saint Louis encephalitis virus (SLEV), a member of the genus Flavivirus (family Flaviviridae), is an encephalitogenic arbovirus broadly distributed in the Americas. Phylogenetic analysis based on the full-length E gene sequences obtained for 30 Brazilian SLEV strains was performed using different methods including Bayesian and relaxed molecular clock approaches. A new genetic lineage was suggested, hereafter named genotype VIII, which co-circulates with the previously described genotype V in the Brazilian Amazon region. Genotypes II and III were restricted to São Paulo state (South-east Atlantic rainforest ecosystem). The analysis also suggested the emergence of an SLEV common ancestor between 1875 and 1973 (mean of 107 years ago), giving rise to two major genetic groups: genotype II, more prevalent in the North America, and a second group comprising the other genotypes (I and III-VIII), broadly dispersed throughout the Americas, suggesting that SLEV initially emerged in South America and spread to North America. In conclusion, the current study demonstrates the high genetic variability of SLEV and its geographical dispersion in Brazil and other New World countries.

Evolutionary history of African mongoose rabies.

PubMed

Van Zyl, N; Markotter, W; Nel, L H

2010-06-01

Two biotypes or variants of rabies virus (RABV) occur in southern Africa. These variants are respectively adapted to hosts belonging to the Canidae family (the canid variant) and hosts belonging to the Herpestidae family (the mongoose variant). Due to the distinct host adaptation and differences in epidemiology and pathogenesis, it has been hypothesized that the two variants were introduced into Africa at different times. The objective of this study was to investigate the molecular phylogeny of representative RABV isolates of the mongoose variant towards a better understanding of the origins of this group. The study was based on an analysis of the full nucleoprotein and glycoprotein gene sequences of a panel of 27 viruses. Phylogenetic analysis of this dataset confirmed extended evolutionary adaptation of isolates in specific geographic areas. The evolutionary dynamics of this virus variant was investigated using Bayesian methodology, allowing for rate variation among viral lineages. Molecular clock analysis estimated the age of the African mongoose RABV to be approximately 200 years old, which is in concurrence with literature describing rabies in mongooses since the early 1800 s. (c) 2010 Elsevier B.V. All rights reserved.

Accounting for rate variation among lineages in comparative demographic analyses

USGS Publications Warehouse

Hope, Andrew G.; Ho, Simon Y. W.; Malaney, Jason L.; Cook, Joseph A.; Talbot, Sandra L.

2014-01-01

Genetic analyses of contemporary populations can be used to estimate the demographic histories of species within an ecological community. Comparison of these demographic histories can shed light on community responses to past climatic events. However, species experience different rates of molecular evolution, and this presents a major obstacle to comparative demographic analyses. We address this problem by using a Bayesian relaxed-clock method to estimate the relative evolutionary rates of 22 small mammal taxa distributed across northwestern North America. We found that estimates of the relative molecular substitution rate for each taxon were consistent across the range of sampling schemes that we compared. Using three different reference rates, we rescaled the relative rates so that they could be used to estimate absolute evolutionary timescales. Accounting for rate variation among taxa led to temporal shifts in our skyline-plot estimates of demographic history, highlighting both uniform and idiosyncratic evolutionary responses to directional climate trends for distinct ecological subsets of the small mammal community. Our approach can be used in evolutionary analyses of populations from multiple species, including comparative demographic studies.

Post-Boreotropical dispersals explain the pantropical disjunction in Paederia (Rubiaceae)

PubMed Central

Nie, Ze-Long; Deng, Tao; Meng, Ying; Sun, Hang; Wen, Jun

2013-01-01

Background and Aims Pantropical intercontinental disjunction is a common biogeographical pattern in flowering plants exhibiting a discontinuous distribution primarily in tropical Asia, Africa and the Americas. Only a few plant groups with this pattern have been investigated at the generic level with molecular phylogenetic and biogeographical methods. Paederia (Rubiaceae) is a pantropical genus of 31 species of woody lianas, with the greatest species diversity in continental Asia and Madagascar and only two species from tropical America. The aim of this study was to reconstruct the biogeographical history of Paederia based on phylogenetic analyses to explore how the genus attained its pantropical distribution. Methods Maximum parsimony and Bayesian inference were used for phylogenetic analyses using sequences of five plastid markers (the rbcL gene, rps16 intron, trnT-F region, atpB-rbcL spacer and psbA-trnH spacer). Biogeographical inferences were based on a Bayesian uncorrelated lognormal relaxed molecular clock together with both Bayesian and likelihood ancestral area reconstructions. Key Results The data suggest an early diverged Asian lineage sister to the clade of the remaining species consisting of a predominantly Asian sub-clade and a primarily Malagasy sub-clade. Paederia is inferred to have originated in the Oligocene in tropical continental Asia. It then reached Africa in the early to middle Miocene, most probably via long-distance dispersal across the Indian Ocean. The two Neotropical species are inferred to have derived independently in the late Miocene from ancestors of Asia and East Africa, respectively. Conclusions The results demonstrate the importance of post-Boreotropical long-distance dispersals (across three major oceans) in shaping the global pantropical disjunction in some plants, such as Paederia, with small, winged diaspores adapted to long-distance dispersal by various agents including wind, ocean currents or birds. Overland migration is less likely to explain its palaeotropical disjunction between Asia and Africa. PMID:23478944

Lego clocks: building a clock from parts.

PubMed

Brunner, Michael; Simons, Mirre J P; Merrow, Martha

2008-06-01

A new finding opens up speculation that the molecular mechanism of circadian clocks in Synechococcus elongatus is composed of multiple oscillator systems (Kitayama and colleagues, this issue, pp. 1513-1521), as has been described in many eukaryotic clock model systems. However, an alternative intepretation is that the pacemaker mechanism-as previously suggested-lies primarily in the rate of ATP hydrolysis by the clock protein KaiC.

Origin of microbial biomineralization and magnetotaxis during the Archean.

PubMed

Lin, Wei; Paterson, Greig A; Zhu, Qiyun; Wang, Yinzhao; Kopylova, Evguenia; Li, Ying; Knight, Rob; Bazylinski, Dennis A; Zhu, Rixiang; Kirschvink, Joseph L; Pan, Yongxin

2017-02-28

Microbes that synthesize minerals, a process known as microbial biomineralization, contributed substantially to the evolution of current planetary environments through numerous important geochemical processes. Despite its geological significance, the origin and evolution of microbial biomineralization remain poorly understood. Through combined metagenomic and phylogenetic analyses of deep-branching magnetotactic bacteria from the Nitrospirae phylum, and using a Bayesian molecular clock-dating method, we show here that the gene cluster responsible for biomineralization of magnetosomes, and the arrangement of magnetosome chain(s) within cells, both originated before or near the Archean divergence between the Nitrospirae and Proteobacteria This phylogenetic divergence occurred well before the Great Oxygenation Event. Magnetotaxis likely evolved due to environmental pressures conferring an evolutionary advantage to navigation via the geomagnetic field. Earth's dynamo must therefore have been sufficiently strong to sustain microbial magnetotaxis in the Archean, suggesting that magnetotaxis coevolved with the geodynamo over geological time.

Pancrustacean phylogeny: hexapods are terrestrial crustaceans and maxillopods are not monophyletic

PubMed Central

Regier, Jerome C.; Shultz, Jeffrey W.; Kambic, Robert E.

2005-01-01

Recent molecular analyses indicate that crustaceans and hexapods form a clade (Pancrustacea or Tetraconata), but relationships among its constituent lineages, including monophyly of crustaceans, are controversial. Our phylogenetic analysis of three protein-coding nuclear genes from 62 arthropods and lobopods (Onychophora and Tardigrada) demonstrates that Hexapoda is most closely related to the crustaceans Branchiopoda (fairy shrimp, water fleas, etc.) and Cephalocarida+Remipedia, thereby making hexapods terrestrial crustaceans and the traditionally defined Crustacea paraphyletic. Additional findings are that Malacostraca (crabs, isopods, etc.) unites with Cirripedia (barnacles, etc.) and they, in turn, with Copepoda, making the traditional crustacean class Maxillopoda paraphyletic. Ostracoda (seed shrimp)—either all or a subgroup—is associated with Branchiura (fish lice) and likely to be basal to all other pancrustaceans. A Bayesian statistical (non-clock) estimate of divergence times suggests a Precambrian origin for Pancrustacea (600 Myr ago or more), which precedes the first unambiguous arthropod fossils by over 60 Myr. PMID:15734694

Pre- versus post-mass extinction divergence of Mesozoic marine reptiles dictated by time-scale dependence of evolutionary rates.

PubMed

Motani, Ryosuke; Jiang, Da-Yong; Tintori, Andrea; Ji, Cheng; Huang, Jian-Dong

2017-05-17

The fossil record of a major clade often starts after a mass extinction even though evolutionary rates, molecular or morphological, suggest its pre-extinction emergence (e.g. squamates, placentals and teleosts). The discrepancy is larger for older clades, and the presence of a time-scale-dependent methodological bias has been suggested, yet it has been difficult to avoid the bias using Bayesian phylogenetic methods. This paradox raises the question of whether ecological vacancies, such as those after mass extinctions, prompt the radiations. We addressed this problem by using a unique temporal characteristic of the morphological data and a high-resolution stratigraphic record, for the oldest clade of Mesozoic marine reptiles, Ichthyosauromorpha. The evolutionary rate was fastest during the first few million years of ichthyosauromorph evolution and became progressively slower over time, eventually becoming six times slower. Using the later slower rates, estimates of divergence time become excessively older. The fast, initial rate suggests the emergence of ichthyosauromorphs after the end-Permian mass extinction, matching an independent result from high-resolution stratigraphic confidence intervals. These reptiles probably invaded the sea as a new ecosystem was formed after the end-Permian mass extinction. Lack of information on early evolution biased Bayesian clock rates. © 2017 The Author(s).

Origin of marine planktonic cyanobacteria.

PubMed

Sánchez-Baracaldo, Patricia

2015-12-01

Marine planktonic cyanobacteria contributed to the widespread oxygenation of the oceans towards the end of the Pre-Cambrian and their evolutionary origin represents a key transition in the geochemical evolution of the Earth surface. Little is known, however, about the evolutionary events that led to the appearance of marine planktonic cyanobacteria. I present here phylogenomic (135 proteins and two ribosomal RNAs), Bayesian relaxed molecular clock (18 proteins, SSU and LSU) and Bayesian stochastic character mapping analyses from 131 cyanobacteria genomes with the aim to unravel key evolutionary steps involved in the origin of marine planktonic cyanobacteria. While filamentous cell types evolved early on at around 2,600-2,300 Mya and likely dominated microbial mats in benthic environments for most of the Proterozoic (2,500-542 Mya), marine planktonic cyanobacteria evolved towards the end of the Proterozoic and early Phanerozoic. Crown groups of modern terrestrial and/or benthic coastal cyanobacteria appeared during the late Paleoproterozoic to early Mesoproterozoic. Decrease in cell diameter and loss of filamentous forms contributed to the evolution of unicellular planktonic lineages during the middle of the Mesoproterozoic (1,600-1,000 Mya) in freshwater environments. This study shows that marine planktonic cyanobacteria evolved from benthic marine and some diverged from freshwater ancestors during the Neoproterozoic (1,000-542 Mya).

Origin of marine planktonic cyanobacteria

PubMed Central

Sánchez-Baracaldo, Patricia

2015-01-01

Marine planktonic cyanobacteria contributed to the widespread oxygenation of the oceans towards the end of the Pre-Cambrian and their evolutionary origin represents a key transition in the geochemical evolution of the Earth surface. Little is known, however, about the evolutionary events that led to the appearance of marine planktonic cyanobacteria. I present here phylogenomic (135 proteins and two ribosomal RNAs), Bayesian relaxed molecular clock (18 proteins, SSU and LSU) and Bayesian stochastic character mapping analyses from 131 cyanobacteria genomes with the aim to unravel key evolutionary steps involved in the origin of marine planktonic cyanobacteria. While filamentous cell types evolved early on at around 2,600–2,300 Mya and likely dominated microbial mats in benthic environments for most of the Proterozoic (2,500–542 Mya), marine planktonic cyanobacteria evolved towards the end of the Proterozoic and early Phanerozoic. Crown groups of modern terrestrial and/or benthic coastal cyanobacteria appeared during the late Paleoproterozoic to early Mesoproterozoic. Decrease in cell diameter and loss of filamentous forms contributed to the evolution of unicellular planktonic lineages during the middle of the Mesoproterozoic (1,600–1,000 Mya) in freshwater environments. This study shows that marine planktonic cyanobacteria evolved from benthic marine and some diverged from freshwater ancestors during the Neoproterozoic (1,000–542 Mya). PMID:26621203

Phylogeny, time divergence, and historical biogeography of the South American Liolaemus alticolor-bibronii group (Iguania: Liolaemidae)

PubMed Central

2018-01-01

The genus Liolaemus comprises more than 260 species and can be divided in two subgenera: Eulaemus and Liolaemus sensu stricto. In this paper, we present a phylogenetic analysis, divergence times, and ancestral distribution ranges of the Liolaemus alticolor-bibronii group (Liolaemus sensu stricto subgenus). We inferred a total evidence phylogeny combining molecular (Cytb and 12S genes) and morphological characters using Maximum Parsimony and Bayesian Inference. Divergence times were calculated using Bayesian MCMC with an uncorrelated lognormal distributed relaxed clock, calibrated with a fossil record. Ancestral ranges were estimated using the Dispersal-Extinction-Cladogenesis (DEC-Lagrange). Effects of some a priori parameters of DEC were also tested. Distribution ranged from central Perú to southern Argentina, including areas at sea level up to the high Andes. The L. alticolor-bibronii group was recovered as monophyletic, formed by two clades: L. walkeri and L. gracilis, the latter can be split in two groups. Additionally, many species candidates were recognized. We estimate that the L. alticolor-bibronii group diversified 14.5 Myr ago, during the Middle Miocene. Our results suggest that the ancestor of the Liolaemus alticolor-bibronii group was distributed in a wide area including Patagonia and Puna highlands. The speciation pattern follows the South-North Diversification Hypothesis, following the Andean uplift. PMID:29479502

Pre- versus post-mass extinction divergence of Mesozoic marine reptiles dictated by time-scale dependence of evolutionary rates

PubMed Central

Ji, Cheng; Huang, Jian-dong

2017-01-01

The fossil record of a major clade often starts after a mass extinction even though evolutionary rates, molecular or morphological, suggest its pre-extinction emergence (e.g. squamates, placentals and teleosts). The discrepancy is larger for older clades, and the presence of a time-scale-dependent methodological bias has been suggested, yet it has been difficult to avoid the bias using Bayesian phylogenetic methods. This paradox raises the question of whether ecological vacancies, such as those after mass extinctions, prompt the radiations. We addressed this problem by using a unique temporal characteristic of the morphological data and a high-resolution stratigraphic record, for the oldest clade of Mesozoic marine reptiles, Ichthyosauromorpha. The evolutionary rate was fastest during the first few million years of ichthyosauromorph evolution and became progressively slower over time, eventually becoming six times slower. Using the later slower rates, estimates of divergence time become excessively older. The fast, initial rate suggests the emergence of ichthyosauromorphs after the end-Permian mass extinction, matching an independent result from high-resolution stratigraphic confidence intervals. These reptiles probably invaded the sea as a new ecosystem was formed after the end-Permian mass extinction. Lack of information on early evolution biased Bayesian clock rates. PMID:28515201

Phylogeography of the Western Lyresnake (Trimorphodon biscutatus): testing aridland biogeographical hypotheses across the Nearctic-Neotropical transition.

PubMed

Devitt, Thomas J

2006-12-01

The Western Lyresnake (Trimorphodon biscutatus) is a widespread, polytypic taxon inhabiting arid regions from the warm deserts of the southwestern United States southward along the Pacific versant of Mexico to the tropical deciduous forests of Mesoamerica. This broadly distributed species provides a unique opportunity to evaluate a priori biogeographical hypotheses spanning two major distinct biogeographical realms (the Nearctic and Neotropical) that are usually treated separately in phylogeographical analyses. I investigated the phylogeography of T. biscutatus using maximum likelihood and Bayesian phylogenetic analysis of mitochondrial DNA (mtDNA) from across this species' range. Phylogenetic analyses recovered five well-supported clades whose boundaries are concordant with existing geographical barriers, a pattern consistent with a model of vicariant allopatric divergence. Assuming a vicariance model, divergence times between mitochondrial lineages were estimated using Bayesian relaxed molecular clock methods calibrated using geological information from putative vicariant events. Divergence time point estimates were bounded by broad confidence intervals, and thus these highly conservative estimates should be considered tentative hypotheses at best. Comparison of mtDNA lineages and taxa traditionally recognized as subspecies based on morphology suggest this taxon is comprised of multiple independent lineages at various stages of divergence, ranging from putative secondary contact and hybridization to sympatry of 'subspecies'.

The circadian clock of Neurospora crassa.

