@article{764, abstract = {Set agreement is a fundamental problem in distributed computing in which processes collectively choose a small subset of values from a larger set of proposals. The impossibility of fault-tolerant set agreement in asynchronous networks is one of the seminal results in distributed computing. In synchronous networks, too, the complexity of set agreement has been a significant research challenge that has now been resolved. Real systems, however, are neither purely synchronous nor purely asynchronous. Rather, they tend to alternate between periods of synchrony and periods of asynchrony. Nothing specific is known about the complexity of set agreement in such a "partially synchronous" setting. In this paper, we address this challenge, presenting the first (asymptotically) tight bound on the complexity of set agreement in such systems. We introduce a novel technique for simulating, in a fault-prone asynchronous shared memory, executions of an asynchronous and failure-prone message-passing system in which some fragments appear synchronous to some processes. We use this simulation technique to derive a lower bound on the round complexity of set agreement in a partially synchronous system by a reduction from asynchronous wait-free set agreement. Specifically, we show that every set agreement protocol requires at least $\lfloor\frac t k \rfloor + 2$ synchronous rounds to decide. We present an (asymptotically) matching algorithm that relies on a distributed asynchrony detection mechanism to decide as soon as possible during periods of synchrony. From these two results, we derive the size of the minimal window of synchrony needed to solve set agreement. By relating synchronous, asynchronous and partially synchronous environments, our simulation technique is of independent interest. In particular, it allows us to obtain a new lower bound on the complexity of early deciding k-set agreement complementary to that of Gafni et al. (in SIAM J. Comput. 40(1):63-78, 2011), and to re-derive the combinatorial topology lower bound of Guerraoui et al. (in Theor. Comput. Sci. 410(6-7):570-580, 2009) in an algorithmic way.}, author = {Alistarh, Dan-Adrian and Gilbert, Seth and Guerraoui, Rachid and Travers, Corentin}, journal = {Algorithmica (New York)}, number = {1-2}, pages = {595 -- 629}, publisher = {Springer}, title = {{Of choices, failures and asynchrony: the many faces of set agreement}}, doi = {10.1007/s00453-011-9581-7}, volume = {62}, year = {2012}, } @inproceedings{766, abstract = {Asynchronous task allocation is a fundamental problem in distributed computing in which p asynchronous processes must execute a set of m tasks. Also known as write-all or do-all, this problem been studied extensively, both independently and as a key building block for various distributed algorithms. In this paper, we break new ground on this classic problem: we introduce the To-Do Tree concurrent data structure, which improves on the best known randomized and deterministic upper bounds. In the presence of an adaptive adversary, the randomized To-Do Tree algorithm has O(m + p log p log2 m) work complexity. We then show that there exists a deterministic variant of the To-Do Tree algorithm with work complexity O(m + p log5 m log2 max(m, p)). For all values of m and p, our algorithms are within log factors of the Ω(m + p log p) lower bound for this problem. The key technical ingredient in our results is a new approach for analyzing concurrent executions against a strong adaptive scheduler. This technique allows us to handle the complex dependencies between the processes' coin flips and their scheduling, and to tightly bound the work needed to perform subsets of the tasks.}, author = {Alistarh, Dan-Adrian and Bender, Michael and Gilbert, Seth and Guerraoui, Rachid}, pages = {331 -- 340}, publisher = {IEEE}, title = {{How to allocate tasks asynchronously}}, doi = {10.1109/FOCS.2012.41}, year = {2012}, } @article{767, abstract = {Synchronous distributed algorithms are easier to design and prove correct than algorithms that tolerate asynchrony. Yet, in the real world, networks experience asynchrony and other timing anomalies. In this paper, we address the question of how to efficiently transform an algorithm that relies on synchronous timing into an algorithm that tolerates asynchronous executions. We introduce a transformation technique from synchronous algorithms to indulgent algorithms (Guerraoui, in PODC, pp. 289-297, 2000), which induces only a constant overhead in terms of time complexity in well-behaved executions. Our technique is based on a new abstraction we call an asynchrony detector, which the participating processes implement collectively. The resulting transformation works for the class of colorless distributed tasks, including consensus and set agreement. Interestingly, we also show that our technique is relevant for colored tasks, by applying it to the renaming problem, to obtain the first indulgent renaming algorithm.