Unique genetic signatures of local adaptation over space and time for diapause, an ecologically relevant complex trait, in < i > Drosophila melanogaster < /i >
by Priscilla A. Erickson, Cory A. Weller, Daniel Y. Song, Alyssa S. Bangerter, Paul Schmidt, Alan O. Bergland Organisms living in seasonally variable environments utilize cues such as light and temperature to induce plastic responses, enabling them to exploit favorable seasons and avoid unfavorable ones. Local adapation can result in variation in seasonal responses, but the genetic basis and evolutionary history of this variation remains elusive. Many insects, includingDrosophila melanogaster, are able to undergo an arrest of reproductive development (diapause) in response to unfavorable conditions. InD.melanogaster, the ...
Source: PLoS Genetics - November 20, 2020 Category: Genetics & Stem Cells Authors: Priscilla A. Erickson Source Type: research

No association between SCN9A and monogenic human epilepsy disorders
by James Fasham, Joseph S. Leslie, Jamie W. Harrison, James Deline, Katie B. Williams, Ashley Kuhl, Jessica Scott Schwoerer, Harold E. Cross, Andrew H. Crosby, Emma L. Baple Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously,SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotyp...
Source: PLoS Genetics - November 20, 2020 Category: Genetics & Stem Cells Authors: James Fasham Source Type: research

Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles
In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants. (Source: PLoS Genetics)
Source: PLoS Genetics - November 20, 2020 Category: Genetics & Stem Cells Authors: Alejandro Martin-Trujillo Source Type: research

< i > Mms19 < /i > promotes spindle microtubule assembly in < i > Drosophila < /i > neural stem cells
by Rohan Chippalkatti, Boris Egger, Beat Suter Mitotic divisions depend on the timely assembly and proper orientation of the mitotic spindle. Malfunctioning of these processes can considerably delay mitosis, thereby compromising tissue growth and homeostasis, and leading to chromosomal instability. Loss of functionalMms19 drastically affects the growth and development of mitotic tissues inDrosophila larvae and we now demonstrate thatMms19 is an important factor that promotes spindle and astral microtubule (MT) growth, and MT stability and bundling.Mms19 function is needed for the coordination of mitotic events and for the...
Source: PLoS Genetics - November 19, 2020 Category: Genetics & Stem Cells Authors: Rohan Chippalkatti Source Type: research

The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice
by Ana Mart ínez-Marchal, Yan Huang, Maria Teresa Guillot-Ferriols, Mònica Ferrer-Roda, Anna Guixé, Montserrat Garcia-Caldés, Ignasi Roig Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in the se processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate ...
Source: PLoS Genetics - November 18, 2020 Category: Genetics & Stem Cells Authors: Ana Mart ínez-Marchal Source Type: research

Stability of SARS-CoV-2 phylogenies
by Yatish Turakhia, Nicola De Maio, Bryan Thornlow, Landen Gozashti, Robert Lanfear, Conor R. Walker, Angie S. Hinrichs, Jason D. Fernandes, Rui Borges, Greg Slodkowicz, Lukas Weilguny, David Haussler, Nick Goldman, Russell Corbett-Detig The SARS-CoV-2 pandemic has led to unprecedented, nearly real-time genetic tracing due to the rapid community sequencing response. Researchers immediately leveraged these data to infer the evolutionary relationships among viral samples and to study key biological questions, including whether host viral genome editing and recombination are features of SARS-CoV-2 evolution. This global sequ...
Source: PLoS Genetics - November 18, 2020 Category: Genetics & Stem Cells Authors: Yatish Turakhia Source Type: research

Inhibition of the < i > de novo < /i > pyrimidine biosynthesis pathway limits ribosomal RNA transcription causing nucleolar stress in glioblastoma cells
In this study, we show that enzymes necessary for thede novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH ’s activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grownin vitro andin vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar o...
Source: PLoS Genetics - November 17, 2020 Category: Genetics & Stem Cells Authors: M. Carmen Lafita-Navarro Source Type: research

