Origins Research Articles

Unveiling human origins of replication using deep learning: accurate prediction and comprehensive analysis.

Accurate identification of replication origins (ORIs) is crucial for a comprehensive investigation into the progression of human cell growth and cancer therapy. Here, we proposed a computational approach Ori-FinderH, which can efficiently and precisely predict the human ORIs of various lengths by combining the Z-curve method with deep learning approach. Compared with existing methods, Ori-FinderH exhibits superior performance, achieving an area under the receiver operating characteristic curve (AUC) of 0.9616 for K562 cell line in 10-fold cross-validation. In addition, we also established a cross-cell-line predictive model, which yielded a further improved AUC of 0.9706. The model was subsequently employed as a fitness function to support genetic algorithm for generating artificial ORIs. Sequence analysis through iORI-Euk revealed that a vast majority of the created sequences, specifically 98% or more, incorporate at least one ORI for three cell lines (Hela, MCF7 and K562). This innovative approach could provide more efficient, accurate and comprehensive information for experimental investigation, thereby further advancing the development of this field.

Accurate Identification of DNA Replication Origin by Fusing Epigenomics and Chromatin Interaction Information

DNA replication initiation is a complex process involving various genetic and epigenomic signatures. The correct identification of replication origins (ORIs) could provide important clues for the study of a variety of diseases caused by replication. Here, we design a computational approach named iORI-Epi to recognize ORIs by incorporating epigenome-based features, sequence-based features, and 3D genome-based features. The iORI-Epi displays excellent robustness and generalization ability on both training datasets and independent datasets of K562 cell line. Further experiments confirm that iORI-Epi is highly scalable in other cell lines (MCF7 and HCT116). We also analyze and clarify the regulatory role of epigenomic marks, DNA motifs, and chromatin interaction in DNA replication initiation of eukaryotic genomes. Finally, we discuss gene enrichment pathways from the perspective of ORIs in different replication timing states and heuristically dissect the effect of promoters on replication initiation. Our computational methodology is worth extending to ORI identification in other eukaryotic species.

The Telomeric Protein TRF2 Regulates Replication Origin Activity within Pericentromeric Heterochromatin.

Heterochromatic regions render the replication process particularly difficult due to the high level of chromatin compaction and the presence of repeated DNA sequences. In humans, replication through pericentromeric heterochromatin requires the binding of a complex formed by the telomeric factor TRF2 and the helicase RTEL1 in order to relieve topological barriers blocking fork progression. Since TRF2 is known to bind the Origin Replication Complex (ORC), we hypothesized that this factor could also play a role at the replication origins (ORI) of these heterochromatin regions. By performing DNA combing analysis, we found that the ORI density is higher within pericentromeric satellite DNA repeats than within bulk genomic DNA and decreased upon TRF2 downregulation. Moreover, we showed that TRF2 and ORC2 interact in pericentromeric DNA, providing a mechanism by which TRF2 is involved in ORI activity. Altogether, our findings reveal an essential role for TRF2 in pericentromeric heterochromatin replication by regulating both replication initiation and elongation.

A deep learning framework combined with word embedding to identify DNA replication origins

The DNA replication influences the inheritance of genetic information in the DNA life cycle. As the distribution of replication origins (ORIs) is the major determinant to precisely regulate the replication process, the correct identification of ORIs is significant in giving an insightful understanding of DNA replication mechanisms and the regulatory mechanisms of genetic expressions. For eukaryotes in particular, multiple ORIs exist in each of their gene sequences to complete the replication in a reasonable period of time. To simplify the identification process of eukaryote’s ORIs, most of existing methods are developed by traditional machine learning algorithms, and target to the gene sequences with a fixed length. Consequently, the identification results are not satisfying, i.e. there is still great room for improvement. To break through the limitations in previous studies, this paper develops sequence segmentation methods, and employs the word embedding technique, ‘Word2vec’, to convert gene sequences into word vectors, thereby grasping the inner correlations of gene sequences with different lengths. Then, a deep learning framework to perform the ORI identification task is constructed by a convolutional neural network with an embedding layer. On the basis of the analysis of similarity reduction dimensionality diagram, Word2vec can effectively transform the inner relationship among words into numerical feature. For four species in this study, the best models are obtained with the overall accuracy of 0.975, 0.765, 0.885, 0.967, the Matthew’s correlation coefficient of 0.940, 0.530, 0.771, 0.934, and the AUC of 0.975, 0.800, 0.888, 0.981, which indicate that the proposed predictor has a stable ability and provide a high confidence coefficient to classify both of ORIs and non-ORIs. Compared with state-of-the-art methods, the proposed predictor can achieve ORI identification with significant improvement. It is therefore reasonable to anticipate that the proposed method will make a useful high throughput tool for genome analysis.