}, author = {Alistarh, Dan-Adrian and Gilbert, Seth and Guerraoui, Rachid and Travers, Corentin}, journal = {Theory of Computing Systems}, number = {4}, pages = {404 -- 424}, publisher = {Elsevier}, title = {{Generating Fast Indulgent Algorithms}}, doi = {10.1007/s00224-012-9407-2}, volume = {51}, year = {2012}, } @article{7749, abstract = {Although studies on laboratory species and natural populations of vertebrates have shown reproduction to impair later performance, little is known of the age‐specific associations between reproduction and survival, and how such findings apply to the ageing of large, long‐lived species. Herein we develop a framework to examine population‐level patterns of reproduction and survival across lifespan in long‐lived organisms, and decompose those changes into individual‐level effects, and the effects of age‐specific trade‐offs between fitness components. We apply this to an extensive longitudinal dataset on female semi‐captive Asian timber elephants (Elephas maximus) and report the first evidence of age‐specific fitness declines that are driven by age‐specific associations between fitness components in a long‐lived mammal. Associations between reproduction and survival are positive in early life, but negative in later life with up to 71% of later‐life survival declines associated with investing in the production of offspring within this population of this critically endangered species.}, author = {Robinson, Matthew Richard and Mar, Khyne U and Lummaa, Virpi}, issn = {1461-023X}, journal = {Ecology Letters}, number = {3}, pages = {260--266}, publisher = {Wiley}, title = {{Senescence and age-specific trade-offs between reproduction and survival in female Asian elephants}}, doi = {10.1111/j.1461-0248.2011.01735.x}, volume = {15}, year = {2012}, } @article{7748, abstract = {Female mate choice acts as an important evolutionary force, yet the influence of the environment on both its expression and the selective pressures acting upon it remains unknown. We found consistent heritable differences between females in their choice of mate based on ornament size during a 25‐year study of a population of collared flycatchers. However, the fitness consequences of mate choice were dependent on environmental conditions experienced whilst breeding. Females breeding with highly ornamented males experienced high relative fitness during dry summer conditions, but low relative fitness during wetter years. Our results imply that sexual selection within a population can be highly variable and dependent upon the prevailing weather conditions experienced by individuals.}, author = {Robinson, Matthew Richard and Sander van Doorn, G. and Gustafsson, Lars and Qvarnström, Anna}, issn = {1461-023X}, journal = {Ecology Letters}, number = {6}, pages = {611--618}, publisher = {Wiley}, title = {{Environment-dependent selection on mate choice in a natural population of birds}}, doi = {10.1111/j.1461-0248.2012.01780.x}, volume = {15}, year = {2012}, } @article{7776, abstract = {We present an analysis of finite-size effects in jammed packings of N soft, frictionless spheres at zero temperature. There is a 1/N correction to the discrete jump in the contact number at the transition so that jammed packings exist only above isostaticity. As a result, the canonical power-law scalings of the contact number and elastic moduli break down at low pressure. These quantities exhibit scaling collapse with a nontrivial scaling function, demonstrating that the jamming transition can be considered a phase transition. Scaling is achieved as a function of N in both two and three dimensions, indicating an upper critical dimension of 2.}, author = {Goodrich, Carl Peter and Liu, Andrea J. and Nagel, Sidney R.