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PLoS Genetics

Marah C Runtsch, Morgan C Nelson, Soh-Hyun Lee, Warren Voth, Margaret Alexander, Ruozhen Hu, Jared Wallace, Charisse Petersen, Vanja Panic, Claudio J Villanueva, Kimberley J Evason, Kaylyn M Bauer, Timothy Mosbruger, Sihem Boudina, Mary Bronner, June L Round, Micah J Drummond, Ryan M O'Connell
Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways...
February 15, 2019: PLoS Genetics
Dmytro Kryvokhyzha, Adriana Salcedo, Mimmi C Eriksson, Tianlin Duan, Nilesh Tawari, Jun Chen, Maria Guerrina, Julia M Kreiner, Tyler V Kent, Ulf Lagercrantz, John R Stinchcombe, Sylvain Glémin, Stephen I Wright, Martin Lascoux
Allopolyploidy is generally perceived as a major source of evolutionary novelties and as an instantaneous way to create isolation barriers. However, we do not have a clear understanding of how two subgenomes evolve and interact once they have fused in an allopolyploid species nor how isolated they are from their relatives. Here, we address these questions by analyzing genomic and transcriptomic data of allotetraploid Capsella bursa-pastoris in three differentiated populations, Asia, Europe, and the Middle East...
February 15, 2019: PLoS Genetics
José I Rojas Echenique, Sergey Kryazhimskiy, Alex N Nguyen Ba, Michael M Desai
Screens for epistatic interactions have long been used to characterize functional relationships corresponding to protein complexes, metabolic pathways, and other functional modules. Although epistasis between adaptive mutations is also common in laboratory evolution experiments, the functional basis for these interactions is less well characterized. Here, we quantify the extent to which gene function (as determined by a genome-wide screen for epistasis among deletion mutants) influences the rate and genetic basis of compensatory adaptation in a set of 37 gene deletion mutants nested within 16 functional modules...
February 15, 2019: PLoS Genetics
Linwei Li, Guozhu Ning, Shuyan Yang, Yifang Yan, Yu Cao, Qiang Wang
Pharyngeal pouches, a series of outpocketings that bud from the foregut endoderm, are essential to the formation of craniofacial skeleton as well as several important structures like parathyroid and thymus. However, whether pharyngeal pouch progenitors exist in the developing gut tube remains unknown. Here, taking advantage of cell lineage tracing and transgenic ablation technologies, we identified a population of nkx2.3+ pouch progenitors in zebrafish embryos and demonstrated an essential requirement of ectodermal BMP2b for their specification...
February 14, 2019: PLoS Genetics
Veroni S Sri Theivakadadcham, Benjamin G Bergey, Emanuel Rosonina
Sequence-specific transcription factors (TFs) represent one of the largest groups of proteins that is targeted for SUMO post-translational modification, in both yeast and humans. SUMO modification can have diverse effects, but recent studies showed that sumoylation reduces the interaction of multiple TFs with DNA in living cells. Whether this relates to a general role for sumoylation in TF binding site selection, however, has not been fully explored because few genome-wide studies aimed at studying such a role have been reported...
February 14, 2019: PLoS Genetics
Laura Ariza, Anabel Rojas, Ramón Muñoz-Chápuli, Rita Carmona
The Wilms' tumor suppressor gene (Wt1) encodes a zinc finger transcription factor that plays an essential role in the development of kidneys, gonads, spleen, adrenals and heart. Recent findings suggest that WT1 could also be playing physiological roles in adults. Systemic deletion of WT1 in mice provokes a severe deterioration of the exocrine pancreas, with mesothelial disruption, E-cadherin downregulation, disorganization of acinar architecture and accumulation of ascitic transudate. Despite this extensive damage, pancreatic stellate cells do not become activated and lose their canonical markers...
February 14, 2019: PLoS Genetics
Neha Varshney, Subhendu Som, Saptarshi Chatterjee, Shreyas Sridhar, Dibyendu Bhattacharyya, Raja Paul, Kaustuv Sanyal
The nuclear division takes place in the daughter cell in the basidiomycetous budding yeast Cryptococcus neoformans. Unclustered kinetochores gradually cluster and the nucleus moves to the daughter bud as cells enter mitosis. Here, we show that the evolutionarily conserved Aurora B kinase Ipl1 localizes to the nucleus upon the breakdown of the nuclear envelope during mitosis in C. neoformans. Ipl1 is shown to be required for timely breakdown of the nuclear envelope as well. Ipl1 is essential for viability and regulates structural integrity of microtubules...