Computational prediction of species-specific yeast DNA replication origin via iterative feature representation.

Deoxyribonucleic acid replication is one of the most crucial tasks taking place in the cell, and it has to be precisely regulated. This process is initiated in the replication origins (ORIs), and thus it is essential to identify such sites for a deeper understanding of the cellular processes and functions related to the regulation of gene expression. Considering the important tasks performed by ORIs, several experimental and computational approaches have been developed in the prediction of such sites. However, existing computational predictors for ORIs have certain curbs, such as building only single-feature encoding models, limited systematic feature engineering efforts and failure to validate model robustness. Hence, we developed a novel species-specific yeast predictor called yORIpred that accurately identify ORIs in the yeast genomes. To develop yORIpred, we first constructed optimal 40 baseline models by exploring eight different sequence-based encodings and five different machine learning classifiers. Subsequently, the predicted probability of 40 models was considered as the novel feature vector and carried out iterative feature learning approach independently using five different classifiers. Our systematic analysis revealed that the feature representation learned by the support vector machine algorithm (yORIpred) could well discriminate the distribution characteristics between ORIs and non-ORIs when compared with the other four algorithms. Comprehensive benchmarking experiments showed that yORIpred achieved superior and stable performance when compared with the existing predictors on the same training datasets. Furthermore, independent evaluation showcased the best and accurate performance of yORIpred thus underscoring the significance of iterative feature representation. To facilitate the users in obtaining their desired results without undergoing any mathematical, statistical or computational hassles, we developed a web server for the yORIpred predictor, which is available at: http://thegleelab.org/yORIpred.

Comprehensive Analysis of Replication Origins in Saccharomyces cerevisiae Genomes.

DNA replication initiates from multiple replication origins (ORIs) in eukaryotes. Discovery and characterization of replication origins are essential for a better understanding of the molecular mechanism of DNA replication. In this study, the features of autonomously replicating sequences (ARSs) in Saccharomyces cerevisiae have been comprehensively analyzed as follows. Firstly, we carried out the analysis of the ARSs available in S. cerevisiae S288C. By evaluating the sequence similarity of experimentally established ARSs, we found that 94.32% of ARSs are unique across the whole genome of S. cerevisiae S288C and those with high sequence similarity are prone to locate in subtelomeres. Subsequently, we built a non-redundant dataset with a total of 520 ARSs, which are based on ARSs annotation of S. cerevisiae S288C from SGD and then supplemented with those from OriDB and DeOri databases. We conducted a large-scale comparison of ORIs among the diverse budding yeast strains from a population genomics perspective. We found that 82.7% of ARSs are not only conserved in genomic sequence but also relatively conserved in chromosomal position. The non-conserved ARSs tend to distribute in the subtelomeric regions. We also conducted a pan-genome analysis of ARSs among the S. cerevisiae strains, and a total of 183 core ARSs existing in all yeast strains were determined. We extracted the genes adjacent to replication origins among the 104 yeast strains to examine whether there are differences in their gene functions. The result showed that the genes involved in the initiation of DNA replication, such as orc3, mcm2, mcm4, mcm6, and cdc45, are conservatively located adjacent to the replication origins. Furthermore, we found the genes adjacent to conserved ARSs are significantly enriched in DNA binding, enzyme activity, transportation, and energy, whereas for the genes adjacent to non-conserved ARSs are significantly enriched in response to environmental stress, metabolites biosynthetic process and biosynthesis of antibiotics. In general, we characterized the replication origins from the genome-wide and population genomics perspectives, which would provide new insights into the replication mechanism of S. cerevisiae and facilitate the design of algorithms to identify genome-wide replication origins in yeast.

Differences in firing efficiency, chromatin, and transcription underlie the developmental plasticity of the Arabidopsis DNA replication origins.

