Gene Duplication and Environmental Adaptation within Yeast Populations

PublishedPopulation-level differences in the number of copies of genes resulting from gene duplication and loss have recently been recognized as an important source of variation in eukaryotes. However, except for a small number of cases, the phenotypic effects of this variation are unknown. Data from the Saccharomyces Genome Resequencing Project permit the study of duplication in genome sequences from a set of individuals within the same population. These sequences can be correlated with available information on the environments from which these yeast strains were isolated. We find that yeast show an abundance of duplicate genes that are lineage specific, leading to a large degree of variation in gene content between individual strains. There is a detectable bias for specific functions, indicating that selection is acting to preferentially retain certain duplicates. Most strikingly, we find that sets of over- and underrepresented duplicates correlate with the environment from which they were isolated. Together, these observations indicate that gene duplication can give rise to substantial phenotypic differences within populations that in turn can offer a shortcut to evolutionary adaptation.This work was funded by BBSRC grant BB/F007620/1

Radio variability of 1st 3-months Fermi blazars at 5 GHz: affected by interstellar scintillation?

Blazars from the first-three-months Fermi-AGN list were observed with the Urumqi 25m radio telescope at 5GHz in IDV (Intra-Day Variability) mode and inter-month observation mode. A significant correlation between the flux density at 5GHz and the gamma-ray intensity for the Fermi-LAT detected blazars is seen. There is a higher IDV detection rate in Fermi detected blazars than those reported for other samples. Stronger variability appears at lower Galactic latitudes; IDV appears to be stronger in weaker sources, indicating that the variability is affected by interstellar scintillation.Comment: 4 pages, 4 figures, in proceedings of 'Multiwavelength Variability of Blazars' in Guangzhou Uni. of China, 22-24, Sep. 2010, to appear in JA

Instability in a marginal coral reef: the shift from natural variability to a human-dominated seascape

As global climate change drives the demise of tropical reef ecosystems, attention is turning to the suitability o refuge habitat. For the Great Barrier Reef, are there historically stable southern refugia where corals from th north might migrate as climate changes? To address this question, we present a precise chronology of margina coral reef development from Moreton Bay, southeast Queensland, Australia. Our chronology shows that ree growth was episodic, responding to natural environmental variation throughout the Holocene, and tha Moreton Bay was inhospitable to corals for about half of the past 7000 years. The only significant change ii coral species composition occurred between similar to 200 and similar to 50 years ago, following anthropogenic alterations of th, bay and its catchments. Natural historical instability of reefs, coupled with environmental degradation sinc, European colonization, suggests that Moreton Bay offers limited potential as refuge habitat for reef species or human time scales

NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains

Hepatitis C virus (HCV) RNA is synthesized by the replicase complex (RC), a macromolecular assembly composed of viral non-structural proteins and cellular co-factors. Inhibitors of the HCV NS5A protein block formation of new RCs but do not affect RNA synthesis by pre-formed RCs. Without new RC formation, existing RCs turn over and are eventually lost from the cell. We aimed to use NS5A inhibitors to estimate the half-life of the functional RC of HCV. We compared different cell culture-infectious strains of HCV that may be grouped based on their sensitivity to lipid peroxidation: robustly replicating, lipid peroxidation resistant (LPOR) viruses (e.g. JFH-1 or H77D) and more slowly replicating, lipid peroxidation sensitive (LPOS) viruses (e.g. H77S.3 and N.2). In luciferase assays, LPOSHCV strains declined under NS5A inhibitor therapy with much slower kinetics compared to LPORHCV strains. This difference in rate of decline was not observed for inhibitors of the NS5B RNA-dependent RNA polymerase suggesting that the difference was not simply a consequence of differences in RNA stability. In further analyses, we compared two isoclonal HCV variants: the LPOSH77S.3 and the LPORH77D that differ only by 12 amino acids. Differences in rate of decline between H77S.3 and H77D following NS5A inhibitor addition were not due to amino acid sequences in NS5A but rather due to a combination of amino acid differences in the non-structural proteins that make up the HCV RC. Mathematical modeling of intracellular HCV RNA dynamics suggested that differences in RC stability (half-lives of 3.5 and 9.9 hours, for H77D and H77S.3, respectively) are responsible for the different kinetics of antiviral suppression between LPOSand LPORviruses. In nascent RNA capture assays, the rate of RNA synthesis decline following NS5A inhibitor addition was significantly faster for H77D compared to H77S.3 indicating different half-lives of functional RCs

Zinc Overload Enhances APP Cleavage and Aβ Deposition in the Alzheimer Mouse Brain