Multivariable G-E interplay in the prediction of educational achievement
by Andrea G. Allegrini, Ville Karhunen, Jonathan R. I. Coleman, Saskia Selzam, Kaili Rimfeld, Sophie von Stumm, Jean-Baptiste Pingault, Robert Plomin Polygenic scores are increasingly powerful predictors of educational achievement. It is unclear, however, how sets of polygenic scores, which partly capture environmental effects, perform jointly with sets of environmental measures, which are themselves heritable, in prediction models of education al achievement. Here, for the first time, we systematically investigate gene-environment correlation (rGE) and interaction (GxE) in the joint analysis of multiple genome-wide polyg...
Source: PLoS Genetics - November 17, 2020 Category: Genetics & Stem Cells Authors: Andrea G. Allegrini Source Type: research

Genotype imputation using the Positional Burrows Wheeler Transform
by Simone Rubinacci, Olivier Delaneau, Jonathan Marchini Genotype imputation is the process of predicting unobserved genotypes in a sample of individuals using a reference panel of haplotypes. In the last 10 years reference panels have increased in size by more than 100 fold. Increasing reference panel size improves accuracy of markers with low minor al lele frequencies but poses ever increasing computational challenges for imputation methods. Here we present IMPUTE5, a genotype imputation method that can scale to reference panels with millions of samples. This method continues to refine the observation made in the IMPUTE...
Source: PLoS Genetics - November 16, 2020 Category: Genetics & Stem Cells Authors: Simone Rubinacci Source Type: research

Identity-by-descent with uncertainty characterises connectivity of < i > Plasmodium falciparum < /i > populations on the Colombian-Pacific coast
by Aimee R. Taylor, Diego F. Echeverry, Timothy J. C. Anderson, Daniel E. Neafsey, Caroline O. Buckee Characterising connectivity between geographically separated biological populations is a common goal in many fields. Recent approaches to understanding connectivity between malaria parasite populations, with implications for disease control efforts, have used estimates of relatedness based on iden tity-by-descent (IBD). However, uncertainty around estimated relatedness has not been accounted for. IBD-based relatedness estimates with uncertainty were computed for pairs of monoclonalPlasmodium falciparum samples collected f...
Source: PLoS Genetics - November 16, 2020 Category: Genetics & Stem Cells Authors: Aimee R. Taylor Source Type: research

Two < i > cis < /i > -regulatory SNPs upstream of < i > ABCG2 < /i > synergistically cause the blue eggshell phenotype in the duck
In conclusion, our results suggest that twocis-regulatory SNPs upstream ofABCG2 are the causative mutations for blue eggshells in ducks. The blue eggshell variant up-regulatedABCG2 expression through recruiting CTCF binding, which may function as a barrier element to shield the downstream region from high methylation levels present upstream.ABCG2 was identified as the only candidate causative gene for blue eggshells; it may function as an efflux transporter of biliverdin to the uterine cavity. (Source: PLoS Genetics)
Source: PLoS Genetics - November 13, 2020 Category: Genetics & Stem Cells Authors: Li Chen Source Type: research

Meiosis reveals the early steps in the evolution of a neo-XY sex chromosome pair in the African pygmy mouse < i > Mus minutoides < /i >
by Ana Gil-Fern ández, Paul A. Saunders, Marta Martín-Ruiz, Marta Ribagorda, Pablo López-Jiménez, Daniel L. Jeffries, María Teresa Parra, Alberto Viera, Julio S. Rufas, Nicolas Perrin, Frederic Veyrunes, Jesús Page Sex chromosomes of eutherian mammals are highly different in size and gene content, and share only a small region of homology (pseudoautosomal region, PAR). They are thought to have evolved through an addition-attrition cycle involving the addition of autosomal segments to sex chromosomes and thei r subsequent differentiation. The events that drive this process are diff...
Source: PLoS Genetics - November 12, 2020 Category: Genetics & Stem Cells Authors: Ana Gil-Fern ández Source Type: research