Eukaryotic genome replication depends on thousands of DNA replication origins (ORIs). A major challenge is to learn ORI biology in multicellular organisms in the context of growing organs to understand their developmental plasticity. We have identified a set of ORIs of Arabidopsis thaliana and their chromatin landscape at two stages of post-embryonic development. ORIs associate with multiple chromatin signatures including transcription start sites (TSS) but also proximal and distal regulatory regions and heterochromatin, where ORIs colocalize with retrotransposons. In addition, quantitative analysis of ORI activity led us to conclude that strong ORIs have high GC content and clusters of GGN trinucleotides. Development primarily influences ORI firing strength rather than ORI location. ORIs that preferentially fire at early developmental stages colocalize with GC-rich heterochromatin, but at later stages with transcribed genes, perhaps as a consequence of changes in chromatin features associated with developmental processes. Our study provides the set of ORIs active in an organism at the post-embryo stage that should allow us to study ORI biology in response to development, environment, and mutations with a quantitative approach. In a wider scope, the computational strategies developed here can be transferred to other eukaryotic systems.

Retrotransposons are specified as DNA replication origins in the gene-poor regions of Arabidopsis heterochromatin.

Genomic stability depends on faithful genome replication. This is achieved by the concerted activity of thousands of DNA replication origins (ORIs) scattered throughout the genome. The DNA and chromatin features determining ORI specification are not presently known. We have generated a high-resolution genome-wide map of 3230 ORIs in cultured Arabidopsis thaliana cells. Here, we focused on defining the features associated with ORIs in heterochromatin. In pericentromeric gene-poor domains ORIs associate almost exclusively with the retrotransposon class of transposable elements (TEs), in particular of the Gypsy family. ORI activity in retrotransposons occurs independently of TE expression and while maintaining high levels of H3K9me2 and H3K27me1, typical marks of repressed heterochromatin. ORI-TEs largely colocalize with chromatin signatures defining GC-rich heterochromatin. Importantly, TEs with active ORIs contain a local GC content higher than the TEs lacking them. Our results lead us to conclude that ORI colocalization with retrotransposons is determined by their transposition mechanism based on transcription, and a specific chromatin landscape. Our detailed analysis of ORIs responsible for heterochromatin replication has implications on the mechanisms of ORI specification in other multicellular organisms in which retrotransposons are major components of heterochromatin and of the entire genome.

Transcriptionally Driven DNA Replication Program of the Human Parasite Leishmania major

Faithful inheritance of eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins (ORIs). Although origin firing is mechanistically conserved, how origins are specified and selected for activation varies across different model systems. Here, we provide a complete analysis of the nucleosomal landscape and replication program of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of the L.major genome and that both the spatial and the temporal program of DNA replication can be explained as associated to RNA polymerase kinetics. This simple scenario likely provides flexibility and robustness to deal with the environmental changes that impose alterations in the genetic programs during parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance.

Nucleosome architecture throughout the cell cycle.

Nucleosomes provide additional regulatory mechanisms to transcription and DNA replication by mediating the access of proteins to DNA. During the cell cycle chromatin undergoes several conformational changes, however the functional significance of these changes to cellular processes are largely unexplored. Here, we present the first comprehensive genome-wide study of nucleosome plasticity at single base-pair resolution along the cell cycle in Saccharomyces cerevisiae. We determined nucleosome organization with a specific focus on two regulatory regions: transcription start sites (TSSs) and replication origins (ORIs). During the cell cycle, nucleosomes around TSSs display rearrangements in a cyclic manner. In contrast to gap (G1 and G2) phases, nucleosomes have a fuzzier organization during S and M phases, Moreover, the choreography of nucleosome rearrangements correlate with changes in gene expression during the cell cycle, indicating a strong association between nucleosomes and cell cycle-dependent gene functionality. On the other hand, nucleosomes are more dynamic around ORIs along the cell cycle, albeit with tighter regulation in early firing origins, implying the functional role of nucleosomes on replication origins. Our study provides a dynamic picture of nucleosome organization throughout the cell cycle and highlights the subsequent impact on transcription and replication activity.

Recent advances in the genome-wide study of DNA replication origins in yeast.

DNA replication, one of the central events in the cell cycle, is the basis of biological inheritance. In order to be duplicated, a DNA double helix must be opened at defined sites, which are called DNA replication origins (ORIs). Unlike in bacteria, where replication initiates from a single replication origin, multiple origins are utilized in the eukaryotic genomes. Among them, the ORIs in budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe have been best characterized. In recent years, advances in DNA microarray and next-generation sequencing technologies have increased the number of yeast species involved in ORIs research dramatically. The ORIs in some non-conventional yeast species such as Kluyveromyces lactis and Pichia pastoris have also been genome-widely identified. Relevant databases of replication origins in yeast were constructed, then the comparative genomic analysis can be carried out. Here, we review several experimental approaches that have been used to map replication origins in yeast and some of the available web resources related to yeast ORIs. We also discuss the sequence characteristics and chromosome structures of ORIs in the four yeast species, which can be utilized to improve yeast replication origins prediction.