}, issn = {0031-9007}, journal = {Physical Review Letters}, number = {9}, publisher = {American Physical Society}, title = {{Finite-size scaling at the jamming transition}}, doi = {10.1103/physrevlett.109.095704}, volume = {109}, year = {2012}, } @article{801, abstract = {Fungal cell walls frequently contain a polymer of mannose and galactose called galactomannan. In the pathogenic filamentous fungus Aspergillus fumigatus, this polysaccharide is made of a linear mannan backbone with side chains of galactofuran and is anchored to the plasma membrane via a glycosylphosphatidylinositol or is covalently linked to the cell wall. To date, the biosynthesis and significance of this polysaccharide are unknown. The present data demonstrate that deletion of the Golgi UDP-galactofuranose transporter GlfB or the GDP-mannose transporter GmtA leads to the absence of galactofuran or galactomannan, respectively. This indicates that the biosynthesis of galactomannan probably occurs in the lumen of the Golgi apparatus and thus contrasts with the biosynthesis of other fungal cell wall polysaccharides studied to date that takes place at the plasma membrane. Transglycosylation of galactomannan from the membrane to the cell wall is hypothesized because both the cell wall-bound and membrane-bound polysaccharide forms are affected in the generated mutants. Considering the severe growth defect of the A. fumigatus GmtA-deficient mutant, proving this paradigm might provide new targets for antifungal therapy.}, author = {Engel, Jakob and Schmalhorst, Philipp S and Routier, Françoise}, journal = {Journal of Biological Chemistry}, number = {53}, pages = {44418 -- 44424}, publisher = {American Society for Biochemistry and Molecular Biology}, title = {{Biosynthesis of the fungal cell wall polysaccharide galactomannan requires intraluminal GDP-mannose}}, doi = {10.1074/jbc.M112.398321}, volume = {287}, year = {2012}, } @article{8024, abstract = {In dynamical models of cortical networks, the recurrent connectivity can amplify the input given to the network in two distinct ways. One is induced by the presence of near-critical eigenvalues in the connectivity matrix W, producing large but slow activity fluctuations along the corresponding eigenvectors (dynamical slowing). The other relies on W not being normal, which allows the network activity to make large but fast excursions along specific directions. Here we investigate the trade-off between non-normal amplification and dynamical slowing in the spontaneous activity of large random neuronal networks composed of excitatory and inhibitory neurons. We use a Schur decomposition of W to separate the two amplification mechanisms. Assuming linear stochastic dynamics, we derive an exact expression for the expected amount of purely non-normal amplification. We find that amplification is very limited if dynamical slowing must be kept weak. We conclude that, to achieve strong transient amplification with little slowing, the connectivity must be structured. We show that unidirectional connections between neurons of the same type together with reciprocal connections between neurons of different types, allow for amplification already in the fast dynamical regime. Finally, our results also shed light on the differences between balanced networks in which inhibition exactly cancels excitation and those where inhibition dominates.}, author = {Hennequin, Guillaume and Vogels, Tim P and Gerstner, Wulfram}, issn = {1539-3755}, journal = {Physical Review E}, number = {1}, publisher = {American Physical Society}, title = {{Non-normal amplification in random balanced neuronal networks}}, doi = {10.1103/physreve.86.011909}, volume = {86}, year = {2012}, } @article{808, abstract = {Using correlated live-cell imaging and electron tomography we found that actin branch junctions in protruding and treadmilling lamellipodia are not concentrated at the front as previously supposed, but link actin filament subsets in which there is a continuum of distances from a junction to the filament plus ends, for up to at least 1 mm. When branch sites were observed closely spaced on the same filament their separation was commonly a multiple of the actin helical repeat of 36 nm. Image averaging of branch junctions in the tomograms yielded a model for the in vivo branch at 2.9 nm resolution, which was comparable with that derived for the in vitro actin- Arp2/3 complex. Lamellipodium initiation was monitored in an intracellular wound-healing model and was found to involve branching from the sides of actin filaments oriented parallel to the plasmalemma. Many filament plus ends, presumably capped, terminated behind the lamellipodium tip and localized on the dorsal and ventral surfaces of the actin network. These findings reveal how branching events initiate and maintain a network of actin filaments of variable length, and provide the first structural model of the branch junction in vivo. A possible role of filament capping in generating the lamellipodium leaflet is discussed and a mathematical model of protrusion is also presented.