PubMed

Baker, Christopher L; Loros, Jennifer J; Dunlap, Jay C

2012-01-01

Circadian clocks organize our inner physiology with respect to the external world, providing life with the ability to anticipate and thereby better prepare for major fluctuations in its environment. Circadian systems are widely represented in nearly all major branches of life, except archaebacteria, and within the eukaryotes, the filamentous fungus Neurospora crassa has served for nearly half a century as a durable model organism for uncovering the basic circadian physiology and molecular biology. Studies using Neurospora have clarified our fundamental understanding of the clock as nested positive and negative feedback loops regulated through transcriptional and post-transcriptional processes. These feedback loops are centered on a limited number of proteins that form molecular complexes, and their regulation provides a physical explanation for nearly all clock properties. This review will introduce the basics of circadian rhythms, the model filamentous fungus N. crassa, and provide an overview of the molecular components and regulation of the circadian clock. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus.

PubMed

Qian, Jingyi; Thomas, Anthony P; Schroeder, Analyne M; Rakshit, Kuntol; Colwell, Christopher S; Matveyenko, Aleksey V

2017-08-01

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1 ) behavioral circadian rhythms, 2 ) photic entrainment of circadian activity, 3 ) SCN and peripheral tissue molecular clock function, and 4 ) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM. Copyright © 2017 the American Physiological Society.

Effects of Different PER Translational Kinetics on the Dynamics of a Core Circadian Clock Model

PubMed Central

Nieto, Paula S.; Revelli, Jorge A.; Garbarino-Pico, Eduardo; Condat, Carlos A.; Guido, Mario E.; Tamarit, Francisco A.

2015-01-01

Living beings display self-sustained daily rhythms in multiple biological processes, which persist in the absence of external cues since they are generated by endogenous circadian clocks. The period (per) gene is a central player within the core molecular mechanism for keeping circadian time in most animals. Recently, the modulation PER translation has been reported, both in mammals and flies, suggesting that translational regulation of clock components is important for the proper clock gene expression and molecular clock performance. Because translational regulation ultimately implies changes in the kinetics of translation and, therefore, in the circadian clock dynamics, we sought to study how and to what extent the molecular clock dynamics is affected by the kinetics of PER translation. With this objective, we used a minimal mathematical model of the molecular circadian clock to qualitatively characterize the dynamical changes derived from kinetically different PER translational mechanisms. We found that the emergence of self-sustained oscillations with characteristic period, amplitude, and phase lag (time delays) between per mRNA and protein expression depends on the kinetic parameters related to PER translation. Interestingly, under certain conditions, a PER translation mechanism with saturable kinetics introduces longer time delays than a mechanism ruled by a first-order kinetics. In addition, the kinetic laws of PER translation significantly changed the sensitivity of our model to parameters related to the synthesis and degradation of per mRNA and PER degradation. Lastly, we found a set of parameters, with realistic values, for which our model reproduces some experimental results reported recently for Drosophila melanogaster and we present some predictions derived from our analysis. PMID:25607544

Effects of different per translational kinetics on the dynamics of a core circadian clock model.

PubMed

Nieto, Paula S; Revelli, Jorge A; Garbarino-Pico, Eduardo; Condat, Carlos A; Guido, Mario E; Tamarit, Francisco A

2015-01-01

Living beings display self-sustained daily rhythms in multiple biological processes, which persist in the absence of external cues since they are generated by endogenous circadian clocks. The period (per) gene is a central player within the core molecular mechanism for keeping circadian time in most animals. Recently, the modulation PER translation has been reported, both in mammals and flies, suggesting that translational regulation of clock components is important for the proper clock gene expression and molecular clock performance. Because translational regulation ultimately implies changes in the kinetics of translation and, therefore, in the circadian clock dynamics, we sought to study how and to what extent the molecular clock dynamics is affected by the kinetics of PER translation. With this objective, we used a minimal mathematical model of the molecular circadian clock to qualitatively characterize the dynamical changes derived from kinetically different PER translational mechanisms. We found that the emergence of self-sustained oscillations with characteristic period, amplitude, and phase lag (time delays) between per mRNA and protein expression depends on the kinetic parameters related to PER translation. Interestingly, under certain conditions, a PER translation mechanism with saturable kinetics introduces longer time delays than a mechanism ruled by a first-order kinetics. In addition, the kinetic laws of PER translation significantly changed the sensitivity of our model to parameters related to the synthesis and degradation of per mRNA and PER degradation. Lastly, we found a set of parameters, with realistic values, for which our model reproduces some experimental results reported recently for Drosophila melanogaster and we present some predictions derived from our analysis.

Evaluating the Autonomy of the Drosophila Circadian Clock in Dissociated Neuronal Culture.

PubMed

Sabado, Virginie; Vienne, Ludovic; Nagoshi, Emi

2017-01-01

Circadian behavioral rhythms offer an excellent model to study intricate interactions between the molecular and neuronal mechanisms of behavior. In mammals, pacemaker neurons in the suprachiasmatic nucleus (SCN) generate rhythms cell-autonomously, which are synchronized by the network interactions within the circadian circuit to drive behavioral rhythms. However, whether this principle is universal to circadian systems in animals remains unanswered. Here, we examined the autonomy of the Drosophila circadian clock by monitoring transcriptional and post-transcriptional rhythms of individual clock neurons in dispersed culture with time-lapse microscopy. Expression patterns of the transcriptional reporter show that CLOCK/CYCLE (CLK/CYC)-mediated transcription is constantly active in dissociated clock neurons. In contrast, the expression profile of the post-transcriptional reporter indicates that PERIOD (PER) protein levels fluctuate and ~10% of cells display rhythms in PER levels with periods in the circadian range. Nevertheless, PER and TIM are enriched in the cytoplasm and no periodic PER nuclear accumulation was observed. These results suggest that repression of CLK/CYC-mediated transcription by nuclear PER is impaired, and thus the negative feedback loop of the molecular clock is incomplete in isolated clock neurons. We further demonstrate that, by pharmacological assays using the non-amidated form of neuropeptide pigment-dispersing factor (PDF), which could be specifically secreted from larval LNvs and adult s-LNvs, downstream events of the PDF signaling are partly impaired in dissociated larval clock neurons. Although non-amidated PDF is likely to be less active than the amidated one, these results point out the possibility that alteration in PDF downstream signaling may play a role in dampening of molecular rhythms in isolated clock neurons. Taken together, our results suggest that Drosophila clocks are weak oscillators that need to be in the intact circadian circuit to generate robust 24-h rhythms.

Phylogenetic relationships within Echinococcus and Taenia tapeworms (Cestoda: Taeniidae): an inference from nuclear protein-coding genes.

PubMed

Knapp, Jenny; Nakao, Minoru; Yanagida, Tetsuya; Okamoto, Munehiro; Saarma, Urmas; Lavikainen, Antti; Ito, Akira

2011-12-01

The family Taeniidae of tapeworms is composed of two genera, Echinococcus and Taenia, which obligately parasitize mammals including humans. Inferring phylogeny via molecular markers is the only way to trace back their evolutionary histories. However, molecular dating approaches are lacking so far. Here we established new markers from nuclear protein-coding genes for RNA polymerase II second largest subunit (rpb2), phosphoenolpyruvate carboxykinase (pepck) and DNA polymerase delta (pold). Bayesian inference and maximum likelihood analyses of the concatenated gene sequences allowed us to reconstruct phylogenetic trees for taeniid parasites. The tree topologies clearly demonstrated that Taenia is paraphyletic and that the clade of Echinococcus oligarthrus and Echinococcusvogeli is sister to all other members of Echinococcus. Both species are endemic in Central and South America, and their definitive hosts originated from carnivores that immigrated from North America after the formation of the Panamanian land bridge about 3 million years ago (Ma). A time-calibrated phylogeny was estimated by a Bayesian relaxed-clock method based on the assumption that the most recent common ancestor of E. oligarthrus and E. vogeli existed during the late Pliocene (3.0 Ma). The results suggest that a clade of Taenia including human-pathogenic species diversified primarily in the late Miocene (11.2 Ma), whereas Echinococcus started to diversify later, in the end of the Miocene (5.8 Ma). Close genetic relationships among the members of Echinococcus imply that the genus is a young group in which speciation and global radiation occurred rapidly. Copyright © 2011 Elsevier Inc. All rights reserved.

Molecular phylogenetic analysis supports a Gondwanan origin of the Hyriidae (Mollusca: Bivalvia: Unionida) and the paraphyly of Australasian taxa.

PubMed

Graf, Daniel L; Jones, Hugh; Geneva, Anthony J; Pfeiffer, John M; Klunzinger, Michael W

2015-04-01

The freshwater mussel family Hyriidae (Mollusca: Bivalvia: Unionida) has a disjunct trans-Pacific distribution in Australasia and South America. Previous phylogenetic analyses have estimated the evolutionary relationships of the family and the major infra-familial taxa (Velesunioninae and Hyriinae: Hyridellini in Australia; Hyriinae: Hyriini, Castaliini, and Rhipidodontini in South America), but taxon and character sampling have been too incomplete to support a predictive classification or allow testing of biogeographical hypotheses. We sampled 30 freshwater mussel individuals representing the aforementioned hyriid taxa, as well as outgroup species representing the five other freshwater mussel families and their marine sister group (order Trigoniida). Our ingroup included representatives of all Australian genera. Phylogenetic relationships were estimated from three gene fragments (nuclear 28S, COI and 16S mtDNA) using maximum parsimony, maximum likelihood, and Bayesian inference, and we applied a Bayesian relaxed clock model calibrated with fossil dates to estimate node ages. Our analyses found good support for monophyly of the Hyriidae and the subfamilies and tribes, as well as the paraphyly of the Australasian taxa (Velesunioninae, (Hyridellini, (Rhipidodontini, (Castaliini, Hyriini)))). The Hyriidae was recovered as sister to a clade comprised of all other Recent freshwater mussel families. Our molecular date estimation supported Cretaceous origins of the major hyriid clades, pre-dating the Tertiary isolation of South America from Antarctica/Australia. We hypothesize that early diversification of the Hyriidae was driven by terrestrial barriers on Gondwana rather than marine barriers following disintegration of the super-continent. Copyright © 2015 Elsevier Inc. All rights reserved.

Regulation of circadian blood pressure: from mice to astronauts.

PubMed

Agarwal, Rajiv

2010-01-01

Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.

Pacemaker-neuron–dependent disturbance of the molecular clockwork by a Drosophila CLOCK mutant homologous to the mouse Clock mutation

PubMed Central

Lee, Euna; Cho, Eunjoo; Kang, Doo Hyun; Jeong, Eun Hee; Chen, Zheng; Yoo, Seung-Hee; Kim, Eun Young

2016-01-01

Circadian clocks are composed of transcriptional/translational feedback loops (TTFLs) at the cellular level. In Drosophila TTFLs, the transcription factor dCLOCK (dCLK)/CYCLE (CYC) activates clock target gene expression, which is repressed by the physical interaction with PERIOD (PER). Here, we show that amino acids (AA) 657–707 of dCLK, a region that is homologous to the mouse Clock exon 19-encoded region, is crucial for PER binding and E-box–dependent transactivation in S2 cells. Consistently, in transgenic flies expressing dCLK with an AA657–707 deletion in the Clock (Clkout) genetic background (p{dClk-Δ};Clkout), oscillation of core clock genes’ mRNAs displayed diminished amplitude compared with control flies, and the highly abundant dCLKΔ657–707 showed significantly decreased binding to PER. Behaviorally, the p{dClk-Δ};Clkout flies exhibited arrhythmic locomotor behavior in the photic entrainment condition but showed anticipatory activities of temperature transition and improved free-running rhythms in the temperature entrainment condition. Surprisingly, p{dClk-Δ};Clkout flies showed pacemaker-neuron–dependent alterations in molecular rhythms; the abundance of dCLK target clock proteins was reduced in ventral lateral neurons (LNvs) but not in dorsal neurons (DNs) in both entrainment conditions. In p{dClk-Δ};Clkout flies, however, strong but delayed molecular oscillations in temperature cycle-sensitive pacemaker neurons, such as DN1s and DN2s, were correlated with delayed anticipatory activities of temperature transition. Taken together, our study reveals that the LNv molecular clockwork is more sensitive than the clockwork of DNs to dysregulation of dCLK by AA657–707 deletion. Therefore, we propose that the dCLK/CYC-controlled TTFL operates differently in subsets of pacemaker neurons, which may contribute to their specific functions. PMID:27489346

Natural Variation of the Circadian Clock in Neurospora.

PubMed

Koritala, Bala S C; Lee, Kwangwon

2017-01-01

Most living organisms on earth experience daily and expected changes from the rotation of the earth. For an organism, the ability to predict and prepare for incoming stresses or resources is a very important skill for survival. This cellular process of measuring daily time of the day is collectively called the circadian clock. Because of its fundamental role in survival in nature, there is a great interest in studying the natural variation of the circadian clock. However, characterizing the genetic and molecular mechanisms underlying natural variation of circadian clocks remains a challenging task. In this chapter, we will summarize the progress in studying natural variation of the circadian clock in the successful eukaryotic model Neurospora, which led to discovering many design principles of the molecular mechanisms of the eukaryotic circadian clock. Despite the success of the system in revealing the molecular mechanisms of the circadian clock, Neurospora has not been utilized to extensively study natural variation. We will review the challenges that hindered the natural variation studies in Neurospora, and how they were overcome. We will also review the advantages of Neurospora for natural variation studies. Since Neurospora is the model fungal species for circadian study, it represents over 5 million species of fungi on earth. These fungi play important roles in ecosystems on earth, and as such Neurospora could serve as an important model for understanding the ecological role of natural variation in fungal circadian clocks. © 2017 Elsevier Inc. All rights reserved.

Timing Embryo Segmentation: Dynamics and Regulatory Mechanisms of the Vertebrate Segmentation Clock

PubMed Central

Resende, Tatiana P.; Andrade, Raquel P.; Palmeirim, Isabel

2014-01-01

All vertebrate species present a segmented body, easily observed in the vertebrate column and its associated components, which provides a high degree of motility to the adult body and efficient protection of the internal organs. The sequential formation of the segmented precursors of the vertebral column during embryonic development, the somites, is governed by an oscillating genetic network, the somitogenesis molecular clock. Herein, we provide an overview of the molecular clock operating during somite formation and its underlying molecular regulatory mechanisms. Human congenital vertebral malformations have been associated with perturbations in these oscillatory mechanisms. Thus, a better comprehension of the molecular mechanisms regulating somite formation is required in order to fully understand the origin of human skeletal malformations. PMID:24895605

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary

PubMed Central

Liu, Liang; Zhang, Jin; Rheindt, Frank E.; Lei, Fumin; Qu, Yanhua; Wang, Yu; Zhang, Yu; Sullivan, Corwin; Nie, Wenhui; Wang, Jinhuan; Yang, Fengtang; Chen, Jinping; Edwards, Scott V.; Meng, Jin; Wu, Shaoyuan

2017-01-01

The timing of the diversification of placental mammals relative to the Cretaceous–Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms. PMID:28808022

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary.

PubMed

Liu, Liang; Zhang, Jin; Rheindt, Frank E; Lei, Fumin; Qu, Yanhua; Wang, Yu; Zhang, Yu; Sullivan, Corwin; Nie, Wenhui; Wang, Jinhuan; Yang, Fengtang; Chen, Jinping; Edwards, Scott V; Meng, Jin; Wu, Shaoyuan

2017-08-29

The timing of the diversification of placental mammals relative to the Cretaceous-Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms.

Origin of the Eumetazoa: testing ecological predictions of molecular clocks against the Proterozoic fossil record

NASA Technical Reports Server (NTRS)

Peterson, Kevin J.; Butterfield, Nicholas J.

2005-01-01

Molecular clocks have the potential to shed light on the timing of early metazoan divergences, but differing algorithms and calibration points yield conspicuously discordant results. We argue here that competing molecular clock hypotheses should be testable in the fossil record, on the principle that fundamentally new grades of animal organization will have ecosystem-wide impacts. Using a set of seven nuclear-encoded protein sequences, we demonstrate the paraphyly of Porifera and calculate sponge/eumetazoan and cnidarian/bilaterian divergence times by using both distance [minimum evolution (ME)] and maximum likelihood (ML) molecular clocks; ME brackets the appearance of Eumetazoa between 634 and 604 Ma, whereas ML suggests it was between 867 and 748 Ma. Significantly, the ME, but not the ML, estimate is coincident with a major regime change in the Proterozoic acritarch record, including: (i) disappearance of low-diversity, evolutionarily static, pre-Ediacaran acanthomorphs; (ii) radiation of the high-diversity, short-lived Doushantuo-Pertatataka microbiota; and (iii) an order-of-magnitude increase in evolutionary turnover rate. We interpret this turnover as a consequence of the novel ecological challenges accompanying the evolution of the eumetazoan nervous system and gut. Thus, the more readily preserved microfossil record provides positive evidence for the absence of pre-Ediacaran eumetazoans and strongly supports the veracity, and therefore more general application, of the ME molecular clock.

HTLV-1aA introduction into Brazil and its association with the trans-Atlantic slave trade.