Genome-wide mapping of human DNA-replication origins: Levels of transcription at ORC1 sites regulate origin selection and replication timing

We report the genome-wide mapping of ORC1 binding sites in mammals, by chromatin immunoprecipitation and parallel sequencing (ChIP-seq). ORC1 binding sites in HeLa cells were validated as active DNA replication origins (ORIs) using Repli-seq, a method that allows identification of ORI-containing regions by parallel sequencing of temporally ordered replicating DNA. ORC1 sites were universally associated with transcription start sites (TSSs) of coding or noncoding RNAs (ncRNAs). Transcription levels at the ORC1 sites directly correlated with replication timing, suggesting the existence of two classes of ORIs: those associated with moderate/high transcription levels (≥1 RNA copy/cell), firing in early S and mapping to the TSSs of coding RNAs; and those associated with low transcription levels (<1 RNA copy/cell), firing throughout the entire S and mapping to TSSs of ncRNAs. These findings are compatible with a scenario whereby TSS expression levels influence the efficiency of ORC1 recruitment at G1 and the probability of firing during S.

Lagrangian coherent structures in the ocean favorable for fishery

Regions rich in nutrients with food grounds for zooplankton, the main feeding resource of pelagic fish, are locations of fishing grounds. Favorable condi� tions are usually formed in the subarctic frontal zones at the boundaries between cold and warm currents and in the periphery of mesoscale eddies. These are regions with high mechanical energy and intense horizontal mixing, in which phytoplankton, the food for zoop� lankton, can concentrate. Numerous investigations in different seas and oceans confirm that fronts and eddies are formations in which favorable conditions are formed for reproduction of plankton and growth of fish [1–3]. In the northwestern part of the Pacific Ocean east of Hokkaido Island (Japan) and the South� ern Kuril Islands, the waters of the cold subarctic Oyashio Current mix with the waters of the warm Kuroshio Current. Owing to the high concentration of nutrients in the cold waters of the Oyashio and high tides facilitating reproduction of phytoplankton in the surface waters, this region is known as one of the rich� est fishing locations in the world. The objective of this work is to distinguish the Lagrangian coherent structures in the ocean at the fronts (boundaries between the waters of different ori� gins), along which favorable conditions for fishery are formed. In the language of the theory of dynamic sys� tems, these structures are called unstable manifolds of hyperbolic points of nonstationary flow. The geo� strophic velocity field was calculated from the data of satellite altimetry. By calculating the displacements D of a large number of particles during a specific time period, one can plot a synoptic chart of this value for any region in which the fronts and the curves of the local minimum of D are clearly pronounced that visu� alize the strongest unstable manifolds in the region. It is shown in this paper that the vessels with the maximum catches of saury in the fall of 2002 and 2004 were located mainly along the unstable manifold depicting the Oyashio front at that period of time. We solve the equation for the advection of a passive admixture

Religion and Schools in a Liquid World

This study is an exploration of the changing contex ts within which schools are required to function. As global borders have become more porous schools are challenged to deal with students from increasingly diverse cultural, linguistic and religious backgrounds, frequently in a political context that is explicitly secular or nondenominati onal. This perspective may not be perceived by all to be as neutral as is sometimes claimed. Our ever-d eveloping technologies, more accessible than ever before, have eliminated many knowledge barriers and created unprecedented awareness of global movements and events. Fewer people live isolated fr om world affairs and this increased knowledge has created a greater sensitivity to human rights. A he ightened rights consciousness has emerged, leading to demands in the areas of education, relig ion, tolerance and the manner in which these constructs are dealt with in schools. There is a gr owing awareness of the geopolitical dangers associated with fundamentalism, whatever their orig ins. This is allied to an appreciation that an educated populace contributes significantly to not only the economic well-being of individual nations but also exhibits the deeper knowledge and understa ndings essential to peace and harmony between peoples of differing backgrounds and diverse religi ous values and beliefs. In our attempts to further democracy, respect pluralism and develop more open and tolerant communities what policies will best inform practice in our schools? How can we prepare and support teachers and administrators so that the underlying values of these policies can be prac ticed and taught in our schools?

