177 research outputs found
Opposite GC skews at the 5' and 3' ends of genes in unicellular fungi
No full textAbstract Background GC-skews have previously been linked to transcription in some eukaryotes. They have been associated with transcription start sites, with the coding strand G-biased in mammals and C-biased in fungi and invertebrates. Results We show a consistent and highly significant pattern of GC-skew within genes of almost all unicellular fungi. The pattern of GC-skew is asymmetrical: the coding strand of genes is typically C-biased at the 5' ends but G-biased at the 3' ends, with intermediate skews at the middle of genes. Thus, the initiation, elongation, and termination phases of transcription are associated with different skews. This pattern influences the encoded proteins by generating differential usage of amino acids at the 5' and 3' ends of genes. These biases also affect fourfold-degenerate positions and extend into promoters and 3' UTRs, indicating that skews cannot be accounted by selection for protein function or translation. Conclusions We propose two explanations, the mutational pressure hypothesis, and the adaptive hypothesis. The mutational pressure hypothesis is that different co-factors bind to RNA pol II at different phases of transcription, producing different mutational regimes. The adaptive hypothesis is that cytidine triphosphate deficiency may lead to C-avoidance at the 3' ends of transcripts to control the flow of RNA pol II molecules and reduce their frequency of collisions.</p
Computational verification of protein-protein interactions by orthologous co-expression
No full textAbstract Background High-throughput methods identify an overwhelming number of protein-protein interactions. However, the limited accuracy of these methods results in the false identification of many spurious interactions. Accordingly, the resulting interactions are regarded as hypothetical and computational methods are needed to increase their confidence. Several methods have recently been suggested for this purpose including co-expression as a confidence measure for interacting proteins, but their performance is still quite poor. Results We introduce a novel computational method for verification of protein-protein interactions based on the co-expression of orthologs of interacting partners. The performance of our method is analysed using known S. cerevisiae interactions, and is shown to overcome limitations of previous methods. We present specific examples of known and putative interactions that are detected by our method and not by previous methods, and suggest that they represent transient interactions that might have been conserved and stabilized in other species. Conclusion Co-expression of orthologous protein-pairs can be used to increase the confidence of hypothetical protein-protein interactions in S. cerevisiae as well as in other species. This approach may be especially useful for species with no available expression profiles and for transient interactions.</p
Inferring regulatory mechanisms from patterns of evolutionary divergence
No full textAbstract The number of sequenced species is increasing at a staggering rate, calling for new approaches for incorporating evolutionary information in the study of biological mechanisms. Evolutionary conservation is widely used for assigning a function to new proteins and for predicting functional coding or non‐coding sequences. Here, we argue for a complementary approach that focuses on the divergence of regulatory programs. Regulatory mechanisms can be learned from patterns of evolutionary divergence in regulatory properties such as gene expression, transcription factor binding or nucleosome positioning. We review examples of this concept using yeast as a model system, and highlight a hybrid‐based approach that is highly instrumental in this analysis
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On the Infinitary Combinatorics of Small Cardinals and the Cardinality of the Continuum
Get PDFThis work is divided into two parts which are concerned, respectively, with the combinatorics of the cardinals and . The first part of the thesis contains the result due to the author and his advisor, Itay Neeman, that the Abraham-Rubin-Shelah Open Coloring Axiom is consistent with a large continuum; this answers a long-standing open question in forcing. Most of Part 1 appears in our submitted manuscript \cite{GN}. After surveying the relevant background in the first chapter, we proceed in the second chapter to define the notion of a Partition Product. This is a type of iteration built out of smaller ones in specific ways, roughly with memory conditions on the names and with isomorphism and coherence conditions on the various ``memories." We will prove a number of useful facts about partition products in Chapter 2. In Chapter 3, we show how to construct so-called Preassignments of Colors in the context of partition products; this forms the technical heart of Part 1. And finally, in Chapter 4, we show how to construct partition products in ; in particular, we construct the partition product which yields the model witnessing our theorem.Part 2 of the thesis addresses questions about a variety of combinatorial principles on . In each chapter in Part 2, we will be concerned with showing that some amount of Stationary Reflection holds at , more specifically showing that various amounts of stationary reflection are compatible with other principles of wide interest. In Chapter 5, we provide an overview of these combinatorial principles and some of their history; we also spend some time collecting standard facts about Mitchell-type forcings which we will use in the subsequent chapters. Chapter 