PubMed

Amoussa, Adjile Edjide Roukiyath; Wilkinson, Eduan; Giovanetti, Marta; de Almeida Rego, Filipe Ferreira; Araujo, Thessika Hialla A; de Souza Gonçalves, Marilda; de Oliveira, Tulio; Alcantara, Luiz Carlos Junior

2017-03-01

Human T-lymphotropic virus (HTLV) is an endemic virus in some parts of the world, with Africa being home to most of the viral genetic diversity. In Brazil, HTLV-1 is endemic amongst Japanese and African immigrant populations. Multiple introductions of the virus in Brazil from other epidemic foci were hypothesized. The long terminal repeat (LTR) region of HTLV-1 was used to infer the origin of the virus in Brazil, using phylogenetic analysis. LTR sequences were obtained from the HTLV-1 database (http://htlv1db.bahia.fiocruz.br). Sequences were aligned and maximum-likelihood and Bayesian tree topologies were inferred. Brazilian specific clusters were identified and molecular-clock and coalescent models were used to estimate each cluster's time to the most recent common ancestor (tMRCA). Three Brazilian clusters were identified with a posterior probability ranged from 0.61 to 0.99. Molecular clock analysis of these three clusters dated back their respective tMRCAs between the year 1499 and the year 1668. Additional analysis also identified a close association between Brazilian sequences and new sequences from South Africa. Our results support the hypothesis of a multiple introductions of HTLV-1 into Brazil, with the majority of introductions occurring in the post-Colombian period. Our results further suggest that HTLV-1 introduction into Brazil was facilitated by the trans-Atlantic slave trade from endemic areas of Africa. The close association between southern African and Brazilian sequences also suggested that greater numbers of the southern African Bantu population might also have been part of the slave trade than previously thought. Copyright © 2016. Published by Elsevier B.V.

A molecular genetic time scale demonstrates Cretaceous origins and multiple diversification rate shifts within the order Galliformes (Aves).

PubMed

Stein, R Will; Brown, Joseph W; Mooers, Arne Ø

2015-11-01

The phylogeny of Galliformes (landfowl) has been studied extensively; however, the associated chronologies have been criticized recently due to misplaced or misidentified fossil calibrations. As a consequence, it is unclear whether any crown-group lineages arose in the Cretaceous and survived the Cretaceous-Paleogene (K-Pg; 65.5 Ma) mass extinction. Using Bayesian phylogenetic inference on an alignment spanning 14,539 bp of mitochondrial and nuclear DNA sequence data, four fossil calibrations, and a combination of uncorrelated lognormally distributed relaxed-clock and strict-clock models, we inferred a time-calibrated molecular phylogeny for 225 of the 291 extant Galliform taxa. These analyses suggest that crown Galliformes diversified in the Cretaceous and that three-stem lineages survived the K-Pg mass extinction. Ideally, characterizing the tempo and mode of diversification involves a taxonomically complete phylogenetic hypothesis. We used simple constraint structures to incorporate 66 data-deficient taxa and inferred the first taxon-complete phylogenetic hypothesis for the Galliformes. Diversification analyses conducted on 10,000 timetrees sampled from the posterior distribution of candidate trees show that the evolutionary history of the Galliformes is best explained by a rate-shift model including 1-3 clade-specific increases in diversification rate. We further show that the tempo and mode of diversification in the Galliformes conforms to a three-pulse model, with three-stem lineages arising in the Cretaceous and inter and intrafamilial diversification occurring after the K-Pg mass extinction, in the Paleocene-Eocene (65.5-33.9 Ma) or in association with the Eocene-Oligocene transition (33.9 Ma). Copyright © 2015 Elsevier Inc. All rights reserved.

Molecular clock integration of brown adipose tissue formation and function

PubMed Central

Nam, Deokhwa; Yechoor, Vijay K.; Ma, Ke

2016-01-01

Abstract The circadian clock is an essential time-keeping mechanism that entrains internal physiology to environmental cues. Despite the well-established link between the molecular clock and metabolic homeostasis, an intimate interplay between the clock machinery and the metabolically active brown adipose tissue (BAT) is only emerging. Recently, we came to appreciate that the formation and metabolic functions of BAT, a key organ for body temperature maintenance, are under an orchestrated circadian clock regulation. Two complementary studies from our group uncover that the cell-intrinsic clock machinery exerts concerted control of brown adipogenesis with consequent impacts on adaptive thermogenesis, which adds a previously unappreciated temporal dimension to the regulatory mechanisms governing BAT development and function. The essential clock transcriptional activator, Bmal1, suppresses adipocyte lineage commitment and differentiation, whereas the clock repressor, Rev-erbα, promotes these processes. This newly discovered temporal mechanism in fine-tuning BAT thermogenic capacity may enable energy utilization and body temperature regulation in accordance with external timing signals during development and functional recruitment. Given the important role of BAT in whole-body metabolic homeostasis, pharmacological interventions targeting the BAT-modulatory activities of the clock circuit may offer new avenues for the prevention and treatment of metabolic disorders, particularly those associated with circadian dysregulation. PMID:27385482

The circadian clock stops ticking during deep hibernation in the European hamster

PubMed Central

Revel, Florent G.; Herwig, Annika; Garidou, Marie-Laure; Dardente, Hugues; Menet, Jérôme S.; Masson-Pévet, Mireille; Simonneaux, Valérie; Saboureau, Michel; Pévet, Paul

2007-01-01

Hibernation is a fascinating, yet enigmatic, physiological phenomenon during which body temperature and metabolism are reduced to save energy. During the harsh season, this strategy allows substantial energy saving by reducing body temperature and metabolism. Accordingly, biological processes are considerably slowed down and reduced to a minimum. However, the persistence of a temperature-compensated, functional biological clock in hibernating mammals has long been debated. Here, we show that the master circadian clock no longer displays 24-h molecular oscillations in hibernating European hamsters. The clock genes Per1, Per2, and Bmal1 and the clock-controlled gene arginine vasopressin were constantly expressed in the suprachiasmatic nucleus during deep torpor, as assessed by radioactive in situ hybridization. Finally, the melatonin rhythm-generating enzyme, arylalkylamine N-acetyltransferase, whose rhythmic expression in the pineal gland is controlled by the master circadian clock, no longer exhibits day/night changes of expression but constantly elevated mRNA levels over 24 h. Overall, these data provide strong evidence that in the European hamster the molecular circadian clock is arrested during hibernation and stops delivering rhythmic output signals. PMID:17715068

The mammalian retina as a clock

NASA Technical Reports Server (NTRS)

Tosini, Gianluca; Fukuhara, Chiaki

2002-01-01

Many physiological, cellular, and biochemical parameters in the retina of vertebrates show daily rhythms that, in many cases, also persist under constant conditions. This demonstrates that they are driven by a circadian pacemaker. The presence of an autonomous circadian clock in the retina of vertebrates was first demonstrated in Xenopus laevis and then, several years later, in mammals. In X. laevis and in chicken, the retinal circadian pacemaker has been localized in the photoreceptor layer, whereas in mammals, such information is not yet available. Recent advances in molecular techniques have led to the identification of a group of genes that are believed to constitute the molecular core of the circadian clock. These genes are expressed in the retina, although with a slightly different 24-h profile from that observed in the central circadian pacemaker. This result suggests that some difference (at the molecular level) may exist between the retinal clock and the clock located in the suprachiasmatic nuclei of hypothalamus. The present review will focus on the current knowledge of the retinal rhythmicity and the mechanisms responsible for its control.

Making the clock tick: the transcriptional landscape of the plant circadian clock.

PubMed

Ronald, James; Davis, Seth J

2017-01-01

Circadian clocks are molecular timekeepers that synchronise internal physiological processes with the external environment by integrating light and temperature stimuli. As in other eukaryotic organisms, circadian rhythms in plants are largely generated by an array of nuclear transcriptional regulators and associated co-regulators that are arranged into a series of interconnected molecular loops. These transcriptional regulators recruit chromatin-modifying enzymes that adjust the structure of the nucleosome to promote or inhibit DNA accessibility and thus guide transcription rates. In this review, we discuss the recent advances made in understanding the architecture of the Arabidopsis oscillator and the chromatin dynamics that regulate the generation of rhythmic patterns of gene expression within the circadian clock.

Intact interval timing in circadian CLOCK mutants.

PubMed

Cordes, Sara; Gallistel, C R

2008-08-28

While progress has been made in determining the molecular basis for the circadian clock, the mechanism by which mammalian brains time intervals measured in seconds to minutes remains a mystery. An obvious question is whether the interval-timing mechanism shares molecular machinery with the circadian timing mechanism. In the current study, we trained circadian CLOCK +/- and -/- mutant male mice in a peak-interval procedure with 10 and 20-s criteria. The mutant mice were more active than their wild-type littermates, but there were no reliable deficits in the accuracy or precision of their timing as compared with wild-type littermates. This suggests that expression of the CLOCK protein is not necessary for normal interval timing.

Reciprocal interactions between circadian clocks and aging.

PubMed

Banks, Gareth; Nolan, Patrick M; Peirson, Stuart N

2016-08-01

Virtually, all biological processes in the body are modulated by an internal circadian clock which optimizes physiological and behavioral performance according to the changing demands of the external 24-h world. This circadian clock undergoes a number of age-related changes, at both the physiological and molecular levels. While these changes have been considered to be part of the normal aging process, there is increasing evidence that disruptions to the circadian system can substantially impact upon aging and these impacts will have clear health implications. Here we review the current data of how both the physiological and core molecular clocks change with age and how feedback from external cues may modulate the aging of the circadian system.

Phylogenetic relationships and timing of diversification in gonorynchiform fishes inferred using nuclear gene DNA sequences (Teleostei: Ostariophysi).

PubMed

Near, Thomas J; Dornburg, Alex; Friedman, Matt

2014-11-01

The Gonorynchiformes are the sister lineage of the species-rich Otophysi and provide important insights into the diversification of ostariophysan fishes. Phylogenies of gonorynchiforms inferred using morphological characters and mtDNA gene sequences provide differing resolutions with regard to the sister lineage of all other gonorynchiforms (Chanos vs. Gonorynchus) and support for monophyly of the two miniaturized lineages Cromeria and Grasseichthys. In this study the phylogeny and divergence times of gonorynchiforms are investigated with DNA sequences sampled from nine nuclear genes and a published morphological character matrix. Bayesian phylogenetic analyses reveal substantial congruence among individual gene trees with inferences from eight genes placing Gonorynchus as the sister lineage to all other gonorynchiforms. Seven gene trees resolve Cromeria and Grasseichthys as a clade, supporting previous inferences using morphological characters. Phylogenies resulting from either concatenating the nuclear genes, performing a multispecies coalescent species tree analysis, or combining the morphological and nuclear gene DNA sequences resolve Gonorynchus as the living sister lineage of all other gonorynchiforms, strongly support the monophyly of Cromeria and Grasseichthys, and resolve a clade containing Parakneria, Cromeria, and Grasseichthys. The morphological dataset, which includes 13 gonorynchiform fossil taxa that range in age from Early Cretaceous to Eocene, was analyzed in combination with DNA sequences from the nine nuclear genes and a relaxed molecular clock to estimate times of evolutionary divergence. This "tip dating" strategy accommodates uncertainty in the phylogenetic resolution of fossil taxa that provide calibration information in the relaxed molecular clock analysis. The estimated age of the most recent common ancestor (MRCA) of living gonorynchiforms is slightly older than estimates from previous node dating efforts, but the molecular tip dating estimated ages of Kneriinae (Kneria, Parakneria, Cromeria, and Grasseichthys) and the two paedomorphic lineages, Cromeria and Grasseichthys, are considerably younger. Copyright © 2014 Elsevier Inc. All rights reserved.

Disruption of the circadian clock within the cardiomyocyte influences mycardial contractile function, metabolism, and gene expression

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variatio...

Molecular and phylogenetic analyses reveal mammalian-like clockwork in the honey bee (Apis mellifera) and shed new light on the molecular evolution of the circadian clock.

PubMed

Rubin, Elad B; Shemesh, Yair; Cohen, Mira; Elgavish, Sharona; Robertson, Hugh M; Bloch, Guy

2006-11-01

The circadian clock of the honey bee is implicated in ecologically relevant complex behaviors. These include time sensing, time-compensated sun-compass navigation, and social behaviors such as coordination of activity, dance language communication, and division of labor. The molecular underpinnings of the bee circadian clock are largely unknown. We show that clock gene structure and expression pattern in the honey bee are more similar to the mouse than to Drosophila. The honey bee genome does not encode an ortholog of Drosophila Timeless (Tim1), has only the mammalian type Cryptochrome (Cry-m), and has a single ortholog for each of the other canonical "clock genes." In foragers that typically have strong circadian rhythms, brain mRNA levels of amCry, but not amTim as in Drosophila, consistently oscillate with strong amplitude and a phase similar to amPeriod (amPer) under both light-dark and constant darkness illumination regimes. In contrast to Drosophila, the honey bee amCYC protein contains a transactivation domain and its brain transcript levels oscillate at virtually an anti-phase to amPer, as it does in the mouse. Phylogenetic analyses indicate that the basal insect lineage had both the mammalian and Drosophila types of Cry and Tim. Our results suggest that during evolution, Drosophila diverged from the ancestral insect clock and specialized in using a set of clock gene orthologs that was lost by both mammals and bees, which in turn converged and specialized in the other set. These findings illustrate a previously unappreciated diversity of insect clockwork and raise critical questions concerning the evolution and functional significance of species-specific variation in molecular clockwork.

Organization of the Drosophila circadian control circuit.

PubMed

Nitabach, Michael N; Taghert, Paul H

2008-01-22

Molecular genetics has revealed the identities of several components of the fundamental circadian molecular oscillator - an evolutionarily conserved molecular mechanism of transcription and translation that can operate in a cell-autonomous manner. Therefore, it was surprising when studies of circadian rhythmic behavior in the fruit fly Drosophila suggested that the normal operations of circadian clock cells, which house the molecular oscillator, in fact depend on non-cell-autonomous effects - interactions between the clock cells themselves. Here we review several genetic analyses that broadly extend that viewpoint. They support a model whereby the approximately 150 circadian clock cells in the brain of the fly are sub-divided into functionally discrete rhythmic centers. These centers alternatively cooperate or compete to control the different episodes of rhythmic behavior that define the fly's daily activity profile.

Segregation of Clock and Non-Clock Regulatory Functions of REV-ERB.

PubMed

Butler, Andrew A; Burris, Thomas P

2015-08-04

The molecular clock is a master controller of circadian cellular processes that affect growth, metabolic homeostasis, and behavior. A report in Science by Zhang et al. (2015) redefines our understanding of how Rev-erba acts as an internal feedback inhibitor that modulates activity of the core clock while simultaneously regulating tissue-specific metabolic processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Circadian signaling in Homarus americanus: Region-specific de novo assembled transcriptomes show that both the brain and eyestalk ganglia possess the molecular components of a putative clock system.

PubMed

Christie, Andrew E; Yu, Andy; Pascual, Micah G; Roncalli, Vittoria; Cieslak, Matthew C; Warner, Amanda N; Lameyer, Tess J; Stanhope, Meredith E; Dickinson, Patsy S; Joe Hull, J

2018-04-11

Essentially all organisms exhibit recurring patterns of physiology/behavior that oscillate with a period of ~24-h and are synchronized to the solar day. Crustaceans are no exception, with robust circadian rhythms having been documented in many members of this arthropod subphylum. However, little is known about the molecular underpinnings of their circadian rhythmicity. Moreover, the location of the crustacean central clock has not been firmly established, although both the brain and eyestalk ganglia have been hypothesized as loci. The American lobster, Homarus americanus, is known to exhibit multiple circadian rhythms, and immunodetection data suggest that its central clock is located within the eyestalk ganglia rather than in the brain. Here, brain- and eyestalk ganglia-specific transcriptomes were generated and used to assess the presence/absence of transcripts encoding the commonly recognized protein components of arthropod circadian signaling systems in these two regions of the lobster central nervous system. Transcripts encoding putative homologs of the core clock proteins clock, cryptochrome 2, cycle, period and timeless were found in both the brain and eyestalk ganglia assemblies, as were transcripts encoding similar complements of putative clock-associated, clock input pathway and clock output pathway proteins. The presence and identity of transcripts encoding core clock proteins in both regions were confirmed using PCR. These findings suggest that both the brain and eyestalk ganglia possess all of the molecular components needed for the establishment of a circadian signaling system. Whether the brain and eyestalk clocks are independent of one another or represent a single timekeeping system remains to be determined. Interestingly, while most of the proteins deduced from the identified transcripts are shared by both the brain and eyestalk ganglia, assembly-specific isoforms were also identified, e.g., several period variants, suggesting the possibility of region-specific variation in clock function, especially if the brain and eyestalk clocks represent independent oscillators. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular Cogs: Interplay between Circadian Clock and Cell Cycle.

PubMed

Gaucher, Jonathan; Montellier, Emilie; Sassone-Corsi, Paolo

2018-05-01

The cell cycle and the circadian clock operate as biological oscillators whose timed functions are tightly regulated. Accumulating evidence illustrates the presence of molecular links between these two oscillators. This mutual interplay utilizes various coupling mechanisms, such as the use of common regulators. The connection between these two cyclic systems has unique interest in the context of aberrant cell proliferation since both of these oscillators are frequently misregulated in cancer cells. Further studies will provide deeper understanding of the detailed molecular connections between the cell cycle and the circadian clock and may also serve as a basis for the design of innovative therapeutic strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that circadian clock within the cardiomyocyte plays a role in regulating myocardia...

The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that the circadian clock within the cardiomyocyte plays a role in regulating myo...

A universal molecular clock of protein folds and its power in tracing the early history of aerobic metabolism and planet oxygenation.