February 14, 2019: PLoS Genetics
Miguel Vasconcelos Almeida, António Miguel de Jesus Domingues, René F Ketting
Endogenous small RNAs (sRNAs) and Argonaute proteins are ubiquitous regulators of gene expression in germline and somatic tissues. sRNA-Argonaute complexes are often expressed in gametes and are consequently inherited by the next generation upon fertilization. In Caenorhabditis elegans, 26G-RNAs are primary endogenous sRNAs that trigger the expression of downstream secondary sRNAs. Two subpopulations of 26G-RNAs exist, each of which displaying strongly compartmentalized expression: one is expressed in the spermatogenic gonad and associates with the Argonautes ALG-3/4; plus another expressed in oocytes and in embryos, which associates with the Argonaute ERGO-1...
February 13, 2019: PLoS Genetics
Helena Cantwell, Paul Nurse
Nuclear size correlates with cell size, but the mechanism by which this scaling is achieved is not known. Here we screen fission yeast gene deletion mutants to identify essential factors involved in this process. Our screen has identified 25 essential factors that alter nuclear size, and our analysis has implicated RNA processing and LINC complexes in nuclear size control. This study has revealed lower and more extreme higher nuclear size phenotypes and has identified global cellular processes and specific structural nuclear components important for nuclear size control...
February 13, 2019: PLoS Genetics
Jing Yuan, Sharon A Kessler
Ovules contain the female gametophytes which are fertilized during pollination to initiate seed development. Thus, the number of ovules that are produced during flower development is an important determinant of seed crop yield and plant fitness. Mutants with pleiotropic effects on development often alter the number of ovules, but specific regulators of ovule number have been difficult to identify in traditional mutant screens. We used natural variation in Arabidopsis accessions to identify new genes involved in the regulation of ovule number...
February 11, 2019: PLoS Genetics
Krishna Reddy Challa, Monalisha Rath, Utpal Nath
Cells in organ primordia undergo active proliferation at an early stage to generate sufficient number, before exiting proliferation and entering differentiation. However, how the actively proliferating cells are developmentally reprogrammed to acquire differentiation potential during organ maturation is unclear. Here, we induced a microRNA-resistant form of TCP4 at various developmental stages of Arabidopsis leaf primordium that lacked the activity of TCP4 and its homologues and followed its effect on growth kinematics...
February 11, 2019: PLoS Genetics
Fitz Gerald S Silao, Meliza Ward, Kicki Ryman, Axel Wallström, Björn Brindefalk, Klas Udekwu, Per O Ljungdahl
Amino acids are among the earliest identified inducers of yeast-to-hyphal transitions in Candida albicans, an opportunistic fungal pathogen of humans. Here, we show that the morphogenic amino acids arginine, ornithine and proline are internalized and metabolized in mitochondria via a PUT1- and PUT2-dependent pathway that results in enhanced ATP production. Elevated ATP levels correlate with Ras1/cAMP/PKA pathway activation and Efg1-induced gene expression. The magnitude of amino acid-induced filamentation is linked to glucose availability; high levels of glucose repress mitochondrial function thereby dampening filamentation...
February 11, 2019: PLoS Genetics
Zanetta Chang, R Blake Billmyre, Soo Chan Lee, Joseph Heitman
Mucormycosis-an emergent, deadly fungal infection-is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug...
February 11, 2019: PLoS Genetics
Jayson Paulose, Joachim Hermisson, Oskar Hallatschek
Adaptation in extended populations often occurs through multiple independent mutations responding in parallel to a common selection pressure. As the mutations spread concurrently through the population, they leave behind characteristic patterns of polymorphism near selected loci-so-called soft sweeps-which remain visible after adaptation is complete. These patterns are well-understood in two limits of the spreading dynamics of beneficial mutations: the panmictic case with complete absence of spatial structure, and spreading via short-ranged or diffusive dispersal events, which tessellates space into distinct compact regions each descended from a unique mutation...