}, author = {Vinzenz, Marlene and Nemethova, Maria and Schur, Florian and Mueller, Jan and Narita, Akihiro and Urban, Edit and Winkler, Christoph and Schmeiser, Christian and Koestler, Stefan and Rottner, Klemens and Resch, Guenter and Maéda, Yuichiro and Small, John}, journal = {Journal of Cell Science}, number = {11}, pages = {2775 -- 2785}, publisher = {Company of Biologists}, title = {{Actin branching in the initiation and maintenance of lamellipodia}}, doi = {10.1242/jcs.107623}, volume = {125}, year = {2012}, } @article{8246, abstract = {The Staphylococcus aureus cell wall stress stimulon (CWSS) is activated by cell envelope-targeting antibiotics or depletion of essential cell wall biosynthesis enzymes. The functionally uncharacterized S. aureus LytR-CpsA-Psr (LCP) proteins, MsrR, SA0908 and SA2103, all belong to the CWSS. Although not essential, deletion of all three LCP proteins severely impairs cell division. We show here that VraSR-dependent CWSS expression was up to 250-fold higher in single, double and triple LCP mutants than in wild type S. aureus in the absence of external stress. The LCP triple mutant was virtually depleted of wall teichoic acids (WTA), which could be restored to different degrees by any of the single LCP proteins. Subinhibitory concentrations of tunicamycin, which inhibits the first WTA synthesis enzyme TarO (TagO), could partially complement the severe growth defect of the LCP triple mutant. Both of the latter findings support a role for S. aureus LCP proteins in late WTA synthesis, as in Bacillus subtilis where LCP proteins were recently proposed to transfer WTA from lipid carriers to the cell wall peptidoglycan. Intrinsic activation of the CWSS upon LCP deletion and the fact that LCP proteins were essential for WTA-loading of the cell wall, highlight their important role(s) in S. aureus cell envelope biogenesis.}, author = {Dengler, Vanina and Meier, Patricia Stutzmann and Heusser, Ronald and Kupferschmied, Peter and Fazekas, Judit and Friebe, Sarah and Staufer, Sibylle Burger and Majcherczyk, Paul A. and Moreillon, Philippe and Berger-Bächi, Brigitte and McCallum, Nadine}, issn = {0378-1097}, journal = {FEMS Microbiology Letters}, number = {2}, pages = {109--120}, publisher = {Oxford University Press}, title = {{Deletion of hypothetical wall teichoic acid ligases in Staphylococcus aureus activates the cell wall stress response}}, doi = {10.1111/j.1574-6968.2012.02603.x}, volume = {333}, year = {2012}, } @article{826, abstract = {Plants exhibit a unique developmental flexibility to ever-changing environmental conditions. To achieve their profound adaptability, plants are able to maintain permanent stem cell populations and form new organs during the entire plant life cycle. Signaling substances, called plant hormones, such as auxin, cytokinin, abscisic acid, brassinosteroid, ethylene, gibberellin, jasmonic acid, and strigolactone, govern and coordinate these developmental processes. Physiological and genetic studies have dissected the molecular components of signal perception and transduction of the individual hormonal pathways. However, over recent years it has become evident that hormones do not act only in a linear pathway. Hormonal pathways are interconnected by a complex network of interactions and feedback circuits that determines the final outcome of the individual hormone actions. This raises questions about the molecular mechanisms underlying hormonal cross talk and about how these hormonal networks are established, maintained, and modulated throughout plant development.}, author = {Vanstraelen, Marleen and Eva Benková}, journal = {Annual Review of Cell and Developmental Biology}, pages = {463 -- 487}, publisher = {Annual Reviews}, title = {{Hormonal interactions in the regulation of plant development}}, doi = {10.1146/annurev-cellbio-101011-155741}, volume = {28}, year = {2012}, } @article{829, abstract = {The architecture of a plant's root system, established postembryonically, results from both coordinated root growth and lateral root branching. The plant hormones auxin and cytokinin are central endogenous signaling molecules that regulate lateral root organogenesis positively and negatively, respectively. Tight control and mutual balance of their antagonistic activities are particularly important during the early phases of lateral root organogenesis to ensure continuous lateral root initiation (LRI) and proper development of lateral root primordia (LRP). Here, we show that the early phases of lateral root organogenesis, including priming and initiation, take place in root zones with a repressed cytokinin response. Accordingly, ectopic overproduction of cytokinin in the root basal meristem most efficiently inhibits LRI. Enhanced cytokinin responses in pericycle cells between existing LRP might restrict LRI near existing LRP and, when compromised, ectopic LRI occurs. Furthermore, our results demonstrate that young LRP are more sensitive to perturbations in the cytokinin activity than are developmentally more advanced primordia. We hypothesize that the effect of cytokinin on the development of primordia possibly depends on the robustness and stability of the auxin gradient.