PubMed

Wang, Minglei; Jiang, Ying-Ying; Kim, Kyung Mo; Qu, Ge; Ji, Hong-Fang; Mittenthal, Jay E; Zhang, Hong-Yu; Caetano-Anollés, Gustavo

2011-01-01

The standard molecular clock describes a constant rate of molecular evolution and provides a powerful framework for evolutionary timescales. Here, we describe the existence and implications of a molecular clock of folds, a universal recurrence in the discovery of new structures in the world of proteins. Using a phylogenomic structural census in hundreds of proteomes, we build phylogenies and time lines of domains at fold and fold superfamily levels of structural complexity. These time lines correlate approximately linearly with geological timescales and were here used to date two crucial events in life history, planet oxygenation and organism diversification. We first dissected the structures and functions of enzymes in simulated metabolic networks. The placement of anaerobic and aerobic enzymes in the time line revealed that aerobic metabolism emerged about 2.9 billion years (giga-annum; Ga) ago and expanded during a period of about 400 My, reaching what is known as the Great Oxidation Event. During this period, enzymes recruited old and new folds for oxygen-mediated enzymatic activities. Remarkably, the first fold lost by a superkingdom disappeared in Archaea 2.6 Ga ago, within the span of oxygen rise, suggesting that oxygen also triggered diversification of life. The implications of a molecular clock of folds are many and important for the neutral theory of molecular evolution and for understanding the growth and diversity of the protein world. The clock also extends the standard concept that was specific to molecules and their timescales and turns it into a universal timescale-generating tool.

The oldest platypus and its bearing on divergence timing of the platypus and echidna clades

PubMed Central

Rowe, Timothy; Rich, Thomas H.; Vickers-Rich, Patricia; Springer, Mark; Woodburne, Michael O.

2008-01-01

Monotremes have left a poor fossil record, and paleontology has been virtually mute during two decades of discussion about molecular clock estimates of the timing of divergence between the platypus and echidna clades. We describe evidence from high-resolution x-ray computed tomography indicating that Teinolophos, an Early Cretaceous fossil from Australia's Flat Rocks locality (121–112.5 Ma), lies within the crown clade Monotremata, as a basal platypus. Strict molecular clock estimates of the divergence between platypus and echidnas range from 17 to 80 Ma, but Teinolophos suggests that the two monotreme clades were already distinct in the Early Cretaceous, and that their divergence may predate even the oldest strict molecular estimates by at least 50%. We generated relaxed molecular clock models using three different data sets, but only one yielded a date overlapping with the age of Teinolophos. Morphology suggests that Teinolophos is a platypus in both phylogenetic and ecological aspects, and tends to contradict the popular view of rapid Cenozoic monotreme diversification. Whereas the monotreme fossil record is still sparse and open to interpretation, the new data are consistent with much slower ecological, morphological, and taxonomic diversification rates for monotremes than in their sister taxon, the therian mammals. This alternative view of a deep geological history for monotremes suggests that rate heterogeneities may have affected mammalian evolution in such a way as to defeat strict molecular clock models and to challenge even relaxed molecular clock models when applied to mammalian history at a deep temporal scale. PMID:18216270

The oldest platypus and its bearing on divergence timing of the platypus and echidna clades.

PubMed

Rowe, Timothy; Rich, Thomas H; Vickers-Rich, Patricia; Springer, Mark; Woodburne, Michael O

2008-01-29

Monotremes have left a poor fossil record, and paleontology has been virtually mute during two decades of discussion about molecular clock estimates of the timing of divergence between the platypus and echidna clades. We describe evidence from high-resolution x-ray computed tomography indicating that Teinolophos, an Early Cretaceous fossil from Australia's Flat Rocks locality (121-112.5 Ma), lies within the crown clade Monotremata, as a basal platypus. Strict molecular clock estimates of the divergence between platypus and echidnas range from 17 to 80 Ma, but Teinolophos suggests that the two monotreme clades were already distinct in the Early Cretaceous, and that their divergence may predate even the oldest strict molecular estimates by at least 50%. We generated relaxed molecular clock models using three different data sets, but only one yielded a date overlapping with the age of Teinolophos. Morphology suggests that Teinolophos is a platypus in both phylogenetic and ecological aspects, and tends to contradict the popular view of rapid Cenozoic monotreme diversification. Whereas the monotreme fossil record is still sparse and open to interpretation, the new data are consistent with much slower ecological, morphological, and taxonomic diversification rates for monotremes than in their sister taxon, the therian mammals. This alternative view of a deep geological history for monotremes suggests that rate heterogeneities may have affected mammalian evolution in such a way as to defeat strict molecular clock models and to challenge even relaxed molecular clock models when applied to mammalian history at a deep temporal scale.

Evaluating the Autonomy of the Drosophila Circadian Clock in Dissociated Neuronal Culture

PubMed Central

Sabado, Virginie; Vienne, Ludovic; Nagoshi, Emi

2017-01-01

Circadian behavioral rhythms offer an excellent model to study intricate interactions between the molecular and neuronal mechanisms of behavior. In mammals, pacemaker neurons in the suprachiasmatic nucleus (SCN) generate rhythms cell-autonomously, which are synchronized by the network interactions within the circadian circuit to drive behavioral rhythms. However, whether this principle is universal to circadian systems in animals remains unanswered. Here, we examined the autonomy of the Drosophila circadian clock by monitoring transcriptional and post-transcriptional rhythms of individual clock neurons in dispersed culture with time-lapse microscopy. Expression patterns of the transcriptional reporter show that CLOCK/CYCLE (CLK/CYC)-mediated transcription is constantly active in dissociated clock neurons. In contrast, the expression profile of the post-transcriptional reporter indicates that PERIOD (PER) protein levels fluctuate and ~10% of cells display rhythms in PER levels with periods in the circadian range. Nevertheless, PER and TIM are enriched in the cytoplasm and no periodic PER nuclear accumulation was observed. These results suggest that repression of CLK/CYC-mediated transcription by nuclear PER is impaired, and thus the negative feedback loop of the molecular clock is incomplete in isolated clock neurons. We further demonstrate that, by pharmacological assays using the non-amidated form of neuropeptide pigment-dispersing factor (PDF), which could be specifically secreted from larval LNvs and adult s-LNvs, downstream events of the PDF signaling are partly impaired in dissociated larval clock neurons. Although non-amidated PDF is likely to be less active than the amidated one, these results point out the possibility that alteration in PDF downstream signaling may play a role in dampening of molecular rhythms in isolated clock neurons. Taken together, our results suggest that Drosophila clocks are weak oscillators that need to be in the intact circadian circuit to generate robust 24-h rhythms. PMID:29075180

The impact of the rate prior on Bayesian estimation of divergence times with multiple Loci.

PubMed

Dos Reis, Mario; Zhu, Tianqi; Yang, Ziheng

2014-07-01

Bayesian methods provide a powerful way to estimate species divergence times by combining information from molecular sequences with information from the fossil record. With the explosive increase of genomic data, divergence time estimation increasingly uses data of multiple loci (genes or site partitions). Widely used computer programs to estimate divergence times use independent and identically distributed (i.i.d.) priors on the substitution rates for different loci. The i.i.d. prior is problematic. As the number of loci (L) increases, the prior variance of the average rate across all loci goes to zero at the rate 1/L. As a consequence, the rate prior dominates posterior time estimates when many loci are analyzed, and if the rate prior is misspecified, the estimated divergence times will converge to wrong values with very narrow credibility intervals. Here we develop a new prior on the locus rates based on the Dirichlet distribution that corrects the problematic behavior of the i.i.d. prior. We use computer simulation and real data analysis to highlight the differences between the old and new priors. For a dataset for six primate species, we show that with the old i.i.d. prior, if the prior rate is too high (or too low), the estimated divergence times are too young (or too old), outside the bounds imposed by the fossil calibrations. In contrast, with the new Dirichlet prior, posterior time estimates are insensitive to the rate prior and are compatible with the fossil calibrations. We re-analyzed a phylogenomic data set of 36 mammal species and show that using many fossil calibrations can alleviate the adverse impact of a misspecified rate prior to some extent. We recommend the use of the new Dirichlet prior in Bayesian divergence time estimation. [Bayesian inference, divergence time, relaxed clock, rate prior, partition analysis.]. © The Author(s) 2014. Published by Oxford University Press, on behalf of the Society of Systematic Biologists.

Impaired light detection of the circadian clock in a zebrafish melanoma model

PubMed Central

Hamilton, Noémie; Diaz-de-Cerio, Natalia; Whitmore, David

2015-01-01

The circadian clock controls the timing of the cell cycle in healthy tissues and clock disruption is known to increase tumourigenesis. Melanoma is one of the most rapidly increasing forms of cancer and the precise molecular circadian changes that occur in a melanoma tumor are unknown. Using a melanoma zebrafish model, we have explored the molecular changes that occur to the circadian clock within tumors. We have found disruptions in melanoma clock gene expression due to a major impairment to the light input pathway, with a parallel loss of light-dependent activation of DNA repair genes. Furthermore, the timing of mitosis in tumors is perturbed, as well as the regulation of certain key cell cycle regulators, such that cells divide arhythmically. The inability to co-ordinate DNA damage repair and cell division is likely to promote further tumourigenesis and accelerate melanoma development. PMID:25832911

Impaired light detection of the circadian clock in a zebrafish melanoma model.

PubMed

Hamilton, Noémie; Diaz-de-Cerio, Natalia; Whitmore, David

2015-01-01

The circadian clock controls the timing of the cell cycle in healthy tissues and clock disruption is known to increase tumourigenesis. Melanoma is one of the most rapidly increasing forms of cancer and the precise molecular circadian changes that occur in a melanoma tumor are unknown. Using a melanoma zebrafish model, we have explored the molecular changes that occur to the circadian clock within tumors. We have found disruptions in melanoma clock gene expression due to a major impairment to the light input pathway, with a parallel loss of light-dependent activation of DNA repair genes. Furthermore, the timing of mitosis in tumors is perturbed, as well as the regulation of certain key cell cycle regulators, such that cells divide arhythmically. The inability to co-ordinate DNA damage repair and cell division is likely to promote further tumourigenesis and accelerate melanoma development.

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

PubMed Central

Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo

2015-01-01

Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional–translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear “hubs” of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control. PMID:25378702

Analysis of Circadian Leaf Movements.

PubMed

Müller, Niels A; Jiménez-Gómez, José M

2016-01-01

The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato.

Intact Interval Timing in Circadian CLOCK Mutants

PubMed Central

Cordes, Sara; Gallistel, C. R.

2008-01-01

While progress has been made in determining the molecular basis for the circadian clock, the mechanism by which mammalian brains time intervals measured in seconds to minutes remains a mystery. An obvious question is whether the interval timing mechanism shares molecular machinery with the circadian timing mechanism. In the current study, we trained circadian CLOCK +/− and −/− mutant male mice in a peak-interval procedure with 10 and 20-s criteria. The mutant mice were more active than their wild-type littermates, but there were no reliable deficits in the accuracy or precision of their timing as compared with wild-type littermates. This suggests that expression of the CLOCK protein is not necessary for normal interval timing. PMID:18602902

Accounting for rate variation among lineages in comparative demographic analyses.

PubMed

Hope, Andrew G; Ho, Simon Y W; Malaney, Jason L; Cook, Joseph A; Talbot, Sandra L

2014-09-01

Genetic analyses of contemporary populations can be used to estimate the demographic histories of species within an ecological community. Comparison of these demographic histories can shed light on community responses to past climatic events. However, species experience different rates of molecular evolution, and this presents a major obstacle to comparative demographic analyses. We address this problem by using a Bayesian relaxed-clock method to estimate the relative evolutionary rates of 22 small mammal taxa distributed across northwestern North America. We found that estimates of the relative molecular substitution rate for each taxon were consistent across the range of sampling schemes that we compared. Using three different reference rates, we rescaled the relative rates so that they could be used to estimate absolute evolutionary timescales. Accounting for rate variation among taxa led to temporal shifts in our skyline-plot estimates of demographic history, highlighting both uniform and idiosyncratic evolutionary responses to directional climate trends for distinct ecological subsets of the small mammal community. Our approach can be used in evolutionary analyses of populations from multiple species, including comparative demographic studies. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Circadian Clock Gene Expression in the Coral Favia fragum over Diel and Lunar Reproductive Cycles

PubMed Central

Hoadley, Kenneth D.; Szmant, Alina M.; Pyott, Sonja J.

2011-01-01

Natural light cycles synchronize behavioral and physiological cycles over varying time periods in both plants and animals. Many scleractinian corals exhibit diel cycles of polyp expansion and contraction entrained by diel sunlight patterns, and monthly cycles of spawning or planulation that correspond to lunar moonlight cycles. The molecular mechanisms for regulating such cycles are poorly understood. In this study, we identified four molecular clock genes (cry1, cry2, clock and cycle) in the scleractinian coral, Favia fragum, and investigated patterns of gene expression hypothesized to be involved in the corals' diel polyp behavior and lunar reproductive cycles. Using quantitative PCR, we measured fluctuations in expression of these clock genes over both diel and monthly spawning timeframes. Additionally, we assayed gene expression and polyp expansion-contraction behavior in experimental corals in normal light:dark (control) or constant dark treatments. Well-defined and reproducible diel patterns in cry1, cry2, and clock expression were observed in both field-collected and the experimental colonies maintained under control light:dark conditions, but no pattern was observed for cycle. Colonies in the control light:dark treatment also displayed diel rhythms of tentacle expansion and contraction. Experimental colonies in the constant dark treatment lost diel patterns in cry1, cry2, and clock expression and displayed a diminished and less synchronous pattern of tentacle expansion and contraction. We observed no pattern in cry1, cry2, clock, or cycle expression correlated with monthly spawning events suggesting these genes are not involved in the entrainment of reproductive cycles to lunar light cycles in F. fragum. Our results suggest a molecular clock mechanism, potentially similar to that in described in fruit flies, exists within F. fragum. PMID:21573070

Circadian gene expression regulates pulsatile gonadotropin-releasing hormone (GnRH) secretory patterns in the hypothalamic GnRH-secreting GT1-7 cell line.

PubMed

Chappell, Patrick E; White, Rachel S; Mellon, Pamela L

2003-12-03

Although it has long been established that episodic secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is required for normal gonadotropin release, the molecular and cellular mechanisms underlying the synchronous release of GnRH are primarily unknown. We used the GT1-7 mouse hypothalamic cell line as a model for GnRH secretion, because these cells release GnRH in a pulsatile pattern similar to that observed in vivo. To explore possible molecular mechanisms governing secretory timing, we investigated the role of the molecular circadian clock in regulation of GnRH secretion. GT1-7 cells express many known core circadian clock genes, and we demonstrate that oscillations of these components can be induced by stimuli such as serum and the adenylyl cyclase activator forskolin, similar to effects observed in fibroblasts. Strikingly, perturbation of circadian clock function in GT1-7 cells by transient expression of the dominant-negative Clock-Delta19 gene disrupts normal ultradian patterns of GnRH secretion, significantly decreasing mean pulse frequency. Additionally, overexpression of the negative limb clock gene mCry1 in GT1-7 cells substantially increases GnRH pulse amplitude without a commensurate change in pulse frequency, demonstrating that an endogenous biological clock is coupled to the mechanism of neurosecretion in these cells and can regulate multiple secretory parameters. Finally, mice harboring a somatic mutation in the Clock gene are subfertile and exhibit a substantial increase in estrous cycle duration as revealed by examination of vaginal cytology. This effect persists in normal light/dark (LD) cycles, suggesting that a suprachiasmatic nucleus-independent endogenous clock in GnRH neurons is required for eliciting normal pulsatile patterns of GnRH secretion.

A dated molecular phylogeny of manta and devil rays (Mobulidae) based on mitogenome and nuclear sequences.

PubMed

Poortvliet, Marloes; Olsen, Jeanine L; Croll, Donald A; Bernardi, Giacomo; Newton, Kelly; Kollias, Spyros; O'Sullivan, John; Fernando, Daniel; Stevens, Guy; Galván Magaña, Felipe; Seret, Bernard; Wintner, Sabine; Hoarau, Galice

2015-02-01

Manta and devil rays are an iconic group of globally distributed pelagic filter feeders, yet their evolutionary history remains enigmatic. We employed next generation sequencing of mitogenomes for nine of the 11 recognized species and two outgroups; as well as additional Sanger sequencing of two mitochondrial and two nuclear genes in an extended taxon sampling set. Analysis of the mitogenome coding regions in a Maximum Likelihood and Bayesian framework provided a well-resolved phylogeny. The deepest divergences distinguished three clades with high support, one containing Manta birostris, Manta alfredi, Mobula tarapacana, Mobula japanica and Mobula mobular; one containing Mobula kuhlii, Mobula eregoodootenkee and Mobula thurstoni; and one containing Mobula munkiana, Mobula hypostoma and Mobula rochebrunei. Mobula remains paraphyletic with the inclusion of Manta, a result that is in agreement with previous studies based on molecular and morphological data. A fossil-calibrated Bayesian random local clock analysis suggests that mobulids diverged from Rhinoptera around 30 Mya. Subsequent divergences are characterized by long internodes followed by short bursts of speciation extending from an initial episode of divergence in the Early and Middle Miocene (19-17 Mya) to a second episode during the Pliocene and Pleistocene (3.6 Mya - recent). Estimates of divergence dates overlap significantly with periods of global warming, during which upwelling intensity - and related high primary productivity in upwelling regions - decreased markedly. These periods are hypothesized to have led to fragmentation and isolation of feeding regions leading to possible regional extinctions, as well as the promotion of allopatric speciation. The closely shared evolutionary history of mobulids in combination with ongoing threats from fisheries and climate change effects on upwelling and food supply, reinforces the case for greater protection of this charismatic family of pelagic filter feeders. Copyright © 2014 Elsevier Inc. All rights reserved.