Nucleosomal organization of replication origins and meiotic recombination hotspots in fission yeast

In Schizosaccharomyces pombe, DNA replication origins (ORIs) and meiotic recombination hotspots lack consensus sequences and show a bias towards mapping to large intergenic regions (IGRs). To explore whether this preference depended on underlying chromatin features, we have generated genome-wide nucleosome profiles during mitosis and meiosis. We have found that meiotic double-strand break sites (DSBs) colocalize with nucleosome-depleted regions (NDRs) and that large IGRs include clusters of NDRs that overlap with almost half of all DSBs. By contrast, ORIs do not colocalize with NDRs and they are regulated independently of DSBs. Physical relocation of NDRs at ectopic loci or modification of their genomic distribution during meiosis was paralleled by the generation of new DSB sites. Over 80% of all meiotic DSBs colocalize with NDRs that are also present during mitosis, indicating that the recombination pattern is largely dependent on constitutive properties of the genome and, to a lesser extent, on the transcriptional profile during meiosis. The organization of ORIs and of DSBs regions in S. pombe reveals similarities and differences relative to Saccharomyces cerevisiae.

Structural diversity and dynamics of genomic replication origins in Schizosaccharomyces pombe

DNA replication origins (ORI) in Schizosaccharomyces pombe colocalize with adenine and thymine (A+T)-rich regions, and earlier analyses have established a size from 0.5 to over 3 kb for a DNA fragment to drive replication in plasmid assays. We have asked what are the requirements for ORI function in the chromosomal context. By designing artificial ORIs, we have found that A+T-rich fragments as short as 100 bp without homology to S. pombe DNA are able to initiate replication in the genome. On the other hand, functional dissection of endogenous ORIs has revealed that some of them span a few kilobases and include several modules that may be as short as 25-30 contiguous A+Ts capable of initiating replication from ectopic chromosome positions. The search for elements with these characteristics across the genome has uncovered an earlier unnoticed class of low-efficiency ORIs that fire late during S phase. These results indicate that ORI specification and dynamics varies widely in S. pombe, ranging from very short elements to large regions reminiscent of replication initiation zones in mammals.

The impact of nucleosome positioning on the organization of replication origins in eukaryotes

The distribution of DNA replication origins (ORIs) on eukaryotic chromosomes is nonrandom, but the reasons behind this are not well understood. Previous studies have suggested a prominent role of transcriptional activity in determining the ORI organization. Here, we identify nucleosome occupancy as a likely candidate to set up ORI distribution. Combining genome-wide data on nucleosome positioning and ORI organization in yeast and humans, we demonstrate that open chromatin domains, characterized by nucleosome depletion, are preferentially permissive for replication. However, contrary to priori claims, the impact of transcriptional activity is considerably weaker than previously proposed and could partly be explained by our nucleosome exclusion model. We propose that the ORI organization imposed by nucleosome positioning is phylogenetically widespread in eukaryotes.

Transcription Initiation Activity Sets Replication Origin Efficiency in Mammalian Cells

Genomic mapping of DNA replication origins (ORIs) in mammals provides a powerful means for understanding the regulatory complexity of our genome. Here we combine a genome-wide approach to identify preferential sites of DNA replication initiation at 0.4% of the mouse genome with detailed molecular analysis at distinct classes of ORIs according to their location relative to the genes. Our study reveals that 85% of the replication initiation sites in mouse embryonic stem (ES) cells are associated with transcriptional units. Nearly half of the identified ORIs map at promoter regions and, interestingly, ORI density strongly correlates with promoter density, reflecting the coordinated organisation of replication and transcription in the mouse genome. Detailed analysis of ORI activity showed that CpG island promoter-ORIs are the most efficient ORIs in ES cells and both ORI specification and firing efficiency are maintained across cell types. Remarkably, the distribution of replication initiation sites at promoter-ORIs exactly parallels that of transcription start sites (TSS), suggesting a co-evolution of the regulatory regions driving replication and transcription. Moreover, we found that promoter-ORIs are significantly enriched in CAGE tags derived from early embryos relative to all promoters. This association implies that transcription initiation early in development sets the probability of ORI activation, unveiling a new hallmark in ORI efficiency regulation in mammalian cells.

"A Reverent and Obedient Evolution": Jonathan Edwards, the New Science, and the Socialism of Henry James Sr.

