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Plos Genetics : the Wilms Tumor Gene, Wt1, is Critical for Mouse S...

By: Nicholas Hastie

Description : Azoospermia is one of the major reproductive disorders which cause male infertility in humans: however, the etiology of this disease is largely unknown. In the present study, six missense mutations of WT1 gene were detected in 529 human patients with non-obstructive azoospermia (NOA), indicating a strong association between WT1 mutation and NOA. The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. To exa...

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Plos Genetics : Differential Genetic Associations for Systemic Lup...

By: Paul I. W. De Bakker

Description : Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,0...

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Plos Genetics : Novel Loci for Adiponectin Levels and Their Influe...

By: Peter M. Visscher

Description : Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (...

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Plos Genetics : Deposition of Histone Variant H2A.Z Within Gene Bo...

By: Tetsuji Kakutani

Description : The regulation of eukaryotic chromatin relies on interactions between many epigenetic factors, including histone modifications, DNA methylation, and the incorporation of histone variants. H2A.Z, one of the most conserved but enigmatic histone variants that is enriched at the transcriptional start sites of genes, has been implicated in a variety of chromosomal processes. Recently, we reported a genome-wide anticorrelation between H2A.Z and DNA methylation, a...

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Plos Genetics : a Negative Feedback Loop That Limits the Ectopic A...

By: William F. Burkholder

Description : Two highly similar RNA polymerase sigma subunits, sF and sG, govern the early and late phases of forespore-specific gene expression during spore differentiation in Bacillus subtilis. sF drives synthesis of sG but the latter only becomes active once engulfment of the forespore by the mother cell is completed, its levels rising quickly due to a positive feedback loop. The mechanisms that prevent premature or ectopic activation of sG while discriminating betwe...

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Plos Genetics : the Sumo Isopeptidase Ulp2P is Required to Prevent...

By: Orna Cohen-fix

Description : SUMO conjugation is a key regulator of the cellular response to DNA replication stress, acting in part to control recombination at stalled DNA replication forks. Here we examine recombination-related phenotypes in yeast mutants defective for the SUMO de-conjugating/chain-editing enzyme Ulp2p. We find that spontaneous recombination is elevated in ulp2 strains and that recombination DNA repair is essential for ulp2 survival. In contrast to other SUMO pathway ...

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Plos Genetics : Allelic Exchange of Pheromones and Their Receptors...

By: Susan K. Dutcher

Description : Cell type specification is a fundamental process that all cells must carry out to ensure appropriate behaviors in response to environmental stimuli. In fungi, cell identity is critical for defining ‘‘sexes’’ known as mating types and is controlled by components of mating type (MAT) loci. MAT–encoded genes function to define sexes via two distinct paradigms : 1) by controlling transcription of components common to both sexes, or 2) by expressing specially en...

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Plos Genetics : Distinct Cdk1 Requirements During Single-strand An...

By: Sue Biggins

Description : Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) in haploid cells is generally restricted to S/ G2 cell cycle phases, when DNA has been replicated and a sister chromatid is available as a repair template. This cell cycle specificity depends on cyclin-dependent protein kinases (Cdk1 in Saccharomyces cerevisiae), which initiate HR by promoting 59–39 nucleolytic degradation of the DSB ends. Whether Cdk1 regulates other HR steps is unk...

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Plos Genetics : Genetic Interactions of Maf1Identify a Role for Me...

By: Michael Snyder

Description : Transcriptional repression of ribosomal components and tRNAs is coordinately regulated in response to a wide variety of environmental stresses. Part of this response involves the convergence of different nutritional and stress signaling pathways on Maf1, a protein that is essential for repressing transcription by RNA polymerase (pol) III in Saccharomyces cerevisiae. Here we identify the functions buffering yeast cells that are unable to down-regulate transc...

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Plos Genetics : Evolutionary Dynamics of Human Toll-like Receptors...

By: Gil McVean

Description : Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Tolllike receptors (TLRs) appear to play a major role in initiating innate immune responses against mi...

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Plos Genetics : Evidence for Pervasive Adaptive Protein Evolution ...