BACKGROUND: Abnormal zinc homeostasis is involved in β-amyloid (Aβ) plaque formation and, therefore, the zinc load is a contributing factor in Alzheimer's disease (AD). However, the involvement of zinc in amyloid precursor protein (APP) processing and Aβ deposition has not been well established in AD animal models in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, APP and presenilin 1 (PS1) double transgenic mice were treated with a high dose of zinc (20 mg/ml ZnSO4 in drinking water). This zinc treatment increased APP expression, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory in the transgenic mice. We further examined the effects of zinc overload on APP processing in SHSY-5Y cells overexpressing human APPsw. The zinc enhancement of APP expression and cleavage was further confirmed in vitro. CONCLUSIONS/SIGNIFICANCE: The present data indicate that excess zinc exposure could be a risk factor for AD pathological processes, and alteration of zinc homeostasis is a potential strategy for the prevention and treatment of AD

Carbon Monitor Cities, near-real-time daily estimates of CO2 emissions from 1500 cities worldwide

Building on near-real-time and spatially explicit estimates of daily carbon dioxide (CO2) emissions, here we present and analyze a new city-level dataset of fossil fuel and cement emissions. Carbon Monitor Cities provides daily, city-level estimates of emissions from January 2019 through December 2021 for 1500 cities in 46 countries, and disaggregates five sectors: power generation, residential (buildings), industry, ground transportation, and aviation. The goal of this dataset is to improve the timeliness and temporal resolution of city-level emission inventories and includes estimates for both functional urban areas and city administrative areas that are consistent with global and regional totals. Comparisons with other datasets (i.e. CEADs, MEIC, Vulcan, and CDP) were performed, and we estimate the overall uncertainty to be 21.7%. Carbon Monitor Cities is a near-real-time, city-level emission dataset that includes cities around the world, including the first estimates for many cities in low-income countries

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53–PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy

Protein Design Using Continuous Rotamers

Optimizing amino acid conformation and identity is a central problem in computational protein design. Protein design algorithms must allow realistic protein flexibility to occur during this optimization, or they may fail to find the best sequence with the lowest energy. Most design algorithms implement side-chain flexibility by allowing the side chains to move between a small set of discrete, low-energy states, which we call rigid rotamers. In this work we show that allowing continuous side-chain flexibility (which we call continuous rotamers) greatly improves protein flexibility modeling. We present a large-scale study that compares the sequences and best energy conformations in 69 protein-core redesigns using a rigid-rotamer model versus a continuous-rotamer model. We show that in nearly all of our redesigns the sequence found by the continuous-rotamer model is different and has a lower energy than the one found by the rigid-rotamer model. Moreover, the sequences found by the continuous-rotamer model are more similar to the native sequences. We then show that the seemingly easy solution of sampling more rigid rotamers within the continuous region is not a practical alternative to a continuous-rotamer model: at computationally feasible resolutions, using more rigid rotamers was never better than a continuous-rotamer model and almost always resulted in higher energies. Finally, we present a new protein design algorithm based on the dead-end elimination (DEE) algorithm, which we call iMinDEE, that makes the use of continuous rotamers feasible in larger systems. iMinDEE guarantees finding the optimal answer while pruning the search space with close to the same efficiency of DEE. Availability: Software is available under the Lesser GNU Public License v3. Contact the authors for source code

Utilizing mitochondrial events as biomarkers for imaging apoptosis

Cells undergoing apoptosis show a plethora of time-dependent changes. The available tools for imaging apoptosis in live cells rely either on the detection of the activity of caspases, or on the visualization of exposure of phosphatidyl serine in the outer leaflet of the cell membrane. We report here a novel method for the detection of mitochondrial events during apoptosis, namely translocation of Bax to mitochondria and release of cytochrome c (Cyt c) using bimolecular fluorescence complementation. Expression of split yellow fluorescent protein (YFP) fragments fused to Bax and Cyt c, resulted in robust induction of YFP fluorescence at the mitochondria of apoptotic cells with very low background. In vivo expression of split YFP protein fragments in liver hepatocytes and intra-vital imaging of subcutaneous tumor showed elevated YFP fluorescence upon apoptosis induction. Thus, YFP complementation could be applied for high-throughput screening and in vivo molecular imaging of mitochondrial events during apoptosis

Regulating amyloid precursor protein synthesis through an internal ribosomal entry site

Expression of amyloid precursor protein (APP) is critical to the etiology of Alzheimer's disease (AD). Consequently, regulating APP expression is one approach to block disease progression. To this end, APP can be targeted at the levels of transcription, translation, and protein stability. Little is currently known about the translation of APP mRNA. Here, we report that endogenous APP mRNA is translated in neural cell lines via an internal ribosome entry site (IRES) located in the 5′-untranslated leader. The functional unit of the APP IRES is located within the 5′ 50 nucleotides of the 5′-leader. In addition, we found that the APP IRES is positively regulated by two conditions correlated with AD, increased intracellular iron concentration and ischemia. Interestingly, the enhancement of APP IRES activity is dependent upon de novo transcription. Taken together, our data suggest that internal initiation of translation of the APP mRNA is an important mode for synthesis of APP, a mechanism which is regulated by conditions that also contribute to AD