New insights into the function of mammalian Argonaute2
by Marek Marzec Uncovering the mechanisms that recognise a microRNA (miRNA) target is 1 of the biggest challenges because the Ago–miRNA complex is able to overcome different derogations of complementarity when binding targets. However, the recently solved crystallographic structure of Argonaute2 (Ago2) and a hi gh-throughput analysis that used repurposed sequencing techniques has brought us closer to achieving this goal. (Source: PLoS Genetics)
Source: PLoS Genetics - November 12, 2020 Category: Genetics & Stem Cells Authors: Marek Marzec Source Type: research

Phosphoregulation of HORMA domain protein HIM-3 promotes asymmetric synaptonemal complex disassembly in meiotic prophase in < i > Caenorhabditis elegans < /i >
by Aya Sato-Carlton, Chihiro Nakamura-Tabuchi, Xuan Li, Hendrik Boog, Madison K. Lehmer, Scott C. Rosenberg, Consuelo Barroso, Enrique Martinez-Perez, Kevin D. Corbett, Peter Mark Carlton In the two cell divisions of meiosis, diploid genomes are reduced into complementary haploid sets through the discrete, two-step removal of chromosome cohesion, a task carried out in most eukaryotes by protecting cohesion at the centromere until the second division. In eukaryotes without defined c entromeres, however, alternative strategies have been innovated. The best-understood of these is found in the nematodeCaenorhabditis elegans: ...
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Aya Sato-Carlton Source Type: research

Natural variation in the sequestosome-related gene, < i > sqst-5 < /i > , underlies zinc homeostasis in < i > Caenorhabditis elegans < /i >
by Kathryn S. Evans, Stefan Zdraljevic, Lewis Stevens, Kimberly Collins, Robyn E. Tanny, Erik C. Andersen Zinc is an essential trace element that acts as a co-factor for many enzymes and transcription factors required for cellular growth and development. Altering intracellular zinc levels can produce dramatic effects ranging from cell proliferation to cell death. To avoid such fates, cells have evolve d mechanisms to handle both an excess and a deficiency of zinc. Zinc homeostasis is largely maintained via zinc transporters, permeable channels, and other zinc-binding proteins. Variation in these proteins might affect thei...
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Kathryn S. Evans Source Type: research

LabWAS: Novel findings and study design recommendations from a meta-analysis of clinical labs in two independent biobanks
This study provides a proof-of-principle for cross health system GWAS and is a framework for future studies of quantitative EHR lab traits. (Source: PLoS Genetics)
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Jeffery A. Goldstein Source Type: research

Dual use and selection of GmSWEET39 for oil and protein improvement in soybean
by Hengyou Zhang, Wolfgang Goettel, Qijian Song, He Jiang, Zhenbin Hu, Ming Li Wang, Yong-qiang Charles An Soybean [Glycine max (L.) Merr.] was domesticated from wild soybean (G.soja Sieb. and Zucc.) and has been further improved as a dual-use seed crop to provide highly valuable oil and protein for food, feed, and industrial applications. However, the underlying genetic and molecular basis remains less understood. Having combined high-confidence bi-parental linkage mapping with high-resolution association analysis based on 631 whole sequenced genomes, we mapped major soybean protein and oil QTLs on chromosome15 to a suga...
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Hengyou Zhang Source Type: research

Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer
by Zhexu Dong, Lei Dai, Yong Zhang, Chao Fang, Gang Shi, Ye Chen, Junshu Li, Qin Wang, Jiamei Fu, Yan Yu, Wenshuang Wang, Lin Cheng, Yi Liu, Yi Lin, Yuan Wang, Qingnan Wang, Huiling Wang, Hantao Zhang, Yujing Zhang, Xiaolan Su, Shuang Zhang, Feng Wang, Meng Qiu, Zongguang Zhou, Hongxin Deng Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methyl ation data in CRC patients from The Ca...
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Zhexu Dong Source Type: research