Divergence Times and the Evolutionary Radiation of New World Monkeys (Platyrrhini, Primates): An Analysis of Fossil and Molecular Data.

PubMed

Perez, S Ivan; Tejedor, Marcelo F; Novo, Nelson M; Aristide, Leandro

2013-01-01

The estimation of phylogenetic relationships and divergence times among a group of organisms is a fundamental first step toward understanding its biological diversification. The time of the most recent or last common ancestor (LCA) of extant platyrrhines is one of the most controversial among scholars of primate evolution. Here we use two molecular based approaches to date the initial divergence of the platyrrhine clade, Bayesian estimations under a relaxed-clock model and substitution rate plus generation time and body size, employing the fossil record and genome datasets. We also explore the robustness of our estimations with respect to changes in topology, fossil constraints and substitution rate, and discuss the implications of our findings for understanding the platyrrhine radiation. Our results suggest that fossil constraints, topology and substitution rate have an important influence on our divergence time estimates. Bayesian estimates using conservative but realistic fossil constraints suggest that the LCA of extant platyrrhines existed at ca. 29 Ma, with the 95% confidence limit for the node ranging from 27-31 Ma. The LCA of extant platyrrhine monkeys based on substitution rate corrected by generation time and body size was established between 21-29 Ma. The estimates based on the two approaches used in this study recalibrate the ages of the major platyrrhine clades and corroborate the hypothesis that they constitute very old lineages. These results can help reconcile several controversial points concerning the affinities of key early Miocene fossils that have arisen among paleontologists and molecular systematists. However, they cannot resolve the controversy of whether these fossil species truly belong to the extant lineages or to a stem platyrrhine clade. That question can only be resolved by morphology. Finally, we show that the use of different approaches and well supported fossil information gives a more robust divergence time estimate of a clade.

Divergence Times and the Evolutionary Radiation of New World Monkeys (Platyrrhini, Primates): An Analysis of Fossil and Molecular Data

PubMed Central

Perez, S. Ivan; Tejedor, Marcelo F.; Novo, Nelson M.; Aristide, Leandro

2013-01-01

The estimation of phylogenetic relationships and divergence times among a group of organisms is a fundamental first step toward understanding its biological diversification. The time of the most recent or last common ancestor (LCA) of extant platyrrhines is one of the most controversial among scholars of primate evolution. Here we use two molecular based approaches to date the initial divergence of the platyrrhine clade, Bayesian estimations under a relaxed-clock model and substitution rate plus generation time and body size, employing the fossil record and genome datasets. We also explore the robustness of our estimations with respect to changes in topology, fossil constraints and substitution rate, and discuss the implications of our findings for understanding the platyrrhine radiation. Our results suggest that fossil constraints, topology and substitution rate have an important influence on our divergence time estimates. Bayesian estimates using conservative but realistic fossil constraints suggest that the LCA of extant platyrrhines existed at ca. 29 Ma, with the 95% confidence limit for the node ranging from 27–31 Ma. The LCA of extant platyrrhine monkeys based on substitution rate corrected by generation time and body size was established between 21–29 Ma. The estimates based on the two approaches used in this study recalibrate the ages of the major platyrrhine clades and corroborate the hypothesis that they constitute very old lineages. These results can help reconcile several controversial points concerning the affinities of key early Miocene fossils that have arisen among paleontologists and molecular systematists. However, they cannot resolve the controversy of whether these fossil species truly belong to the extant lineages or to a stem platyrrhine clade. That question can only be resolved by morphology. Finally, we show that the use of different approaches and well supported fossil information gives a more robust divergence time estimate of a clade. PMID:23826358

Rate variation and estimation of divergence times using strict and relaxed clocks.

PubMed

Brown, Richard P; Yang, Ziheng

2011-09-26

Understanding causes of biological diversity may be greatly enhanced by knowledge of divergence times. Strict and relaxed clock models are used in Bayesian estimation of divergence times. We examined whether: i) strict clock models are generally more appropriate in shallow phylogenies where rate variation is expected to be low, ii) the likelihood ratio test of the clock (LRT) reliably informs which model is appropriate for dating divergence times. Strict and relaxed models were used to analyse sequences simulated under different levels of rate variation. Published shallow phylogenies (Black bass, Primate-sucking lice, Podarcis lizards, Gallotiinae lizards, and Caprinae mammals) were also analysed to determine natural levels of rate variation relative to the performance of the different models. Strict clock analyses performed well on data simulated under the independent rates model when the standard deviation of log rate on branches, σ, was low (≤ 0.1), but were inappropriate when σ>0.1 (95% of rates fall within 0.0082-0.0121 subs/site/Ma when σ = 0.1, for a mean rate of 0.01). The independent rates relaxed clock model performed well at all levels of rate variation, although posterior intervals on times were significantly wider than for the strict clock. The strict clock is therefore superior when rate variation is low. The performance of a correlated rates relaxed clock model was similar to the strict clock. Increased numbers of independent loci led to slightly narrower posteriors under the relaxed clock while older root ages provided proportionately narrower posteriors. The LRT had low power for σ = 0.01-0.1, but high power for σ = 0.5-2.0. Posterior means of σ2 were useful for assessing rate variation in published datasets. Estimates of natural levels of rate variation ranged from 0.05-3.38 for different partitions. Differences in divergence times between relaxed and strict clock analyses were greater in two datasets with higher σ2 for one or more partitions, supporting the simulation results. The strict clock can be superior for trees with shallow roots because of low levels of rate variation between branches. The LRT allows robust assessment of suitability of the clock model as does examination of posteriors on σ2.

Molecular clock on a neutral network.

PubMed

Raval, Alpan

2007-09-28

The number of fixed mutations accumulated in an evolving population often displays a variance that is significantly larger than the mean (the overdispersed molecular clock). By examining a generic evolutionary process on a neutral network of high-fitness genotypes, we establish a formalism for computing all cumulants of the full probability distribution of accumulated mutations in terms of graph properties of the neutral network, and use the formalism to prove overdispersion of the molecular clock. We further show that significant overdispersion arises naturally in evolution when the neutral network is highly sparse, exhibits large global fluctuations in neutrality, and small local fluctuations in neutrality. The results are also relevant for elucidating aspects of neutral network topology from empirical measurements of the substitution process.

Molecular Clock on a Neutral Network

NASA Astrophysics Data System (ADS)

Raval, Alpan

2007-09-01

The number of fixed mutations accumulated in an evolving population often displays a variance that is significantly larger than the mean (the overdispersed molecular clock). By examining a generic evolutionary process on a neutral network of high-fitness genotypes, we establish a formalism for computing all cumulants of the full probability distribution of accumulated mutations in terms of graph properties of the neutral network, and use the formalism to prove overdispersion of the molecular clock. We further show that significant overdispersion arises naturally in evolution when the neutral network is highly sparse, exhibits large global fluctuations in neutrality, and small local fluctuations in neutrality. The results are also relevant for elucidating aspects of neutral network topology from empirical measurements of the substitution process.

Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus.

PubMed

Besing, Rachel C; Paul, Jodi R; Hablitz, Lauren M; Rogers, Courtney O; Johnson, Russell L; Young, Martin E; Gamble, Karen L

2015-04-01

The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprising clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least 5 core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3β isoform. Whether phosphorylation of the other primary isoform (GSK3α) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (α and β) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN from wild-type mice housed in constant darkness for 2 weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 µM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN. © 2015 The Author(s).

The Circadian Oscillator of the Cerebral Cortex: Molecular, Biochemical and Behavioral Effects of Deleting the Arntl Clock Gene in Cortical Neurons.

PubMed

Bering, Tenna; Carstensen, Mikkel Bloss; Wörtwein, Gitta; Weikop, Pia; Rath, Martin Fredensborg

2018-02-01

A molecular circadian oscillator resides in neurons of the cerebral cortex, but its role is unknown. Using the Cre-LoxP method, we have here abolished the core clock gene Arntl in those neurons. This mouse represents the first model carrying a deletion of a circadian clock component specifically in an extrahypothalamic cell type of the brain. Molecular analyses of clock gene expression in the cerebral cortex of the Arntl conditional knockout mouse revealed disrupted circadian expression profiles, whereas clock gene expression in the suprachiasmatic nucleus was still rhythmic, thus showing that Arntl is required for normal function of the cortical circadian oscillator. Daily rhythms in running activity and temperature were not influenced, whereas the resynchronization response to experimental jet-lag exhibited minor though significant differences between genotypes. The tail-suspension test revealed significantly prolonged immobility periods in the knockout mouse indicative of a depressive-like behavioral state. This phenotype was accompanied by reduced norepinephrine levels in the cerebral cortex. Our data show that Arntl is required for normal cortical clock function and further give reason to suspect that the circadian oscillator of the cerebral cortex is involved in regulating both circadian biology and mood-related behavior and biochemistry. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet

USDA-ARS?s Scientific Manuscript database

Introduction: The success of obesity therapy is dependent on the genetic background of the patient. Circadian Locomotor Output Cycles Kaput (CLOCK), one of the transcription factors from the positive limb of the molecular clock, is involved in metabolic alterations. Objective: To investigate whethe...

Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks

PubMed Central

Wolff, Gretchen; Duncan, Marilyn J.

2013-01-01

Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

Investigations of the CLOCK and BMAL1 Proteins Binding to DNA: A Molecular Dynamics Simulation Study.

PubMed

Xue, Tuo; Song, Chunnian; Wang, Qing; Wang, Yan; Chen, Guangju

2016-01-01

The circadian locomotor output cycles kaput (CLOCK), and brain and muscle ARNT-like 1 (BMAL1) proteins are important transcriptional factors of the endogenous circadian clock. The CLOCK and BMAL1 proteins can regulate the transcription-translation activities of the clock-related genes through the DNA binding. The hetero-/homo-dimerization and DNA combination of the CLOCK and BMAL1 proteins play a key role in the positive and negative transcriptional feedback processes. In the present work, we constructed a series of binary and ternary models for the bHLH/bHLH-PAS domains of the CLOCK and BMAL1 proteins, and the DNA molecule, and carried out molecular dynamics simulations, free energy calculations and conformational analysis to explore the interaction properties of the CLOCK and BMAL1 proteins with DNA. The results show that the bHLH domains of CLOCK and BMAL1 can favorably form the heterodimer of the bHLH domains of CLOCK and BMAL1 and the homodimer of the bHLH domains of BMAL1. And both dimers could respectively bind to DNA at its H1-H1 interface. The DNA bindings of the H1 helices in the hetero- and homo-bHLH dimers present the rectangular and diagonal binding modes, respectively. Due to the function of the α-helical forceps in these dimers, the tight gripping of the H1 helices to the major groove of DNA would cause the decrease of interactions at the H1-H2 interfaces in the CLOCK and BMAL1 proteins. The additional PAS domains in the CLOCK and BMAL1 proteins affect insignificantly the interactions of the CLOCK and BMAL1 proteins with the DNA molecule due to the flexible and long loop linkers located at the middle of the PAS and bHLH domains. The present work theoretically explains the interaction mechanisms of the bHLH domains of the CLOCK and BMAL1 proteins with DNA.

Speed control: cogs and gears that drive the circadian clock.

PubMed

Zheng, Xiangzhong; Sehgal, Amita

2012-09-01

In most organisms, an intrinsic circadian (~24-h) timekeeping system drives rhythms of physiology and behavior. Within cells that contain a circadian clock, specific transcriptional activators and repressors reciprocally regulate each other to generate a basic molecular oscillator. A mismatch of the period generated by this oscillator with the external environment creates circadian disruption, which can have adverse effects on neural function. Although several clock genes have been extensively characterized, a fundamental question remains: how do these genes work together to generate a ~24-h period? Period-altering mutations in clock genes can affect any of multiple regulated steps in the molecular oscillator. In this review, we examine the regulatory mechanisms that contribute to setting the pace of the circadian oscillator. Copyright © 2012 Elsevier Ltd. All rights reserved.

Phylogeny and temporal diversification of darters (Percidae: Etheostomatinae).

PubMed

Near, Thomas J; Bossu, Christen M; Bradburd, Gideon S; Carlson, Rose L; Harrington, Richard C; Hollingsworth, Phillip R; Keck, Benjamin P; Etnier, David A

2011-10-01

Discussions aimed at resolution of the Tree of Life are most often focused on the interrelationships of major organismal lineages. In this study, we focus on the resolution of some of the most apical branches in the Tree of Life through exploration of the phylogenetic relationships of darters, a species-rich clade of North American freshwater fishes. With a near-complete taxon sampling of close to 250 species, we aim to investigate strategies for efficient multilocus data sampling and the estimation of divergence times using relaxed-clock methods when a clade lacks a fossil record. Our phylogenetic data set comprises a single mitochondrial DNA (mtDNA) gene and two nuclear genes sampled from 245 of the 248 darter species. This dense sampling allows us to determine if a modest amount of nuclear DNA sequence data can resolve relationships among closely related animal species. Darters lack a fossil record to provide age calibration priors in relaxed-clock analyses. Therefore, we use a near-complete species-sampled phylogeny of the perciform clade Centrarchidae, which has a rich fossil record, to assess two distinct strategies of external calibration in relaxed-clock divergence time estimates of darters: using ages inferred from the fossil record and molecular evolutionary rate estimates. Comparison of Bayesian phylogenies inferred from mtDNA and nuclear genes reveals that heterospecific mtDNA is present in approximately 12.5% of all darter species. We identify three patterns of mtDNA introgression in darters: proximal mtDNA transfer, which involves the transfer of mtDNA among extant and sympatric darter species, indeterminate introgression, which involves the transfer of mtDNA from a lineage that cannot be confidently identified because the introgressed haplotypes are not clearly referable to mtDNA haplotypes in any recognized species, and deep introgression, which is characterized by species diversification within a recipient clade subsequent to the transfer of heterospecific mtDNA. The results of our analyses indicate that DNA sequences sampled from single-copy nuclear genes can provide appreciable phylogenetic resolution for closely related animal species. A well-resolved near-complete species-sampled phylogeny of darters was estimated with Bayesian methods using a concatenated mtDNA and nuclear gene data set with all identified heterospecific mtDNA haplotypes treated as missing data. The relaxed-clock analyses resulted in very similar posterior age estimates across the three sampled genes and methods of calibration and therefore offer a viable strategy for estimating divergence times for clades that lack a fossil record. In addition, an informative rank-free clade-based classification of darters that preserves the rich history of nomenclature in the group and provides formal taxonomic communication of darter clades was constructed using the mtDNA and nuclear gene phylogeny. On the whole, the appeal of mtDNA for phylogeny inference among closely related animal species is diminished by the observations of extensive mtDNA introgression and by finding appreciable phylogenetic signal in a modest sampling of nuclear genes in our phylogenetic analyses of darters.

Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver.

PubMed

Guillaumond, Fabienne; Gréchez-Cassiau, Aline; Subramaniam, Malayannan; Brangolo, Sophie; Peteri-Brünback, Brigitta; Staels, Bart; Fiévet, Catherine; Spelsberg, Thomas C; Delaunay, Franck; Teboul, Michèle

2010-06-01

The circadian timing system coordinates many aspects of mammalian physiology and behavior in synchrony with the external light/dark cycle. These rhythms are driven by endogenous molecular clocks present in most body cells. Many clock outputs are transcriptional regulators, suggesting that clock genes primarily control physiology through indirect pathways. Here, we show that Krüppel-like factor 10 (KLF10) displays a robust circadian expression pattern in wild-type mouse liver but not in clock-deficient Bmal1 knockout mice. Consistently, the Klf10 promoter recruited the BMAL1 core clock protein and was transactivated by the CLOCK-BMAL1 heterodimer through a conserved E-box response element. Profiling the liver transcriptome from Klf10(-/-) mice identified 158 regulated genes with significant enrichment for transcripts involved in lipid and carbohydrate metabolism. Importantly, approximately 56% of these metabolic genes are clock controlled. Male Klf10(-/-) mice displayed postprandial and fasting hyperglycemia, a phenotype accompanied by a significant time-of-day-dependent upregulation of the gluconeogenic gene Pepck and increased hepatic glucose production. Consistently, functional data showed that the proximal Pepck promoter is repressed directly by KLF10. Klf10(-/-) females were normoglycemic but displayed higher plasma triglycerides. Correspondingly, rhythmic gene expression of components of the lipogenic pathway, including Srebp1c, Fas, and Elovl6, was altered in females. Collectively, these data establish KLF10 as a required circadian transcriptional regulator that links the molecular clock to energy metabolism in the liver.

Phylogeographic patterns in suckermouth catfish Hypostomus ancistroides (Loricariidae): dispersion, vicariance and species complexity across a Neotropical biogeographic region.