By: Michael W. Nachman

Description : The relative contributions of neutral and adaptive substitutions to molecular evolution has been one of the most controversial issues in evolutionary biology for more than 40 years. The analysis of within-species nucleotide polymorphism and between-species divergence data supports a widespread role for adaptive protein evolution in certain taxa. For example, estimates of the proportion of adaptive amino acid substitutions (a) are 50% or more in enteric bact...

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Plos Genetics : No Influence of Indy on Lifespan in Drosophila Aft...

By: Stuart K. Kim

Description : To investigate whether alterations in mitochondrial metabolism affect longevity in Drosophila melanogaster, we studied lifespan in various single gene mutants, using inbred and outbred genetic backgrounds. As positive controls we included the two most intensively studied mutants of Indy, which encodes a Drosophila Krebs cycle intermediate transporter. It has been reported that flies heterozygous for these Indy mutations, which lie outside the coding region,...

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Plos Genetics : Dynamics of Brassinosteroid Response Modulated by ...

By: Jia Qu

Description : Brassinosteroids (BRs) regulate rice plant architecture, including leaf bending, which affects grain yield. Although BR signaling has been investigated in Arabidopsis thaliana, the components negatively regulating this pathway are less well understood. Here, we demonstrate that Oryza sativa LEAF and TILLER ANGLE INCREASED CONTROLLER (LIC) acts as an antagonistic transcription factor of BRASSINAZOLE-RESISTANT 1 (BZR1) to attenuate the BR signaling pathway. T...

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Plos Genetics : Stretching the Rules ; Monocentric Chromosomes wit...

By: Beth A. Sullivan

Description : The centromere is a functional chromosome domain that is essential for faithful chromosome segregation during cell division and that can be reliably identified by the presence of the centromere-specific histone H3 variant CenH3. In monocentric chromosomes, the centromere is characterized by a single CenH3-containing region within a morphologically distinct primary constriction. This region usually spans up to a few Mbp composed mainly of centromere-specific...

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Plos Genetics : the Impact of Recombination on Nucleotide Substitu...

By: Molly Przeworski

Description : Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GCcontent (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-...

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Plos Genetics : the Phylogenetic Origin of Oskar Coincided with th...

By: Artyom Kopp

Description : The establishment of the germline is a critical, yet surprisingly evolutionarily labile, event in the development of sexually reproducing animals. In the fly Drosophila, germ cells acquire their fate early during development through the inheritance of the germ plasm, a specialized maternal cytoplasm localized at the posterior pole of the oocyte. The gene oskar (osk) is both necessary and sufficient for assembling this substance. Both maternal germ plasm and...

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Plos Genetics : Metabolic Actions of Estrogen Receptor Beta Erb Ar...

By: Johan Auwerx

Description : Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERa seems to have a protective role in such diseases, the function of ERb is not clear. To characterize the metabolic function of ERb, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARc, in vitro and in high-fat diet (HFD)-fed ERb -/- mice (bERKO) mice. Our in vitro experi...

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Plos Genetics : Aging and Chronic Sun Exposure Cause Distinct Epig...

By: Wolf Reik

Description : Epigenetic changes are widely considered to play an important role in aging, but experimental evidence to support this hypothesis has been scarce. We have used array-based analysis to determine genome-scale DNA methylation patterns from human skin samples and to investigate the effects of aging, chronic sun exposure, and tissue variation. Our results reveal a high degree of tissue specificity in the methylation patterns and also showed very little interindi...

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Plos Genetics : Polyglutamine Toxicity is Controlled by Prion Comp...

By: Tricia R. Serio

Description : Polyglutamine expansion causes diseases in humans and other mammals. One example is Huntington’s disease. Fragments of human huntingtin protein having an expanded polyglutamine stretch form aggregates and cause cytotoxicity in yeast cells bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline(P)-rich region targets polyglutamines to the large perinuclear deposit (aggresome). Aggresome formation ameliorates polyglutamin...

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Plos Genetics : Role of Pirh2 in Mediating the Regulation of P53 a...

By: Marshall S. Horwitz

Description : Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c- Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation...

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