The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition
by Gloria Gonzalez Curto, Audrey Der Vartanian, Youcef El-Mokhtar Frarma, Line Manceau, Lorenzo Baldi, Selene Prisco, Nabila Elarouci, Fr édéric Causeret, Daniil Korenkov, Muriel Rigolet, Frédéric Aurade, Aurélien De Reynies, Vincent Contremoulins, Frédéric Relaix, Orestis Faklaris, James Briscoe, Pascale Gilardi-Hebenstreit, Vanessa Ribes The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription fac...
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Gloria Gonzalez Curto Source Type: research

Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects
by Glen B. Banks, Jeffrey S. Chamberlain, Guy L. Odom Gene therapy approaches for DMD using recombinant adeno-associated viral (rAAV) vectors to deliver miniaturized (or micro) dystrophin genes to striated muscles have shown significant progress. However, concerns remain about the potential for immune responses against dystrophin in some patients. Ut rophin, a developmental paralogue of dystrophin, may provide a viable treatment option. Here we examine the functional capacity of an rAAV-mediated microutrophin (μUtrn) therapy in themdx4cv mouse model of DMD. We found that rAAV- μUtrn led to improvement in dystrophic ...
Source: PLoS Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Glen B. Banks Source Type: research

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics
In this study, KMO deficientDrosophila melanogaster were investigated for mitochondrial phenotypesin vitro andin vivo. We find that a loss of function allele or RNAi knockdown of theDrosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably,cinnabar genetically interacts with the Parkinson ’s disease associated genesPink1 andparkin, as well as the mitochondrial fission geneDrp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondr...
Source: PLoS Genetics - November 10, 2020 Category: Genetics & Stem Cells Authors: Daniel C. Maddison Source Type: research

A frog with three sex chromosomes that co-mingle together in nature: < i > Xenopus tropicalis < /i > has a degenerate W and a Y that evolved from a Z chromosome
by Benjamin L. S. Furman, Caroline M. S. Cauret, Martin Knytl, Xue-Ying Song, Tharindu Premachandra, Caleb Ofori-Boateng, Danielle C. Jordan, Marko E. Horb, Ben J. Evans In many species, sexual differentiation is a vital prelude to reproduction, and disruption of this process can have severe fitness effects, including sterility. It is thus interesting that genetic systems governing sexual differentiation vary among—and even within—species. To understand these systems more, we investigated a rare example of a frog with three sex chromosomes: the Western clawed frog,Xenopus tropicalis. We demonstrate that natura...
Source: PLoS Genetics - November 9, 2020 Category: Genetics & Stem Cells Authors: Benjamin L. S. Furman Source Type: research

Formal commentary
by Gustavo D. Aguirre, Hannes Lohi, Maria Kaukonen, Leonardo Murgiano (Source: PLoS Genetics)
Source: PLoS Genetics - November 5, 2020 Category: Genetics & Stem Cells Authors: Gustavo D. Aguirre Source Type: research

The RSC (Remodels the Structure of Chromatin) complex of < i > Candida albicans < /i > shows compositional divergence with distinct roles in regulating pathogenic traits
by Vinutha K. Balachandra, Jiyoti Verma, Madhu Shankar, Timothy M. Tucey, Ana Traven, Ralf B. Schittenhelm, Santanu K. Ghosh Regulation of gene expression programs is crucial for the survival of microbial pathogens in host environments and for their ability to cause disease. Here we investigated the epigenetic regulator RSC (Remodels the Structure of Chromatin) in the most prevalent human fungal pathogenCandida albicans. Biochemical analysis showed that CaRSC comprises 13 subunits and contains two novel non-essential members, which we named Nri1 and Nri2 (Novel RSC Interactors) that are exclusive to the CTG clade ofSaccha...
Source: PLoS Genetics - November 5, 2020 Category: Genetics & Stem Cells Authors: Vinutha K. Balachandra Source Type: research