5 concludes with a proof that various Mitchell-type posets and their quotients are proper, a result which we assume is known, but which we have not encountered ourselves elsewhere.Chapters 6 and 7 address questions arising from the recent paper \emph{The Eightfold Way} by Cummings, Friedman, Magidor, Rinot, and Sinapova (see \cite{8fold}). In Chapter 6, we answer an open question asked at the end of that paper by showing that it is consistent, from a Mahlo cardinal, that the Tree Property (\TP) and Approachability (\AP) both fail at \om_2, while stationary reflection (\RP) holds at . The authors of \cite{8fold} obtained the consistency of this same configuration from a weakly compact cardinal; our result proves the consistency of this configuration from optimal assumptions. We remark here that we present the original proof discovered by the author of this thesis. Later, the author, working with John Krueger, provided a more streamlined proof of this same result; this proof will appear in the forthcoming paper \cite{GiltonKrueger8}. Chapter 6 also includes an unrelated Easton-style lemma for preserving stationary subsets of countable cofinality; this result is due to the author and Omer Ben-Neria.In Chapter 7, we show that for any Boolean combination, , of \TP and \AP, is consistent with a strong form of simultaneous stationary reflection on , namely that every stationary S\seq\om_2\cap\cof(\om) reflects almost everywhere. This strengthens some of the results from \cite{8fold}. In Chapter 8, we return to the model from \cite{GiltonKruegerHS}, making good on a promise from the postscript therein. In \cite{GiltonKruegerHS}, the author and John Krueger originally sought to show that stationary reflection on \om_2 is consistent with a large continuum, and we built an involved mixed-support iteration to achieve such a model. However, we later learned from I. Neeman that such a model can be constructed by simply adding Cohen reals over the original Harrington-Shelah model (\cite{HS}). In Chapter 8 we will show that after a modification of our original preparatory iteration, we may obtain a model in which \RP and \AP both hold, in which 2^\om>\om_2, and in which there are neither special Aronszajn trees on \om_2 nor weak Kurepa trees on . This is a configuration which cannot be obtained simply by adding Cohen reals over the original Harrington-Shelah model nor by the methods of disjoint stationary sequences from \cite{GiltonKrueger8}. We hope that this demonstrates the usefulness of such a mixed support iteration.In the final chapter, we provide a list of open questions which we would like to address in future work
Autocorrelation analysis reveals widespread spatial biases in microarray experiments
No full textAbstract Background DNA microarrays provide the ability to interrogate multiple genes in a single experiment and have revolutionized genomic research. However, the microarray technology suffers from various forms of biases and relatively low reproducibility. A particular source of false data has been described, in which non-random placement of gene probes on the microarray surface is associated with spurious correlations between genes. Results In order to assess the prevalence of this effect and better understand its origins, we applied an autocorrelation analysis of the relationship between chromosomal position and expression level to a database of over 2000 individual yeast microarray experiments. We show that at least 60% of these experiments exhibit spurious chromosomal position-dependent gene correlations, which nonetheless appear in a stochastic manner within each experimental dataset. Using computer simulations, we show that large spatial biases caused in the microarray hybridization step and independently of printing procedures can exclusively account for the observed spurious correlations, in contrast to previous suggestions. Our data suggest that such biases may generate more than 15% false data per experiment. Importantly, spatial biases are expected to occur regardless of microarray design and over a wide range of microarray platforms, organisms and experimental procedures. Conclusions Spatial biases comprise a major source of noise in microarray studies; revision of routine experimental practices and normalizations to account for these biases may significantly and comprehensively improve the quality of new as well as existing DNA microarray data.</p
Coupled evolution of transcription and mRNA degradation.
No full textmRNA levels are determined by the balance between transcription and mRNA degradation, and while transcription has been extensively studied, very little is known regarding the regulation of mRNA degradation and its coordination with transcription. Here we examine the evolution of mRNA degradation rates between two closely related yeast species. Surprisingly, we find that around half of the evolutionary changes in mRNA degradation were coupled to transcriptional changes that exert opposite effects on mRNA levels. Analysis of mRNA degradation rates in an interspecific hybrid further suggests that opposite evolutionary changes in transcription and in mRNA degradation are mechanistically coupled and were generated by the same individual mutations. Coupled changes are associated with divergence of two complexes that were previously implicated both in transcription and in mRNA degradation (Rpb4/7 and Ccr4-Not), as well as with sequence divergence of transcription factor binding motifs. These results suggest that an opposite coupling between the regulation of transcription and that of mRNA degradation has shaped the evolution of gene regulation in yeast
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