}, author = {Bielach, Agnieszka and Podlesakova, Katerina and Peter Marhavy and Duclercq, Jérôme and Candela Cuesta and Muller, Bruno and Grunewald, Wim and Tarkowski, Petr and Eva Benková}, journal = {The Plant Cell}, number = {10}, pages = {3967 -- 3981}, publisher = {American Society of Plant Biologists}, title = {{Spatiotemporal regulation of lateral root organogenesis in Arabidopsis by cytokinin}}, doi = {10.1105/tpc.112.103044}, volume = {24}, year = {2012}, } @article{846, abstract = {Whether or not evolutionary change is inherently irreversible remains a controversial topic. Some examples of evolutionary irreversibility are known; however, this question has not been comprehensively addressed at the molecular level. Here, we use data from 221 human genes with known pathogenic mutations to estimate the rate of irreversibility in protein evolution. For these genes, we reconstruct ancestral amino acid sequences along the mammalian phylogeny and identify ancestral amino acid states that match known pathogenic mutations. Such cases represent inherent evolutionary irreversibility because, at the present moment, reversals to these ancestral amino acid states are impossible for the human lineage. We estimate that approximately 10% of all amino acid substitutions along the mammalian phylogeny are irreversible, such that a return to the ancestral amino acid state would lead to a pathogenic phenotype. For a subset of 51 genes with high rates of irreversibility, as much as 40% of all amino acid evolution was estimated to be irreversible. Because pathogenic phenotypes do not resemble ancestral phenotypes, the molecular nature of the high rate of irreversibility in proteins is best explained by evolution with a high prevalence of compensatory, epistatic interactions between amino acid sites. Under such mode of protein evolution, once an amino acid substitution is fixed, the probability of its reversal declines as the protein sequence accumulates changes that affect the phenotypic manifestation of the ancestral state. The prevalence of epistasis in evolution indicates that the observed high rate of irreversibility in protein evolution is an inherent property of protein structure and function.}, author = {Soylemez, Onuralp and Fyodor Kondrashov}, journal = {Genome Biology and Evolution}, number = {12}, pages = {1213 -- 1222}, publisher = {Oxford University Press}, title = {{Estimating the rate of irreversibility in protein evolution}}, doi = {10.1093/gbe/evs096}, volume = {4}, year = {2012}, } @article{8463, abstract = {The 1H dipolar network, which is the major obstacle for applying proton detection in the solid-state, can be reduced by deuteration, employing the RAP (Reduced Adjoining Protonation) labeling scheme, which yields random protonation at non-exchangeable sites. We present here a systematic study on the optimal degree of random sidechain protonation in RAP samples as a function of the MAS (magic angle spinning) frequency. In particular, we compare 1H sensitivity and linewidth of a microcrystalline protein, the SH3 domain of chicken α-spectrin, for samples, prepared with 5–25 % H2O in the E. coli growth medium, in the MAS frequency range of 20–60 kHz. At an external field of 19.96 T (850 MHz), we find that using a proton concentration between 15 and 25 % in the M9 medium yields the best compromise in terms of sensitivity and resolution, with an achievable average 1H linewidth on the order of 40–50 Hz. Comparing sensitivities at a MAS frequency of 60 versus 20 kHz, a gain in sensitivity by a factor of 4–4.5 is observed in INEPT-based 1H detected 1D 1H,13C correlation experiments. In total, we find that spectra recorded with a 1.3 mm rotor at 60 kHz have almost the same sensitivity as spectra recorded with a fully packed 3.2 mm rotor at 20 kHz, even though ~20× less material is employed. The improved sensitivity is attributed to 1H line narrowing due to fast MAS and to the increased efficiency of the 1.3 mm coil.