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease
by Tanja Mederer, Stefanie Schmitteckert, Julia Volz, Cristina Mart ínez, Ralph Röth, Thomas Thumberger, Volker Eckstein, Jutta Scheuerer, Cornelia Thöni, Felix Lasitschka, Leonie Carstensen, Patrick Günther, Stefan Holland-Cunz, Robert Hofstra, Erwin Brosens, Jill A. Rosenfeld, Christian P. Schaaf, Duco Schriemer, Isabella Ceccherini, Marta Rusmini, Joseph Tilg hman, Berta Luzón-Toro, Ana Torroglosa, Salud Borrego, Clara Sze-man Tang, Mercè Garcia-Barceló, Paul Tam, Nagarajan Paramasivam, Melanie Bewerunge-Hudler, Carolina De La Torre, Norbert Gretz, Gudrun A. Rappold, Philipp Ro...
Source: PLoS Genetics - November 5, 2020 Category: Genetics & Stem Cells Authors: Tanja Mederer Source Type: research

The Bric- à-Brac BTB/POZ transcription factors are necessary in niche cells for germline stem cells establishment and homeostasis through control of BMP/DPP signaling in the < i > Drosophila melanogaster < /i > ovary
by Laurine Miscopein Saler, Virginie Hauser, Mathieu Bartoletti, Charlotte Mallart, Marianne Malartre, Laura Lebrun, Anne-Marie Pret, Laurent Th éodore, Fabienne Chalvet, Sophie Netter Many studies have focused on the mechanisms of stem cell maintenancevia their interaction with a particular niche or microenvironment in adult tissues, but how formation of a functional niche is initiated, including how stem cells within a niche are established, is less well understood. AdultDrosophila melanogaster ovary Germline Stem Cell (GSC) niches are comprised of somatic cells forming a stack called a Terminal Filament (TF) and...
Source: PLoS Genetics - November 5, 2020 Category: Genetics & Stem Cells Authors: Laurine Miscopein Saler Source Type: research

Kingdom Come
by Gregory S. Barsh, Gregory P. Copenhaver, Claudia K öhler, Li-Jia Qu (Source: PLoS Genetics)
Source: PLoS Genetics - November 5, 2020 Category: Genetics & Stem Cells Authors: Gregory S. Barsh Source Type: research

Loss of hepatocyte cell division leads to liver inflammation and fibrosis
by Matthew R. Dewhurst, Jin Rong Ow, G özde Zafer, Noémi K. M. van Hul, Heike Wollmann, Xavier Bisteau, David Brough, Hyungwon Choi, Philipp Kaldis The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. He re, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inf...
Source: PLoS Genetics - November 4, 2020 Category: Genetics & Stem Cells Authors: Matthew R. Dewhurst Source Type: research

A genetic variant controls interferon- β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer
by Ana ïs Assouvie, Maxime Rotival, Juliette Hamroune, Didier Busso, Paul-Henri Romeo, Lluis Quintana-Murci, Germain Rousselet Interferon β (IFN-β) is a cytokine that induces a global antiviral proteome, and regulates the adaptive immune response to infections and tumors. Its effects strongly depend on its level and timing of expression. Therefore, the transcription of its coding geneIFNB1 is strictly controlled. We have previously shown that in mice, the TRIM33 protein restrainsIfnb1 transcription in activated myeloid cells through an upstream inhibitory sequence called ICE. Here, we show that the deregula...
Source: PLoS Genetics - November 4, 2020 Category: Genetics & Stem Cells Authors: Ana ïs Assouvie Source Type: research

Mutations in PIH proteins MOT48, TWI1 and PF13 define common and unique steps for preassembly of each, different ciliary dynein
by Ryosuke Yamamoto, Shiho Yanagi, Masahito Nagao, Yuya Yamasaki, Yui Tanaka, Winfield S. Sale, Toshiki Yagi, Takahide Kon Ciliary dyneins are preassembled in the cytoplasm before being transported into cilia, and a family of proteins containing the PIH1 domain, PIH proteins, are involved in the assembly process. However, the functional differences and relationships between members of this family of proteins remain la rgely unknown. UsingChlamydomonas reinhardtii as a model, we isolated and characterized two novelChlamydomonas PIH preassembly mutants,mot48-2 andtwi1-1. A new allele ofmot48 (ida10),mot48-2, shows large def...
Source: PLoS Genetics - November 3, 2020 Category: Genetics & Stem Cells Authors: Ryosuke Yamamoto Source Type: research