February 11, 2019: PLoS Genetics
Sebastian Scholz, Janys Pleßmann, Balaji Enugutti, Regina Hüttl, Katrin Wassmer, Kay Schneitz
Tissue morphogenesis critically depends on the coordination of cellular growth patterns. In plants, many organs consist of clonally distinct cell layers, such as the epidermis, whose cells undergo divisions that are oriented along the plane of the layer. The developmental control of such planar growth is poorly understood. We have previously identified the Arabidopsis AGCVIII-class protein kinase UNICORN (UCN) as a central regulator of this process. Plants lacking UCN activity show spontaneous formation of ectopic multicellular protrusions in integuments and malformed petals indicating that UCN suppresses uncontrolled growth in those tissues...
February 11, 2019: PLoS Genetics
Tamar Ben-Zvi, Alina Pushkarev, Hemda Seri, Maya Elgrably-Weiss, Kai Papenfort, Shoshy Altuvia
Putrescine belongs to the large group of polyamines, an essential class of metabolites that exists throughout all kingdoms of life. The Salmonella speF gene encodes an inducible ornithine decarboxylase that produces putrescine from ornithine. Putrescine can be also synthesized from arginine in a parallel metabolic pathway. Here, we show that speF expression is controlled at multiple levels through regulatory elements contained in a long leader sequence. At the heart of this regulation is a short open reading frame, orf34, which is required for speF production...
February 11, 2019: PLoS Genetics
Alexandra Bezler, Fabian Braukmann, Sean M West, Arthur Duplan, Raffaella Conconi, Frédéric Schütz, Pierre Gönczy, Fabio Piano, Kristin Gunsalus, Eric A Miska, Laurent Keller
RNA interference (RNAi) related pathways are essential for germline development and fertility in metazoa and can contribute to inter- and trans-generational inheritance. In the nematode Caenorhabditis elegans, environmental double-stranded RNA provided by feeding can lead to heritable changes in phenotype and gene expression. Notably, transmission efficiency differs between the male and female germline, yet the underlying mechanisms remain elusive. Here we use high-throughput sequencing of dissected gonads to quantify sex-specific endogenous piRNAs, miRNAs and siRNAs in the C...
February 8, 2019: PLoS Genetics
Clara Gobé, Maëva Elzaiat, Nicolas Meunier, Marjolaine André, Eli Sellem, Patrice Congar, Luc Jouneau, Aurélie Allais-Bonnet, Ikrame Naciri, Bruno Passet, Eric Pailhoux, Maëlle Pannetier
Gonad differentiation is a crucial step conditioning the future fertility of individuals and most of the master genes involved in this process have been investigated in detail. However, transcriptomic analyses of developing gonads from different animal models have revealed that hundreds of genes present sexually dimorphic expression patterns. DMXL2 was one of these genes and its function in mammalian gonads was unknown. We therefore investigated the phenotypes of total and gonad-specific Dmxl2 knockout mouse lines...
February 8, 2019: PLoS Genetics
Kelvin W Pond, Christelle de Renty, Mary K Yagle, Nathan A Ellis
NSMCE2 is an E3 SUMO ligase and a subunit of the SMC5/6 complex that associates with the replication fork and protects against genomic instability. Here, we study the fate of collapsed replication forks generated by prolonged hydroxyurea treatment in human NSMCE2-deficient cells. Double strand breaks accumulate during rescue by converging forks in normal cells but not in NSMCE2-deficient cells. Un-rescued forks persist into mitosis, leading to increased mitotic DNA damage. Excess RAD51 accumulates and persists at collapsed forks in NSMCE2-deficient cells, possibly due to lack of BLM recruitment to stalled forks...
February 8, 2019: PLoS Genetics
Daniel E Runcie, Lorin Crawford
Linear mixed effect models are powerful tools used to account for population structure in genome-wide association studies (GWASs) and estimate the genetic architecture of complex traits. However, fully-specified models are computationally demanding and common simplifications often lead to reduced power or biased inference. We describe Grid-LMM (, an extendable algorithm for repeatedly fitting complex linear models that account for multiple sources of heterogeneity, such as additive and non-additive genetic variance, spatial heterogeneity, and genotype-environment interactions...
February 8, 2019: PLoS Genetics
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