}, author = {Asami, Sam and Szekely, Kathrin and Schanda, Paul and Meier, Beat H. and Reif, Bernd}, issn = {0925-2738}, journal = {Journal of Biomolecular NMR}, number = {2}, pages = {155--168}, publisher = {Springer Nature}, title = {{Optimal degree of protonation for 1H detection of aliphatic sites in randomly deuterated proteins as a function of the MAS frequency}}, doi = {10.1007/s10858-012-9659-9}, volume = {54}, year = {2012}, } @article{8465, abstract = {We demonstrate that conformational exchange processes in proteins on microsecond-to-millisecond time scales can be detected and quantified by solid-state NMR spectroscopy. We show two independent approaches that measure the effect of conformational exchange on transverse relaxation parameters, namely Carr–Purcell–Meiboom–Gill relaxation-dispersion experiments and measurement of differential multiple-quantum coherence decay. Long coherence lifetimes, as required for these experiments, are achieved by the use of highly deuterated samples and fast magic-angle spinning. The usefulness of the approaches is demonstrated by application to microcrystalline ubiquitin. We detect a conformational exchange process in a region of the protein for which dynamics have also been observed in solution. Interestingly, quantitative analysis of the data reveals that the exchange process is more than 1 order of magnitude slower than in solution, and this points to the impact of the crystalline environment on free energy barriers.}, author = {Tollinger, Martin and Sivertsen, Astrid C. and Meier, Beat H. and Ernst, Matthias and Schanda, Paul}, issn = {0002-7863}, journal = {Journal of the American Chemical Society}, number = {36}, pages = {14800--14807}, publisher = {American Chemical Society}, title = {{Site-resolved measurement of microsecond-to-millisecond conformational-exchange processes in proteins by solid-state NMR spectroscopy}}, doi = {10.1021/ja303591y}, volume = {134}, year = {2012}, } @article{8466, abstract = {Recent advances in NMR spectroscopy and the availability of high magnetic field strengths now offer the possibility to record real-time 3D NMR spectra of short-lived protein states, e.g., states that become transiently populated during protein folding. Here we present a strategy for obtaining sequential NMR assignments as well as atom-resolved information on structural and dynamic features within a folding intermediate of the amyloidogenic protein β2-microglobulin that has a half-lifetime of only 20 min.}, author = {Rennella, Enrico and Cutuil, Thomas and Schanda, Paul and Ayala, Isabel and Forge, Vincent and Brutscher, Bernhard}, issn = {0002-7863}, journal = {Journal of the American Chemical Society}, number = {19}, pages = {8066--8069}, publisher = {American Chemical Society}, title = {{Real-time NMR characterization of structure and dynamics in a transiently populated protein folding intermediate}}, doi = {10.1021/ja302598j}, volume = {134}, year = {2012}, } @article{8467, abstract = {Partial deuteration is a powerful tool to increase coherence life times and spectral resolution in proton solid-state NMR. The J coupling to deuterium needs, however, to be decoupled to maintain the good resolution in the (usually indirect) 13C dimension(s). We present a simple and reversible way to expand a commercial 1.3 mm HCN MAS probe with a 2H channel with sufficient field strength for J-decoupling of deuterium, namely 2–3 kHz. The coil is placed at the outside of the stator and requires no significant modifications to the probe. The performance and the realizable gains in sensitivity and resolution are demonstrated using perdeuterated ubiquitin, with selectively CHD2-labeled methyl groups.}, author = {Huber, Matthias and With, Oliver and Schanda, Paul and Verel, René and Ernst, Matthias and Meier, Beat H.}, issn = {1090-7807}, journal = {Journal of Magnetic Resonance}, pages = {76--80}, publisher = {Elsevier}, title = {{A supplementary coil for 2H decoupling with commercial HCN MAS probes}}, doi = {10.1016/j.jmr.2011.10.010}, volume = {214}, year = {2012}, } @article{8502, abstract = {The famous ergodic hypothesis suggests that for a typical Hamiltonian on a typical energy surface nearly all trajectories are dense. KAM theory disproves it. Ehrenfest (The Conceptual Foundations of the Statistical Approach in Mechanics. Ithaca, NY: Cornell University Press, 1959) and Birkhoff (Collected Math Papers. Vol 2, New York: Dover, pp 462–465, 1968) stated the quasi-ergodic hypothesis claiming that a typical Hamiltonian on a typical energy surface has a dense orbit. This question is wide open. Herman (Proceedings of the International Congress of Mathematicians, Vol II (Berlin, 1998). Doc Math 1998, Extra Vol II, Berlin: Int Math Union, pp 797–808, 1998) proposed to look for an example of a Hamiltonian near H0(I)=⟨I,I⟩2 with a dense orbit on the unit energy surface. In this paper we construct a Hamiltonian H0(I)+εH1(θ,I,ε) which has an orbit dense in a set of maximal Hausdorff dimension equal to 5 on the unit energy surface.