PubMed

Hollanda Carvalho, Pedro; Maia Queiroz Lima, Sergio; Henrique Zawadzki, Cláudio; Oliveira, Cláudio; de Pinna, Mario

2016-09-01

The upper Paraná River system (UP) is a highly diverse biogeographic province for freshwater fishes, but little is known about processes which shaped that diversity. This study describes the phylogeographic pattern in Hypostomus ancistroides, a suckermouth catfish species that is widespread in the UP and also reported from the adjoining Ribeira do Iguape basin. We used complete mtDNA sequences of ATPase 6/8 of 162 specimens to infer haplotype distribution using phylogenetic and demographic analyses and a Bayesian molecular clock. Results suggest that during the Quaternary H. ancistroides has undergone superimposed phylogeographic histories, alternating between isolation and subsequent merging of different populations. Occurrence of an isolated population on the Ribeira de Iguape is demonstrated to be a Pleistocene headwater capture event. Widely distributed haplotypes indicate deep genetic differences and suggest that populations of H. ancistroides were isolated for considerable time, but did not undergo speciation because of recurrent population mixing.

Divergence time estimates of mammals from molecular clocks and fossils: relevance of new fossil finds from India.

PubMed

Prasad, G V R

2009-11-01

This paper presents a brief review of recent advances in the classification of mammals at higher levels using fossils and molecular clocks. It also discusses latest fossil discoveries from the Cretaceous - Eocene (66-55 m.y.) rocks of India and their relevance to our current understanding of placental mammal origins and diversifications.

Fluorescence circadian imaging reveals a PDF-dependent transcriptional regulation of the Drosophila molecular clock.

PubMed

Sabado, Virginie; Vienne, Ludovic; Nunes, José Manuel; Rosbash, Michael; Nagoshi, Emi

2017-01-30

Circadian locomotor behaviour is controlled by a pacemaker circuit composed of clock-containing neurons. To interrogate the mechanistic relationship between the molecular clockwork and network communication critical to the operation of the Drosophila circadian pacemaker circuit, we established new fluorescent circadian reporters that permit single-cell recording of transcriptional and post-transcriptional rhythms in brain explants and cultured neurons. Live-imaging experiments combined with pharmacological and genetic manipulations demonstrate that the neuropeptide pigment-dispersing factor (PDF) amplifies the molecular rhythms via time-of-day- and activity-dependent upregulation of transcription from E-box-containing clock gene promoters within key pacemaker neurons. The effect of PDF on clock gene transcription and the known role of PDF in enhancing PER/TIM stability occur via independent pathways downstream of the PDF receptor, the former through a cAMP-independent mechanism and the latter through a cAMP-PKA dependent mechanism. These results confirm and extend the mechanistic understanding of the role of PDF in controlling the synchrony of the pacemaker neurons. More broadly, our results establish the utility of the new live-imaging tools for the study of molecular-neural interactions important for the operation of the circadian pacemaker circuit.

Fluorescence circadian imaging reveals a PDF-dependent transcriptional regulation of the Drosophila molecular clock

PubMed Central

Sabado, Virginie; Vienne, Ludovic; Nunes, José Manuel; Rosbash, Michael; Nagoshi, Emi

2017-01-01

Circadian locomotor behaviour is controlled by a pacemaker circuit composed of clock-containing neurons. To interrogate the mechanistic relationship between the molecular clockwork and network communication critical to the operation of the Drosophila circadian pacemaker circuit, we established new fluorescent circadian reporters that permit single-cell recording of transcriptional and post-transcriptional rhythms in brain explants and cultured neurons. Live-imaging experiments combined with pharmacological and genetic manipulations demonstrate that the neuropeptide pigment-dispersing factor (PDF) amplifies the molecular rhythms via time-of-day- and activity-dependent upregulation of transcription from E-box-containing clock gene promoters within key pacemaker neurons. The effect of PDF on clock gene transcription and the known role of PDF in enhancing PER/TIM stability occur via independent pathways downstream of the PDF receptor, the former through a cAMP-independent mechanism and the latter through a cAMP-PKA dependent mechanism. These results confirm and extend the mechanistic understanding of the role of PDF in controlling the synchrony of the pacemaker neurons. More broadly, our results establish the utility of the new live-imaging tools for the study of molecular-neural interactions important for the operation of the circadian pacemaker circuit. PMID:28134281

Strong resetting of the mammalian clock by constant light followed by constant darkness

PubMed Central

Chen, Rongmin; Seo, Dong-oh; Bell, Elijah; von Gall, Charlotte; Lee, Choogon

2008-01-01

The mammalian molecular circadian clock in the suprachiasmatic nuclei (SCN) regulates locomotor activity rhythms as well as clocks in peripheral tissues (Reppert and Weaver, 2002; Ko and Takahashi, 2006). Constant light (LL) can induce behavioral and physiological arrhythmicity, by desynchronizing clock cells in the SCN (Ohta et al., 2005). We examined how the disordered clock cells resynchronize by probing the molecular clock and measuring behavior in mice transferred from LL to constant darkness (DD). The circadian locomotor activity rhythms disrupted in LL become robustly rhythmic again from the beginning of DD, and the starting phase of the rhythm in DD is specific, not random, suggesting that the desynchronized clock cells are quickly reset in an unconventional manner by the L:D transition. By measuring mPERIOD protein rhythms, we showed that the SCN and peripheral tissue clocks quickly become rhythmic again in phase with the behavioral rhythms. We propose that this resetting mechanism may be different from conventional phase shifting, which involves light-induction of Period genes (Albrecht et al., 1997; Shearman et al., 1997; Shigeyoshi et al., 1997). Using our functional insights, we could shift the circadian phase of locomotor activity rhythms by 12 hours using a 15-hour LL treatment: essentially producing phase reversal by a single light pulse, a feat that has not been reported previously in wild-type mice and that has potential clinical utility. PMID:19005049

Redox regulation and pro-oxidant reactions in the physiology of circadian systems.

PubMed

Méndez, Isabel; Vázquez-Martínez, Olivia; Hernández-Muñoz, Rolando; Valente-Godínez, Héctor; Díaz-Muñoz, Mauricio

2016-05-01

Rhythms of approximately 24 h are pervasive in most organisms and are known as circadian. There is a molecular circadian clock in each cell sustained by a feedback system of interconnected "clock" genes and transcription factors. In mammals, the timing system is formed by a central pacemaker, the suprachiasmatic nucleus, in coordination with a collection of peripheral oscillators. Recently, an extensive interconnection has been recognized between the molecular circadian clock and the set of biochemical pathways that underlie the bioenergetics of the cell. A principle regulator of metabolic networks is the flow of electrons between electron donors and acceptors. The concomitant reduction and oxidation (redox) reactions directly influence the balance between anabolic and catabolic processes. This review summarizes and discusses recent findings concerning the mutual and dynamic interactions between the molecular circadian clock, redox reactions, and redox signaling. The scope includes the regulatory role played by redox coenzymes (NAD(P)+/NAD(P)H, GSH/GSSG), reactive oxygen species (superoxide anion, hydrogen peroxide), antioxidants (melatonin), and physiological events that modulate the redox state (feeding condition, circadian rhythms) in determining the timing capacity of the molecular circadian clock. In addition, we discuss a purely metabolic circadian clock, which is based on the redox enzymes known as peroxiredoxins and is present in mammalian red blood cells and in other biological systems. Both the timing system and the metabolic network are key to a better understanding of widespread pathological conditions such as the metabolic syndrome, obesity, and diabetes. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Novel transcriptional networks regulated by CLOCK in human neurons.

PubMed

Fontenot, Miles R; Berto, Stefano; Liu, Yuxiang; Werthmann, Gordon; Douglas, Connor; Usui, Noriyoshi; Gleason, Kelly; Tamminga, Carol A; Takahashi, Joseph S; Konopka, Genevieve

2017-11-01

The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function. © 2017 Fontenot et al.; Published by Cold Spring Harbor Laboratory Press.

Identification and temporal expression of putative circadian clock transcripts in the amphipod crustacean Talitrus saltator

PubMed Central

O’Grady, Joseph F.; Hoelters, Laura S.; Swain, Martin T.

2016-01-01

Background Talitrus saltator is an amphipod crustacean that inhabits the supralittoral zone on sandy beaches in the Northeast Atlantic and Mediterranean. T. saltator exhibits endogenous locomotor activity rhythms and time-compensated sun and moon orientation, both of which necessitate at least one chronometric mechanism. Whilst their behaviour is well studied, currently there are no descriptions of the underlying molecular components of a biological clock in this animal, and very few in other crustacean species. Methods We harvested brain tissue from animals expressing robust circadian activity rhythms and used homology cloning and Illumina RNAseq approaches to sequence and identify the core circadian clock and clock-related genes in these samples. We assessed the temporal expression of these genes in time-course samples from rhythmic animals using RNAseq. Results We identified a comprehensive suite of circadian clock gene homologues in T. saltator including the ‘core’ clock genes period (Talper), cryptochrome 2 (Talcry2), timeless (Taltim), clock (Talclk), and bmal1 (Talbmal1). In addition we describe the sequence and putative structures of 23 clock-associated genes including two unusual, extended isoforms of pigment dispersing hormone (Talpdh). We examined time-course RNAseq expression data, derived from tissues harvested from behaviourally rhythmic animals, to reveal rhythmic expression of these genes with approximately circadian period in Talper and Talbmal1. Of the clock-related genes, casein kinase IIβ (TalckIIβ), ebony (Talebony), jetlag (Taljetlag), pigment dispensing hormone (Talpdh), protein phosphatase 1 (Talpp1), shaggy (Talshaggy), sirt1 (Talsirt1), sirt7 (Talsirt7) and supernumerary limbs (Talslimb) show temporal changes in expression. Discussion We report the sequences of principle genes that comprise the circadian clock of T. saltator and highlight the conserved structural and functional domains of their deduced cognate proteins. Our sequencing data contribute to the growing inventory of described comparative clocks. Expression profiling of the identified clock genes illuminates tantalising targets for experimental manipulation to elucidate the molecular and cellular control of clock-driven phenotypes in this crustacean. PMID:27761341

Casein Kinase 1 Promotes Synchrony of the Circadian Clock Network

PubMed Central

Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun

2014-01-01

Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbtEY02910 loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbtEY02910 flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (∼32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbtEY02910 mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures.

PubMed

Petrenko, Volodymyr; Saini, Camille; Perrin, Laurent; Dibner, Charna

2016-11-11

Circadian clocks are functional in all light-sensitive organisms, allowing for an adaptation to the external world by anticipating daily environmental changes. Considerable progress in our understanding of the tight connection between the circadian clock and most aspects of physiology has been made in the field over the last decade. However, unraveling the molecular basis that underlies the function of the circadian oscillator in humans stays of highest technical challenge. Here, we provide a detailed description of an experimental approach for long-term (2-5 days) bioluminescence recording and outflow medium collection in cultured human primary cells. For this purpose, we have transduced primary cells with a lentiviral luciferase reporter that is under control of a core clock gene promoter, which allows for the parallel assessment of hormone secretion and circadian bioluminescence. Furthermore, we describe the conditions for disrupting the circadian clock in primary human cells by transfecting siRNA targeting CLOCK. Our results on the circadian regulation of insulin secretion by human pancreatic islets, and myokine secretion by human skeletal muscle cells, are presented here to illustrate the application of this methodology. These settings can be used to study the molecular makeup of human peripheral clocks and to analyze their functional impact on primary cells under physiological or pathophysiological conditions.

Molecular phylogeny of Pompilinae (Hymenoptera: Pompilidae): Evidence for rapid diversification and host shifts in spider wasps.

PubMed

Rodriguez, Juanita; Pitts, James P; Florez, Jaime A; Bond, Jason E; von Dohlen, Carol D

2016-01-01

Pompilinae is one of the largest subfamilies of spider wasps (Pompilidae). Most pompilines are generalist spider predators at the family level, but some taxa exhibit ecological specificity (i.e., to spider-host guild). Here we present the first molecular phylogenetic analysis of Pompilinae, toward the aim of evaluating the monophyly of tribes and genera. We further test whether changes in the rate of diversification are associated with host-guild shifts. Molecular data were collected from five nuclear loci (28S, EF1-F2, LWRh, Wg, Pol2) for 76 taxa in 39 genera. Data were analyzed using maximum likelihood (ML) and Bayesian inference (BI). The phylogenetic results were compared with previous hypotheses of subfamilial and tribal classification, as well as generic relationships in the subfamily. The classification of Pompilus and Agenioideus is also discussed. A Bayesian relaxed molecular clock analysis was used to examine divergence times. Diversification rate-shift tests accounted for taxon-sampling bias using ML and BI approaches. Ancestral host family and host guild were reconstructed using MP and ML methods. Ancestral host guild for all Pompilinae, for the ancestor at the node where a diversification rate-shift was detected, and two more nodes back in time was inferred using BI. In the resulting phylogenies, Aporini was the only previously proposed monophyletic tribe. Several genera (e.g., Pompilus, Microphadnus and Schistonyx) are also not monophyletic. Dating analyses produced a well-supported chronogram consistent with topologies from BI and ML results. The BI ancestral host-use reconstruction inferred the use of spiders belonging to the guild "other hunters" (frequenting the ground and vegetation) as the ancestral state for Pompilinae. This guild had the highest probability for the ML reconstruction and was equivocal for the MP reconstruction; various switching events to other guilds occurred throughout the evolution of the group. The diversification of Pompilinae shows one main rate-shift coinciding with a shift to ground-hunter spiders, as reconstructed by the BI ancestral character-state analysis. Copyright © 2015 Elsevier Inc. All rights reserved.

Regulation of molecular clock oscillations and phagocytic activity via muscarinic Ca2+ signaling in human retinal pigment epithelial cells

PubMed Central

Ikarashi, Rina; Akechi, Honami; Kanda, Yuzuki; Ahmad, Alsawaf; Takeuchi, Kouhei; Morioka, Eri; Sugiyama, Takashi; Ebisawa, Takashi; Ikeda, Masaaki; Ikeda, Masayuki

2017-01-01

Vertebrate eyes are known to contain circadian clocks, however, the intracellular mechanisms regulating the retinal clockwork remain largely unknown. To address this, we generated a cell line (hRPE-YC) from human retinal pigmental epithelium, which stably co-expressed reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). The hRPE-YC cells demonstrated circadian rhythms in Bmal1 transcription. Also, these cells represented circadian rhythms in Ca2+-spiking frequencies, which were canceled by dominant-negative Bmal1 transfections. The muscarinic agonist carbachol, but not photic stimulation, phase-shifted Bmal1 transcriptional rhythms with a type-1 phase response curve. This is consistent with significant M3 muscarinic receptor expression and little photo-sensor (Cry2 and Opn4) expression in these cells. Moreover, forskolin phase-shifted Bmal1 transcriptional rhythm with a type-0 phase response curve, in accordance with long-lasting CREB phosphorylation levels after forskolin exposure. Interestingly, the hRPE-YC cells demonstrated apparent circadian rhythms in phagocytic activities, which were abolished by carbachol or dominant-negative Bmal1 transfection. Because phagocytosis in RPE cells determines photoreceptor disc shedding, molecular clock oscillations and cytosolic Ca2+ signaling may be the driving forces for disc-shedding rhythms known in various vertebrates. In conclusion, the present study provides a cellular model to understand molecular and intracellular signaling mechanisms underlying human retinal circadian clocks. PMID:28276525

Evolution and the Distribution of Glutaminyl and Asparaginyl Residues in Proteins

PubMed Central

Robinson, Arthur B.

1974-01-01

Recent experiments on the deamidation of glutaminyl and asparaginyl residues in peptides and proteins support the hypothesis that these residues may serve as molecular clocks that control biological processes. A hypothesis is now offered that suggests that these molecular clocks are set by rejection or accumulation of appropriate sequences of residues including a glutaminyl or asparaginyl residue during evolution. PMID:4522799

Identification of a current hot spot of HIV type 1 transmission in Mongolia by molecular epidemiological analysis.

PubMed

Davaalkham, Jagdagsuren; Unenchimeg, Puntsag; Baigalmaa, Chultem; Erdenetuya, Gombo; Nyamkhuu, Dulmaa; Shiino, Teiichiro; Tsuchiya, Kiyoto; Hayashida, Tsunefusa; Gatanaga, Hiroyuki; Oka, Shinichi

2011-10-01

We investigated the current molecular epidemiological status of HIV-1 in Mongolia, a country with very low incidence of HIV-1 though with rapid expansion in recent years. HIV-1 pol (1065 nt) and env (447 nt) genes were sequenced to construct phylogenetic trees. The evolutionary rates, molecular clock phylogenies, and other evolutionary parameters were estimated from heterochronous genomic sequences of HIV-1 subtype B by the Bayesian Markov chain Monte Carlo method. We obtained 41 sera from 56 reported HIV-1-positive cases as of May 2009. The main route of infection was men who have sex with men (MSM). Dominant subtypes were subtype B in 32 cases (78%) followed by subtype CRF02_AG (9.8%). The phylogenetic analysis of the pol gene identified two clusters in subtype B sequences. Cluster 1 consisted of 21 cases including MSM and other routes of infection, and cluster 2 consisted of eight MSM cases. The tree analyses demonstrated very short branch lengths in cluster 1, suggesting a surprisingly active expansion of HIV-1 transmission during a short period with the same ancestor virus. Evolutionary analysis indicated that the outbreak started around the early 2000s. This study identified a current hot spot of HIV-1 transmission and potential seed of the epidemic in Mongolia. Comprehensive preventive measures targeting this group are urgently needed.