Unlike other nineteenth-century critics of Darwin?who cherished a six day creation and the fixity and permanence of species and who were repulsed by the relegation of Adam and Eve to the status of apes?Henry James Sr. was a religious socialist who believed that evolutionary science had little relevant to say about true origins, which he construed to emerge exclusively through a process of creation. He therefore sub sumed the ideas of Darwin, Huxley, and their scientific forerunners within the edifices of Berkeleyan idealism and Swedenborgian spiritualism that accommodated in renovated form, at least to James's satisfaction, the tangible foundations and ultimate grandeur of evolutionary theories con structed by naturalists. James's philosophy of spiritual creation and ori gins sidestepped the evolutionary descent of multiple species from simpler common ancestors; nor, as scholarship has shown, was James troubled by theories concerning descent, mutation, natural selection, adaptation, and extinction.1 For James, true origins result from spiritual evolution, an idea according to which a phenomenalistic universe awaits spiritual creation and redemption via the infusion (or communication, as James would have phrased it) of preexisting true Being into the vacant, provisional forms that

The Red Notebook by Arantxa Urretabizkaia, Kristin Addis

are earth's plague, rotten. The earth would be calmer if it were green less,without thisfury,thisblindwill that consumes everything but craves more...." This beautifullywritten, deeply disturbing vision has precedents in Merce Rodoreda's earlier fiction, and Tennent's translation will inter est readers takenwith The Time of theDoves. Death in Springwill also intrigue those who appreciate sur realist or experimental art, for the plasticity of itsdescriptions evokes comparisons to visual artists who were contemporaries of Rodoreda, such as Frida Kahlo, Louise Bour geois, Georgia O'Keefe, orRemedios Varo. The book itself is a pleasure to (be)hold. Open Letter has pro vided a beautiful setting fora trans lation so successful that one scarcely recalls that thenovel was written in another language. [Editorialnote:For more fictionby Rodoreda, see the short storyon page 57 of this issue.] GeraldineC. Nichols UniversityofFlorida Teresa Solana. A Not So Perfect Crime. Peter Bush, tr. London. Bitter Lemon (Consortium, distr.).2009 (?2008). 286 pages. $14.95. isbn978-1-904738-34-3 After winning the 2007 Brigada 21 prize forbest crimenovel inCatalan and enjoying translated success, A Not So PerfectCrime sets the stage for a series of comic novels featur ing detectives Borja and his brother Eduard. Unfortunately, the title as translated invites the comment that thebook should be called "a not so perfect crime novel." Because the author's intent seems to be more to satirize Barcelona society than to create yet another mystery, it takes quite a while to get moving. We are 122 pages in before the body hits the floor and, even after that, TERESA SOLANA -r MURDER AND MAYHEM IN BARCELONA the background stories and digres sions regularly interrupt. Sometimes these are entertaining,but often they make one impatient to get on with the story. The unlikely private eyes are twinswho pretend not to be twins and conceal their lower-class ori gins. Borja has a married mistress and a dalliance with the narrator's sister-in-law. Eduard's relationship with his wife complicates almost every attempt at detecting because she does not know he and his broth er are detectives. Borja, a sort of Poirot with a shortage of graymat ter,seems tobe in thedetecting busi ness to tease money out of high-soci ety clients and enjoy the good life. He bumbles more than he deduces and with a lotof luck talkshimself out of various pickles. Eduard seems to be in the business because Borja talkedhim into it. None of this has anything to do with the crime. A prominent politician's wife is poisoned with a marron glace that arrives anony mously in a gift box on Christmas day. The politician has a mistress, of course, and ironically hired the E brothers to discover whether his E wife was having an affairwith a E Catalan painter who never actually E appears inperson in thebook. After E about 250 pages, the solution to the E crime pops up abruptly and eas- E ily.The killer confesses quickly and E conveniently. A reader with famil- E iaritywith themerry-go-round of E Catalan politics and societypresum- E ably finds numerous inside jokes, E but most of thesewould be lost on E outsiders. The book is not without E itsmoments, however. The dialogue E is often funny, the situations hilari- E ous, and the characters similar to E theexaggerated typeswe enjoy in a E Kaufman and Hart play. E /. Madison Davis E UniversityofOklahoma E Arantxa Urretabizkaia. The Red Note- E book. Kristin Addis, tr. Reno. Center for E Basque Studies, University of Nevada. E 2008. 126 pages. $19.95. isbn 978-1-| 877802-82-9 1 Itwill come as no surprise to any E reader familiar with the political E situation in the Basque Country to E learn that the theme of politics is E never far from the surface of con- E temporary Basque fiction.What is E trulystriking, however, is thedegree E of subtlety and nuance with which E the most able writers in Euskara E have dealt with such a vexing and E complex topic.While Arantxa Urre- E tabizkaia isperhaps lesswell known E outside the Basque Country than E her peers such as Bernardo Atxaga E...