A < i > C < /i > . < i > elegans < /i > Zona Pellucida domain protein functions via its ZPc domain
by Jennifer D. Cohen, Jessica G. Bermudez, Matthew C. Good, Meera V. Sundaram Zona Pellucida domain (ZP) proteins are critical components of the body’s external-most protective layers, apical extracellular matrices (aECMs). Although their loss or dysfunction is associated with many diseases, it remains unclear how ZP proteins assemble in aECMs. Current models suggest that ZP proteins polymerize via their ZPn subdomains, while ZPc subdomains modulate ZPn behavior. Using the model organismC.elegans, we investigated the aECM assembly of one ZP protein, LET-653, which shapes several tubes. Contrary to prevailing models,...
Source: PLoS Genetics - November 3, 2020 Category: Genetics & Stem Cells Authors: Jennifer D. Cohen Source Type: research

Genetic compensation prevents myopathy and heart failure in an < i > in vivo < /i > model of Bag3 deficiency
by Federica Diofano, Karolina Weinmann, Isabelle Schneider, Kevin D. Thiessen, Wolfgang Rottbauer, Steffen Just Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in cont...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Federica Diofano Source Type: research

A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse
by Ines Leca, Alexander Phillips, Iris Hofer, Lukas Landler, Lyubov Ushakova, Thomas David Cushion, Gerhard D ürnberger, Karel Stejskal, Karl Mechtler, David Anthony Keays Microtubules play a critical role in multiple aspects of neurodevelopment, including the generation, migration and differentiation of neurons. A recurrent mutation (R402H) in the α-tubulin geneTUBA1A is known to cause lissencephaly with cerebellar and striatal phenotypes. Previous work has shown that this mutation does not perturb the chaperone-mediated folding of tubulin heterodimers, which are able to assemble and incorporate into the micro...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Ines Leca Source Type: research

Inferring causal direction between two traits in the presence of horizontal pleiotropy with GWAS summary data
We report the following new contributions. First, we propose a single SNP-based alternative, overcoming a severe limitation of S teiger’s method in simply assuming, instead of inferring, the existence of a causal relationship. We also clarify a condition necessary for the validity of the methods in the presence of hidden confounding. Second, to improve statistical power, we propose combining the results from multiple, and p ossibly correlated, SNPs as multiple instruments. Third, we develop three goodness-of-fit tests to check modeling assumptions, including those required for valid IVs. Fourth, by relaxing one of th...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Haoran Xue Source Type: research

A pair of ascending neurons in the subesophageal zone mediates aversive sensory inputs-evoked backward locomotion in < i > Drosophila < /i > larvae
by Natsuko Omamiuda-Ishikawa, Moeka Sakai, Kazuo Emoto Animals typically avoid unwanted situations with stereotyped escape behavior. For instance,Drosophila larvae often escape from aversive stimuli to the head, such as mechanical stimuli and blue light irradiation, by backward locomotion. Responses to these aversive stimuli are mediated by a variety of sensory neurons including mechanosensory class III da (C3da) sensory neurons and blue-light responsive class IV da (C4da) sensory neurons and Bolwig ’s organ (BO). How these distinct sensory pathways evoke backward locomotion at the circuit level is still incompletel...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Natsuko Omamiuda-Ishikawa Source Type: research

< i > In vivo < /i > miRNA knockout screening identifies miR-190b as a novel tumor suppressor
by Hui Hong, Shun Yao, Yuanyuan Zhang, Yi Ye, Cheng Li, Liang Hu, Yihua Sun, Hsin-Yi Huang, Hongbin Ji MicroRNAs (miRNAs) play important roles in the development of various cancers including lung cancer which is one of the devastating diseases worldwide. How miRNAs function inde novo lung tumorigenesis remains largely unknown. We here developed a CRISPR/Cas9-mediated dual guide RNA (dgRNA) system to knockout miRNAs in genetically engineered mouse model (GEMM). Through bioinformatic analyses of human lung cancer miRNA database, we identified 16 downregulated miRNAs associated with malignant progression and performed indivi...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Hui Hong Source Type: research