Using more than the oldest fossils: dating osmundaceae with three Bayesian clock approaches.

PubMed

Grimm, Guido W; Kapli, Paschalia; Bomfleur, Benjamin; McLoughlin, Stephen; Renner, Susanne S

2015-05-01

A major concern in molecular clock dating is how to use information from the fossil record to calibrate genetic distances from DNA sequences. Here we apply three Bayesian dating methods that differ in how calibration is achieved-"node dating" (ND) in BEAST, "total evidence" (TE) dating in MrBayes, and the "fossilized birth-death" (FBD) in FDPPDiv-to infer divergence times in the royal ferns. Osmundaceae have 16-17 species in four genera, two mainly in the Northern Hemisphere and two in South Africa and Australasia; they are the sister clade to the remaining leptosporangiate ferns. Their fossil record consists of at least 150 species in ∼17 genera. For ND, we used the five oldest fossils, whereas for TE and FBD dating, which do not require forcing fossils to nodes and thus can use more fossils, we included up to 36 rhizomes and frond compression/impression fossils, which for TE dating were scored for 33 morphological characters. We also subsampled 10%, 25%, and 50% of the 36 fossils to assess model sensitivity. FBD-derived divergence ages were generally greater than those inferred from ND; two of seven TE-derived ages agreed with FBD-obtained ages, the others were much younger or much older than ND or FBD ages. We prefer the FBD-derived ages because they best fit the Osmundales fossil record (including Triassic fossils not used in our study). Under the preferred model, the clade encompassing extant Osmundaceae (and many fossils) dates to the latest Paleozoic to Early Triassic; divergences of the extant species occurred during the Neogene. Under the assumption of constant speciation and extinction rates, the FBD approach yielded speciation and extinction rates that overlapped those obtained from just neontological data. However, FBD estimates of speciation and extinction are sensitive to violations in the assumption of continuous fossil sampling; therefore, these estimates should be treated with caution. © The Author(s) 2014. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Circadian Clock Coordinates Ribosome Biogenesis

PubMed Central

Symul, Laura; Martin, Eva; Atger, Florian; Naef, Felix; Gachon, Frédéric

2013-01-01

Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis. PMID:23300384

Regulatory principles and experimental approaches to the circadian control of starch turnover

PubMed Central

Seaton, Daniel D.; Ebenhöh, Oliver; Millar, Andrew J.; Pokhilko, Alexandra

2014-01-01

In many plants, starch is synthesized during the day and degraded during the night to avoid carbohydrate starvation in darkness. The circadian clock participates in a dynamic adjustment of starch turnover to changing environmental condition through unknown mechanisms. We used mathematical modelling to explore the possible scenarios for the control of starch turnover by the molecular components of the plant circadian clock. Several classes of plausible models were capable of describing the starch dynamics observed in a range of clock mutant plants and light conditions, including discriminating circadian protocols. Three example models of these classes are studied in detail, differing in several important ways. First, the clock components directly responsible for regulating starch degradation are different in each model. Second, the intermediate species in the pathway may play either an activating or inhibiting role on starch degradation. Third, the system may include a light-dependent interaction between the clock and downstream processes. Finally, the clock may be involved in the regulation of starch synthesis. We discuss the differences among the models’ predictions for diel starch profiles and the properties of the circadian regulators. These suggest additional experiments to elucidate the pathway structure, avoid confounding results and identify the molecular components involved. PMID:24335560

Common features in diverse insect clocks.

PubMed

Numata, Hideharu; Miyazaki, Yosuke; Ikeno, Tomoko

2015-01-01

This review describes common features among diverse biological clocks in insects, including circadian, circatidal, circalunar/circasemilunar, and circannual clocks. These clocks control various behaviors, physiological functions, and developmental events, enabling adaptation to periodic environmental changes. Circadian clocks also function in time-compensation for celestial navigation and in the measurement of day or night length for photoperiodism. Phase response curves for such clocks reported thus far exhibit close similarities; specifically, the circannual clock in Anthrenus verbasci shows striking similarity to circadian clocks in its phase response. It is suggested that diverse biological clocks share physiological properties in their phase responses irrespective of period length. Molecular and physiological mechanisms are best understood for the optic-lobe and mid-brain circadian clocks, although there is no direct evidence that these clocks are involved in rhythmic phenomena other than circadian rhythms in daily events. Circadian clocks have also been localized in peripheral tissues, and research on their role in various rhythmic phenomena has been started. Although clock genes have been identified as controllers of circadian rhythms in daily events, some of these genes have also been shown to be involved in photoperiodism and possibly in time-compensated celestial navigation. In contrast, there is no experimental evidence indicating that any known clock gene is involved in biological clocks other than circadian clocks.

A sense of time: how molecular clocks organize metabolism.

PubMed

Kohsaka, Akira; Bass, Joseph

2007-01-01

The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past decade, a molecular transcription-translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue 'senses time' set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.

Circadian rhythms synchronize mitosis in Neurospora crassa.

PubMed

Hong, Christian I; Zámborszky, Judit; Baek, Mokryun; Labiscsak, Laszlo; Ju, Kyungsu; Lee, Hyeyeong; Larrondo, Luis F; Goity, Alejandra; Chong, Hin Siong; Belden, William J; Csikász-Nagy, Attila

2014-01-28

The cell cycle and the circadian clock communicate with each other, resulting in circadian-gated cell division cycles. Alterations in this network may lead to diseases such as cancer. Therefore, it is critical to identify molecular components that connect these two oscillators. However, molecular mechanisms between the clock and the cell cycle remain largely unknown. A model filamentous fungus, Neurospora crassa, is a multinucleate system used to elucidate molecular mechanisms of circadian rhythms, but not used to investigate the molecular coupling between these two oscillators. In this report, we show that a conserved coupling between the circadian clock and the cell cycle exists via serine/threonine protein kinase-29 (STK-29), the Neurospora homolog of mammalian WEE1 kinase. Based on this finding, we established a mathematical model that predicts circadian oscillations of cell cycle components and circadian clock-dependent synchronized nuclear divisions. We experimentally demonstrate that G1 and G2 cyclins, CLN-1 and CLB-1, respectively, oscillate in a circadian manner with bioluminescence reporters. The oscillations of clb-1 and stk-29 gene expression are abolished in a circadian arrhythmic frq(ko) mutant. Additionally, we show the light-induced phase shifts of a core circadian component, frq, as well as the gene expression of the cell cycle components clb-1 and stk-29, which may alter the timing of divisions. We then used a histone hH1-GFP reporter to observe nuclear divisions over time, and show that a large number of nuclear divisions occur in the evening. Our findings demonstrate the circadian clock-dependent molecular dynamics of cell cycle components that result in synchronized nuclear divisions in Neurospora.

The Clock gene clone and its circadian rhythms in Pelteobagrus vachelli

NASA Astrophysics Data System (ADS)

Qin, Chuanjie; Shao, Ting

2015-05-01

The Clock gene, a key molecule in circadian systems, is widely distributed in the animal kingdom. We isolated a 936-bp partial cDNA sequence of the Clock gene ( Pva-clock) from the darkbarbel catfish Pelteobagrus vachelli that exhibited high identity with Clock genes of other species of fish and animals (65%-88%). The putative domains included a basic helix-loop-helix (bHLH) domain and two period-ARNT-single-minded (PAS) domains, which were also similar to those in other species of fish and animals. Pva-Clock was primarily expressed in the brain, and was detected in all of the peripheral tissues sampled. Additionally, the pattern of Pva-Clock expression over a 24-h period exhibited a circadian rhythm in the brain, liver and intestine, with the acrophase at zeitgeber time 21:35, 23:00, and 23:23, respectively. Our results provide insight into the function of the molecular Clock of P. vachelli.

Chloroplast and nuclear gene sequences indicate late Pennsylvanian time for the last common ancestor of extant seed plants.

PubMed Central

Savard, L; Li, P; Strauss, S H; Chase, M W; Michaud, M; Bousquet, J

1994-01-01

We have estimated the time for the last common ancestor of extant seed plants by using molecular clocks constructed from the sequences of the chloroplastic gene coding for the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (rbcL) and the nuclear gene coding for the small subunit of rRNA (Rrn18). Phylogenetic analyses of nucleotide sequences indicated that the earliest divergence of extant seed plants is likely represented by a split between conifer-cycad and angiosperm lineages. Relative-rate tests were used to assess homogeneity of substitution rates among lineages, and annual angiosperms were found to evolve at a faster rate than other taxa for rbcL and, thus, these sequences were excluded from construction of molecular clocks. Five distinct molecular clocks were calibrated using substitution rates for the two genes and four divergence times based on fossil and published molecular clock estimates. The five estimated times for the last common ancestor of extant seed plants were in agreement with one another, with an average of 285 million years and a range of 275-290 million years. This implies a substantially more recent ancestor of all extant seed plants than suggested by some theories of plant evolution. PMID:8197201

Temperature-dependent resetting of the molecular circadian oscillator in Drosophila

PubMed Central

Goda, Tadahiro; Sharp, Brandi; Wijnen, Herman

2014-01-01

Circadian clocks responsible for daily time keeping in a wide range of organisms synchronize to daily temperature cycles via pathways that remain poorly understood. To address this problem from the perspective of the molecular oscillator, we monitored temperature-dependent resetting of four of its core components in the fruitfly Drosophila melanogaster: the transcripts and proteins for the clock genes period (per) and timeless (tim). The molecular circadian cycle in adult heads exhibited parallel responses to temperature-mediated resetting at the levels of per transcript, tim transcript and TIM protein. Early phase adjustment specific to per transcript rhythms was explained by clock-independent temperature-driven transcription of per. The cold-induced expression of Drosophila per contrasts with the previously reported heat-induced regulation of mammalian Period 2. An altered and more readily re-entrainable temperature-synchronized circadian oscillator that featured temperature-driven per transcript rhythms and phase-shifted TIM and PER protein rhythms was found for flies of the ‘Tim 4’ genotype, which lacked daily tim transcript oscillations but maintained post-transcriptional temperature entrainment of tim expression. The accelerated molecular and behavioural temperature entrainment observed for Tim 4 flies indicates that clock-controlled tim expression constrains the rate of temperature cycle-mediated circadian resetting. PMID:25165772

Feedback repression is required for mammalian circadian clock function.

PubMed

Sato, Trey K; Yamada, Rikuhiro G; Ukai, Hideki; Baggs, Julie E; Miraglia, Loren J; Kobayashi, Tetsuya J; Welsh, David K; Kay, Steve A; Ueda, Hiroki R; Hogenesch, John B

2006-03-01

Direct evidence for the requirement of transcriptional feedback repression in circadian clock function has been elusive. Here, we developed a molecular genetic screen in mammalian cells to identify mutants of the circadian transcriptional activators CLOCK and BMAL1, which were uncoupled from CRYPTOCHROME (CRY)-mediated transcriptional repression. Notably, mutations in the PER-ARNT-SIM domain of CLOCK and the C terminus of BMAL1 resulted in synergistic insensitivity through reduced physical interactions with CRY. Coexpression of these mutant proteins in cultured fibroblasts caused arrhythmic phenotypes in population and single-cell assays. These data demonstrate that CRY-mediated repression of the CLOCK/BMAL1 complex activity is required for maintenance of circadian rhythmicity and provide formal proof that transcriptional feedback is required for mammalian clock function.

A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

PubMed Central

Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L.; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L.; White, Kevin P.; Dinner, Aaron R.; Lear, Bridget C.; Ren, Dejian; Diekman, Casey O.; Raman, Indira M.; Allada, Ravi

2015-01-01

Summary Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake. PMID:26276633

Molecular oscillation behind the clockface.

PubMed

Fukada, Yoshitaka

2003-12-01

The earth rotates on its own axis while orbiting around the sun. This regular movement of the solar system results in cyclic changes of the light condition of the earth with a period of 24 h, although the lengths of daytime and nighttime depend on the latitude. The organisms living on the earth have evolved an internal time-measuring system called the "circadian clock," which ticks with a period of approximately 24 h in order to adapt to the environment and to anticipate the next cycle. The fact that most of existing organisms retain the circadian clock suggests that the clock-ownership must have been advantageous over non-ownership during their evolution. Here I will introduce the background of the research field of circadian rhythm and present an outline of this Special Review series, which is composed of three articles that review recent research into the molecular mechanisms of the three types of circadian clock systems in vertebrates.

Cinnamic acid shortens the period of the circadian clock in mice.

PubMed

Oishi, Katsutaka; Yamamoto, Saori; Oike, Hideaki; Ohkura, Naoki; Taniguchi, Masahiko

2017-03-01

Cinnamic acid (CA) derivatives have recently received focus due to their anticancer, antioxidant, and antidiabetic properties. The present study aimed to determine the effects of cinnamic acid on the circadian clock, which is a cell-autonomous endogenous system that generates circadian rhythms that govern the behavior and physiology of most organisms. Cinnamic acid significantly shortened the circadian period of PER2::LUC expression in neuronal cells that differentiated from neuronal progenitor cells derived from PER2::LUC mouse embryos. Cinnamic acid did not induce the transient mRNA expression of clock genes such as Per1 and Per2 in neuronal cells, but significantly shortened the half-life of PER2::LUC protein in neuronal cells incubated with actinomycin D, suggested that CA post-transcriptionally affects the molecular clock by decreasing Per2 mRNA stability. A continuous infusion of CA into mice via an Alzet osmotic pump under constant darkness significantly shortened the free-running period of wheel-running rhythms. These findings suggest that CA shortens the circadian period of the molecular clock in mammals.

The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.

PubMed

Bouchard-Cannon, Pascale; Mendoza-Viveros, Lucia; Yuen, Andrew; Kærn, Mads; Cheng, Hai-Ying M

2013-11-27

The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Evidence of transoceanic dispersion of the genus Vanilla based on plastid DNA phylogenetic analysis.

PubMed

Bouetard, Anthony; Lefeuvre, Pierre; Gigant, Rodolphe; Bory, Séverine; Pignal, Marc; Besse, Pascale; Grisoni, Michel

2010-05-01

The phylogeny and the biogeographical history of the genus Vanilla was investigated using four chloroplastic genes (psbB, psbC; psaB and rbcL), on 47 accessions of Vanilla chosen from the ex situ CIRAD collection maintained in Reunion Island and additional sequences from GenBank. Bayesian methods provided a fairly well supported reconstruction of the phylogeny of the Vanilloideae sub-family and more particularly of the genus Vanilla. Three major phylogenetic groups in the genus Vanilla were differentiated, which is in disagreement with the actual classification in two sections (Foliosae and Aphyllae) based on morphological traits. Recent Bayesian relaxed molecular clock methods allowed to test the two main hypotheses of the phylogeography of the genus Vanilla. Early radiation of the Vanilla genus and diversification by vicariance consecutive to the break-up of Gondwana, 95 million years ago (Mya), was incompatible with the admitted age of origin of Angiosperm. Based on the Vanilloideae age recently estimated to 71 million years ago (Mya), we conclude that the genus Vanilla would have appeared approximately 34 Mya in South America, when continents were already separated. Nevertheless, whatever the two extreme scenarios tested, at least three long distance migration events are needed to explain the present distribution of Vanilla species in tropical areas. These transoceanic dispersions could have occurred via transoceanic passageway such as the Rio Grande Ridge and the involvement of floating vegetation mats and migratory birds. Copyright 2010 Elsevier Inc. All rights reserved.

Novel patterns of historical isolation, dispersal, and secondary contact across Baja California in the Rosy Boa (Lichanura trivirgata).

PubMed

Wood, Dustin A; Fisher, Robert N; Reeder, Tod W

2008-02-01

Mitochondrial DNA (mtDNA) sequence variation was examined in 131 individuals of the Rosy Boa (Lichanura trivirgata) from across the species range in southwestern North America. Bayesian inference and nested clade phylogeographic analyses (NCPA) were used to estimate relationships and infer evolutionary processes. These patterns were evaluated as they relate to previously hypothesized vicariant events and new insights are provided into the biogeographic and evolutionary processes important in Baja California and surrounding North American deserts. Three major lineages (Lineages A, B, and C) are revealed with very little overlap. Lineage A and B are predominately separated along the Colorado River and are found primarily within California and Arizona (respectively), while Lineage C consists of disjunct groups distributed along the Baja California peninsula as well as south-central Arizona, southward along the coastal regions of Sonora, Mexico. Estimated divergence time points (using a Bayesian relaxed molecular clock) and geographic congruence with postulated vicariant events suggest early extensions of the Gulf of California and subsequent development of the Colorado River during the Late Miocene-Pliocene led to the formation of these mtDNA lineages. Our results also suggest that vicariance hypotheses alone do not fully explain patterns of genetic variation. Therefore, we highlight the importance of dispersal to explain these patterns and current distribution of populations. We also compare the mtDNA lineages with those based on morphological variation and evaluate their implications for taxonomy.

Novel patterns of historical isolation, dispersal, and secondary contact across Baja California in the Rosy Boa (Lichanura trivirgata)

USGS Publications Warehouse

Wood, D.A.; Fisher, R.N.; Reeder, T.W.