}, author = {Kaloshin, Vadim and Saprykina, Maria}, issn = {0010-3616}, journal = {Communications in Mathematical Physics}, keywords = {Mathematical Physics, Statistical and Nonlinear Physics}, number = {3}, pages = {643--697}, publisher = {Springer Nature}, title = {{An example of a nearly integrable Hamiltonian system with a trajectory dense in a set of maximal Hausdorff dimension}}, doi = {10.1007/s00220-012-1532-x}, volume = {315}, year = {2012}, } @article{858, abstract = {ackground: The evolution and genomic stop codon frequencies have not been rigorously studied with the exception of coding of non-canonical amino acids. Here we study the rate of evolution and frequency distribution of stop codons in bacterial genomes.Results: We show that in bacteria stop codons evolve slower than synonymous sites, suggesting the action of weak negative selection. However, the frequency of stop codons relative to genomic nucleotide content indicated that this selection regime is not straightforward. The frequency of TAA and TGA stop codons is GC-content dependent, with TAA decreasing and TGA increasing with GC-content, while TAG frequency is independent of GC-content. Applying a formal, analytical model to these data we found that the relationship between stop codon frequencies and nucleotide content cannot be explained by mutational biases or selection on nucleotide content. However, with weak nucleotide content-dependent selection on TAG, -0.5 < Nes < 1.5, the model fits all of the data and recapitulates the relationship between TAG and nucleotide content. For biologically plausible rates of mutations we show that, in bacteria, TAG stop codon is universally associated with lower fitness, with TAA being the optimal for G-content < 16% while for G-content > 16% TGA has a higher fitness than TAG.Conclusions: Our data indicate that TAG codon is universally suboptimal in the bacterial lineage, such that TAA is likely to be the preferred stop codon for low GC content while the TGA is the preferred stop codon for high GC content. The optimization of stop codon usage may therefore be useful in genome engineering or gene expression optimization applications.Reviewers: This article was reviewed by Michail Gelfand, Arcady Mushegian and Shamil Sunyaev. For the full reviews, please go to the Reviewers' Comments section.}, author = {Povolotskaya, Inna and Fyodor Kondrashov and Ledda, Alice and Vlasov, Peter K}, journal = {Biology Direct}, publisher = {BioMed Central}, title = {{Stop codons in bacteria are not selectively equivalent}}, doi = {10.1186/1745-6150-7-30}, volume = {7}, year = {2012}, } @article{900, abstract = {The main forces directing long-term molecular evolution remain obscure. A sizable fraction of amino-acid substitutions seem to be fixed by positive selection, but it is unclear to what degree long-term protein evolution is constrained by epistasis, that is, instances when substitutions that are accepted in one genotype are deleterious in another. Here we obtain a quantitative estimate of the prevalence of epistasis in long-term protein evolution by relating data on amino-acid usage in 14 organelle proteins and 2 nuclear-encoded proteins to their rates of short-term evolution. We studied multiple alignments of at least 1,000 orthologues for each of these 16 proteins from species from a diverse phylogenetic background and found that an average site contained approximately eight different amino acids. Thus, without epistasis an average site should accept two-fifths of all possible amino acids, and the average rate of amino-acid substitutions should therefore be about three-fifths lower than the rate of neutral evolution. However, we found that the measured rate of amino-acid substitution in recent evolution is 20 times lower than the rate of neutral evolution and an order of magnitude lower than that expected in the absence of epistasis. These data indicate that epistasis is pervasive throughout protein evolution: about 90 per cent of all amino-acid substitutions have a neutral or beneficial impact only in the genetic backgrounds in which they occur, and must therefore be deleterious in a different background of other species. Our findings show that most amino-acid substitutions have different fitness effects in different species and that epistasis provides the primary conceptual framework to describe the tempo and mode of long-term protein evolution.}, author = {Breen, Michael S and Kemena, Carsten and Vlasov, Peter K and Notredame, Cédric and Fyodor Kondrashov}, journal = {Nature}, number = {7421}, pages = {535 -- 538}, publisher = {Nature Publishing Group}, title = {{Epistasis as the primary factor in molecular evolution}}, doi = {10.1038/nature11510}, volume = {490}, year = {2012}, }