2008-01-01

Mitochondrial DNA (mtDNA) sequence variation was examined in 131 individuals of the Rosy Boa (Lichanura trivirgata) from across the species range in southwestern North America. Bayesian inference and nested clade phylogeographic analyses (NCPA) were used to estimate relationships and infer evolutionary processes. These patterns were evaluated as they relate to previously hypothesized vicariant events and new insights are provided into the biogeographic and evolutionary processes important in Baja California and surrounding North American deserts. Three major lineages (Lineages A, B, and C) are revealed with very little overlap. Lineage A and B are predominately separated along the Colorado River and are found primarily within California and Arizona (respectively), while Lineage C consists of disjunct groups distributed along the Baja California peninsula as well as south-central Arizona, southward along the coastal regions of Sonora, Mexico. Estimated divergence time points (using a Bayesian relaxed molecular clock) and geographic congruence with postulated vicariant events suggest early extensions of the Gulf of California and subsequent development of the Colorado River during the Late Miocene-Pliocene led to the formation of these mtDNA lineages. Our results also suggest that vicariance hypotheses alone do not fully explain patterns of genetic variation. Therefore, we highlight the importance of dispersal to explain these patterns and current distribution of populations. We also compare the mtDNA lineages with those based on morphological variation and evaluate their implications for taxonomy. ?? 2007 Elsevier Inc. All rights reserved.

Biogeographical Consequences of Cenozoic Tectonic Events within East Asian Margins: A Case Study of Hynobius Biogeography

PubMed Central

Li, Jun; Fu, Cuizhang; Lei, Guangchun

2011-01-01

Few studies have explored the role of Cenozoic tectonic evolution in shaping patterns and processes of extant animal distributions within East Asian margins. We select Hynobius salamanders (Amphibia: Hynobiidae) as a model to examine biogeographical consequences of Cenozoic tectonic events within East Asian margins. First, we use GenBank molecular data to reconstruct phylogenetic interrelationships of Hynobius by Bayesian and maximum likelihood analyses. Second, we estimate the divergence time using the Bayesian relaxed clock approach and infer dispersal/vicariance histories under the ‘dispersal–extinction–cladogenesis’ model. Finally, we test whether evolutionary history and biogeographical processes of Hynobius should coincide with the predictions of two major hypotheses (the ‘vicariance’/‘out of southwestern Japan’ hypothesis). The resulting phylogeny confirmed Hynobius as a monophyletic group, which could be divided into nine major clades associated with six geographical areas. Our results show that: (1) the most recent common ancestor of Hynobius was distributed in southwestern Japan and Hokkaido Island, (2) a sister taxon relationship between Hynobius retardatus and all remaining species was the results of a vicariance event between Hokkaido Island and southwestern Japan in the Middle Eocene, (3) ancestral Hynobius in southwestern Japan dispersed into the Taiwan Island, central China, ‘Korean Peninsula and northeastern China’ as well as northeastern Honshu during the Late Eocene–Late Miocene. Our findings suggest that Cenozoic tectonic evolution plays an important role in shaping disjunctive distributions of extant Hynobius within East Asian margins. PMID:21738684

Dating of the human-ape splitting by a molecular clock of mitochondrial DNA.

PubMed

Hasegawa, M; Kishino, H; Yano, T

1985-01-01

A new statistical method for estimating divergence dates of species from DNA sequence data by a molecular clock approach is developed. This method takes into account effectively the information contained in a set of DNA sequence data. The molecular clock of mitochondrial DNA (mtDNA) was calibrated by setting the date of divergence between primates and ungulates at the Cretaceous-Tertiary boundary (65 million years ago), when the extinction of dinosaurs occurred. A generalized least-squares method was applied in fitting a model to mtDNA sequence data, and the clock gave dates of 92.3 +/- 11.7, 13.3 +/- 1.5, 10.9 +/- 1.2, 3.7 +/- 0.6, and 2.7 +/- 0.6 million years ago (where the second of each pair of numbers is the standard deviation) for the separation of mouse, gibbon, orangutan, gorilla, and chimpanzee, respectively, from the line leading to humans. Although there is some uncertainty in the clock, this dating may pose a problem for the widely believed hypothesis that the pipedal creature Australopithecus afarensis, which lived some 3.7 million years ago at Laetoli in Tanzania and at Hadar in Ethiopia, was ancestral to man and evolved after the human-ape splitting. Another likelier possibility is that mtDNA was transferred through hybridization between a proto-human and a proto-chimpanzee after the former had developed bipedalism.

Architecture and mechanism of the central gear in an ancient molecular timer.

PubMed

Egli, Martin

2017-03-01

Molecular clocks are the product of natural selection in organisms from bacteria to human and their appearance early in evolution such as in the prokaryotic cyanobacterium Synechococcus elongatus suggests that these timers served a crucial role in genetic fitness. Thus, a clock allows cyanobacteria relying on photosynthesis and nitrogen fixation to temporally space the two processes and avoid exposure of nitrogenase carrying out fixation to high levels of oxygen produced during photosynthesis. Fascinating properties of molecular clocks are the long time constant, their precision and temperature compensation. Although these are hallmarks of all circadian oscillators, the actual cogs and gears that control clocks vary widely between organisms, indicating that circadian timers evolved convergently multiple times, owing to the selective pressure of an environment with a daily light/dark cycle. In S. elongatus , the three proteins KaiA, KaiB and KaiC in the presence of ATP constitute a so-called post-translational oscillator (PTO). The KaiABC PTO can be reconstituted in an Eppendorf tube and keeps time in a temperature-compensated manner. The ease by which the KaiABC clock can be studied in vitro has made it the best-investigated molecular clock system. Over the last decade, structures of all three Kai proteins and some of their complexes have emerged and mechanistic aspects have been analysed in considerable detail. This review focuses on the central gear of the S. elongatus clock and only enzyme among the three proteins: KaiC. Our determination of the three-dimensional structure of KaiC early in the quest for a better understanding of the inner workings of the cyanobacterial timer revealed its unusual architecture and conformational differences and unique features of the two RecA-like domains constituting KaiC. The structure also pinpointed phosphorylation sites and differential interactions with ATP molecules at subunit interfaces, and helped guide experiments to ferret out mechanistic aspects of the ATPase, auto-phosphorylation and auto-dephosphorylation reactions catalysed by the homo-hexamer. Comparisons between the structure of KaiC and those of nanomachines such as F1-ATPase and CaMKII also exposed shared architectural features (KaiC/ATPase), mechanistic principles (KaiC/CaMKII) and phenomena, such as subunit exchange between hexameric particles critical for function (clock synchronization, KaiABC; memory-storage, CaMKII). © 2017 The Author(s).

Phylogeography above the species level for perennial species in a composite genus

PubMed Central

Tremetsberger, Karin; Ortiz, María Ángeles; Terrab, Anass; Balao, Francisco; Casimiro-Soriguer, Ramón; Talavera, María; Talavera, Salvador

2016-01-01

In phylogeography, DNA sequence and fingerprint data at the population level are used to infer evolutionary histories of species. Phylogeography above the species level is concerned with the genealogical aspects of divergent lineages. Here, we present a phylogeographic study to examine the evolutionary history of a western Mediterranean composite, focusing on the perennial species of Helminthotheca (Asteraceae, Cichorieae). We used molecular markers (amplified fragment length polymorphism (AFLP), internal transcribed spacer and plastid DNA sequences) to infer relationships among populations throughout the distributional range of the group. Interpretation is aided by biogeographic and molecular clock analyses. Four coherent entities are revealed by Bayesian mixture clustering of AFLP data, which correspond to taxa previously recognized at the rank of subspecies. The origin of the group was in western North Africa, from where it expanded across the Strait of Gibraltar to the Iberian Peninsula and across the Strait of Sicily to Sicily. Pleistocene lineage divergence is inferred within western North Africa as well as within the western Iberian region. The existence of the four entities as discrete evolutionary lineages suggests that they should be elevated to the rank of species, yielding H. aculeata, H. comosa, H. maroccana and H. spinosa, whereby the latter two necessitate new combinations. PMID:26644340

Non-canonical Phototransduction Mediates Synchronization of the Drosophila melanogaster Circadian Clock and Retinal Light Responses.

PubMed

Ogueta, Maite; Hardie, Roger C; Stanewsky, Ralf

2018-06-04

The daily light-dark cycles represent a key signal for synchronizing circadian clocks. Both insects and mammals possess dedicated "circadian" photoreceptors but also utilize the visual system for clock resetting. In Drosophila, circadian clock resetting is achieved by the blue-light photoreceptor cryptochrome (CRY), which is expressed within subsets of the brain clock neurons. In addition, rhodopsin-expressing photoreceptor cells contribute to light synchronization. Light resets the molecular clock by CRY-dependent degradation of the clock protein Timeless (TIM), although in specific subsets of key circadian pacemaker neurons, including the small ventral lateral neurons (s-LNvs), TIM and Period (PER) oscillations can be synchronized by light independent of CRY and canonical visual Rhodopsin phototransduction. Here, we show that at least three of the seven Drosophila rhodopsins can utilize an alternative transduction mechanism involving the same α-subunit of the heterotrimeric G protein operating in canonical visual phototransduction (Gq). Surprisingly, in mutants lacking the canonical phospholipase C-β (PLC-β) encoded by the no receptor potential A (norpA) gene, we uncovered a novel transduction pathway using a different PLC-β encoded by the Plc21C gene. This novel pathway is important for behavioral clock resetting to semi-natural light-dark cycles and mediates light-dependent molecular synchronization within the s-LNv clock neurons. The same pathway appears to be responsible for norpA-independent light responses in the compound eye. We show that Rhodopsin 5 (Rh5) and Rh6, present in the R8 subset of retinal photoreceptor cells, drive both the long-term circadian and rapid light responses in the eye. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity

PubMed Central

Silver, Adam C.; Arjona, Alvaro; Walker, Wendy E.; Fikrig, Erol

2012-01-01

Circadian rhythms refer to biologic processes that oscillate with a period of approximately 24 hours. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of toll like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy. PMID:22342842

The Complete Mitochondrial Genome and Song Evolution of the Monotypic Genus U. Tarbinsky, 1932 (Orthoptera: Tettigoniidae).

PubMed

Wang, Yinliang; Zhao, Hanbo; Zhang, Xue; Ren, Bingzhong

2016-04-23

The insect Uvarovites inflatus Uvarov is highly appreciated in China. It is known for its distinctive songs and horn-like forewings and is raised commercially for insect lovers. U. inflatus was previously categorized as part of the monotypic genus Uvarovites; however, there was little molecular evidence to support this taxonomic classification. This study obtained and investigated the mitogenome of U. inflatus, and its songs were characterized and compared with other Ensifera species whose mitogenomes are available. By performing the mitochondrial analysis, we were able to assess the phylogenetic relationships between these species and discuss the evolution of Ensifera calling songs. The mitogenome of U. inflatus is 15,956 bp in length and contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region. The organization and orientation of the U. inflatus mitogenome are similar to those of other Tettigonioidea species. Phylogenetic analysis based on 13 protein-coding genes showed that the superfamily Tettigonioidea is monophyletic, as are the other six tested subfamilies from Tettigonioidea. Our results also indicated that Grylloidea is monophyletic. A Bayesian relaxed clock analysis showed that the differentiation of U. inflatus and Gampsocleis gratiosa Brunner occurred in the middle Miocene, suggesting that their speciation occurred over a long evolutionary period. The results provide significant support for the establishment of the monotypic genus Uvarovites. Calling song analysis showed that at least two discrete steps of independent evolution occurred during the change from pure tone to broadband noise, and that the ancestor of existing Ensifera was more likely to have emitted pure-tone songs than broadband signals. Together, the mitogenome, molecular clock, and acoustic data allowed us to clarify the taxonomic state of U. inflatus and propose a timeline for the evolution of Ensifera songs. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Bennett clocking of quantum-dot cellular automata and the limits to binary logic scaling.

PubMed

Lent, Craig S; Liu, Mo; Lu, Yuhui

2006-08-28

We examine power dissipation in different clocking schemes for molecular quantum-dot cellular automata (QCA) circuits. 'Landauer clocking' involves the adiabatic transition of a molecular cell from the null state to an active state carrying data. Cell layout creates devices which allow data in cells to interact and thereby perform useful computation. We perform direct solutions of the equation of motion for the system in contact with the thermal environment and see that Landauer's Principle applies: one must dissipate an energy of at least k(B)T per bit only when the information is erased. The ideas of Bennett can be applied to keep copies of the bit information by echoing inputs to outputs, thus embedding any logically irreversible circuit in a logically reversible circuit, at the cost of added circuit complexity. A promising alternative which we term 'Bennett clocking' requires only altering the timing of the clocking signals so that bit information is simply held in place by the clock until a computational block is complete, then erased in the reverse order of computation. This approach results in ultralow power dissipation without additional circuit complexity. These results offer a concrete example in which to consider recent claims regarding the fundamental limits of binary logic scaling.

Bennett clocking of quantum-dot cellular automata and the limits to binary logic scaling

NASA Astrophysics Data System (ADS)

Lent, Craig S.; Liu, Mo; Lu, Yuhui

2006-08-01

We examine power dissipation in different clocking schemes for molecular quantum-dot cellular automata (QCA) circuits. 'Landauer clocking' involves the adiabatic transition of a molecular cell from the null state to an active state carrying data. Cell layout creates devices which allow data in cells to interact and thereby perform useful computation. We perform direct solutions of the equation of motion for the system in contact with the thermal environment and see that Landauer's Principle applies: one must dissipate an energy of at least kBT per bit only when the information is erased. The ideas of Bennett can be applied to keep copies of the bit information by echoing inputs to outputs, thus embedding any logically irreversible circuit in a logically reversible circuit, at the cost of added circuit complexity. A promising alternative which we term 'Bennett clocking' requires only altering the timing of the clocking signals so that bit information is simply held in place by the clock until a computational block is complete, then erased in the reverse order of computation. This approach results in ultralow power dissipation without additional circuit complexity. These results offer a concrete example in which to consider recent claims regarding the fundamental limits of binary logic scaling.

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

PubMed

Narasimamurthy, Rajesh; Virshup, David M

2017-01-01

An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells.

PubMed

Lin, Changpo; Tang, Xiao; Xu, Lirong; Qian, Ruizhe; Shi, Zhenyu; Wang, Lixin; Cai, Tingting; Yan, Dong; Fu, Weiguo; Guo, Daqiao

2017-07-10

The clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs. Furthermore, we compared the cholesterol and triglycerides levels between two groups and the link to clock genes and CCGs expressions. Seven health donors' normal carotids and 19 carotid plaques yielded viable cultured NVSMCs and PVSMCs. The expression levels of target genes were measured by quantitative real-time PCR and Western-blot. The intracellular cholesterol and triglycerides levels were measured by kits. The circadian expressions of apoptosis-related genes and fibrinolytic-related genes were disordered. Besides, the cholesterol levels were significant higher in PVSMCs. After treated with cholesterol or oxidized low density lipoprotein (ox-LDL), the expressions of clock genes were inhibited; and the rhythmic expressions of clock genes, apoptosis-related genes and fibrinolytic-related genes were disturbed in NVSMCs, which were similar to PVSMCs. The results suggested that intracellular high cholesterol content of PVSMCs would lead to the disorders of clock genes and CCGs rhythmic expressions. And further studies should be conducted to demonstrate the specific molecular mechanisms involved.

Potential Conservation of Circadian Clock Proteins in the phylum Nematoda as Revealed by Bioinformatic Searches

PubMed Central

Romanowski, Andrés; Garavaglia, Matías Javier; Goya, María Eugenia; Ghiringhelli, Pablo Daniel; Golombek, Diego Andrés

2014-01-01

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system. PMID:25396739

Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches.

PubMed

Romanowski, Andrés; Garavaglia, Matías Javier; Goya, María Eugenia; Ghiringhelli, Pablo Daniel; Golombek, Diego Andrés

2014-01-01

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.

The molecular clock of neutral evolution can be accelerated or slowed by asymmetric spatial structure.

PubMed

Allen, Benjamin; Sample, Christine; Dementieva, Yulia; Medeiros, Ruben C; Paoletti, Christopher; Nowak, Martin A

2015-02-01

Over time, a population acquires neutral genetic substitutions as a consequence of random drift. A famous result in population genetics asserts that the rate, K, at which these substitutions accumulate in the population coincides with the mutation rate, u, at which they arise in individuals: K = u. This identity enables genetic sequence data to be used as a "molecular clock" to estimate the timing of evolutionary events. While the molecular clock is known to be perturbed by selection, it is thought that K = u holds very generally for neutral evolution. Here we show that asymmetric spatial population structure can alter the molecular clock rate for neutral mutations, leading to either Ku. Our results apply to a general class of haploid, asexually reproducing, spatially structured populations. Deviations from K = u occur because mutations arise unequally at different sites and have different probabilities of fixation depending on where they arise. If birth rates are uniform across sites, then K ≤ u. In general, K can take any value between 0 and Nu. Our model can be applied to a variety of population structures. In one example, we investigate the accumulation of genetic mutations in the small intestine. In another application, we analyze over 900 Twitter networks to study the effect of network topology on the fixation of neutral innovations in social evolution.