Suppression of retinal degeneration by two novel ERAD ubiquitin E3 ligases SORDD1/2 in < i > Drosophila < /i >
by Jaiwei Xu, Haifang Zhao, Tao Wang Mutations in the gene rhodopsin are one of the major causes of autosomal dominant retinitis pigmentosa (adRP). Mutant forms of Rhodopsin frequently accumulate in the endoplasmic reticulum (ER), cause ER stress, and trigger photoreceptor cell degeneration. Here, we performed a genome-wide screen to identify suppressors of retinal degeneration in aDrosophila model of adRP, carrying a point mutation in the major rhodopsin, Rh1 (Rh1G69D). We identified two novel E3 ubiquitin ligases SORDD1 and SORDD2 that effectively suppressed Rh1G69D-induced photoreceptor dysfunction and retinal degenera...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Jaiwei Xu Source Type: research

Dual genome-wide CRISPR knockout and CRISPR activation screens identify  mechanisms that regulate the resistance to multiple ATR inhibitors
by Emily M. Schleicher, Ashna Dhoonmoon, Lindsey M. Jackson, Kristen E. Clements, Coryn L. Stump, Claudia M. Nicolae, George-Lucian Moldovan The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of the cellular response to DNA damage. Due to increased amount of replication stress, cancer cells heavily rely on ATR to complete DNA replication and cell cycle progression. Thus, ATR inhibition is an emerging tar get in cancer therapy, with multiple ATR inhibitors currently undergoing clinical trials. Here, we describe dual genome-wide CRISPR knockout and CRISPR activation screens employed to compre...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Emily M. Schleicher Source Type: research

Genetic engineering of sex chromosomes for batch cultivation of non-transgenic, sex-sorted males
by Siba R. Das, Maciej Maselko, Ambuj Upadhyay, Michael J. Smanski The field performance of Sterile Insect Technique (SIT) is improved by sex-sorting and releasing only sterile males. This can be accomplished by resource-intensive separation of males from females by morphology. Alternatively, sex-ratio biasing genetic constructs can be used to selectively remove one sex without the need for manual or automated sorting, but the resulting genetically engineered (GE) control agents would be subject to additional governmental regulation. Here we describe and demonstrate a genetic method for the batch production of non-GE male...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Siba R. Das Source Type: research

Differential transcript usage in the Parkinson ’s disease brain
by Fiona Dick, Gonzalo S. Nido, Guido Werner Alves, Ole-Bj ørn Tysnes, Gry Hilde Nilsen, Christian Dölle, Charalampos Tzoulis Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcrip...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Fiona Dick Source Type: research

The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation
by Franck Chesnel, Anne Couturier, Adrien Alusse, Jean-Philippe Gagn é, Guy G. Poirier, Dominique Jean, François-Michel Boisvert, Pauline Hascoet, Luc Paillard, Yannick Arlot-Bonnemains, Xavier Le Goff Loss of von Hippel-Lindau protein pVHL function promotes VHL diseases, including sporadic and inherited clear cell Renal Cell Carcinoma (ccRCC). Mechanisms controlling pVHL function and regulation, including folding and stability, remain elusive. Here, we have identified the conserved cochaperone prefoldin complex in a screen for pVHL interactors. The prefoldin complex delivers non-native proteins to the chape...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Franck Chesnel Source Type: research

Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis
by Damien Garrido, Mohammed Bourouh, Éric Bonneil, Pierre Thibault, Andrew Swan, Vincent Archambault In mitosis and meiosis, chromosome segregation is triggered by the Anaphase-Promoting Complex/Cyclosome (APC/C), a multi-subunit ubiquitin ligase that targets proteins for degradation, leading to the separation of chromatids. APC/C activation requires phosphorylation of its APC3 and APC1 subunits, which allows the APC/C to bind its co-activator Cdc20. The identity of the kinase(s) responsible for APC/C activationin vivo is unclear. Cyclin B3 (CycB3) is an activator of the Cyclin-Dependent Kinase 1 (Cdk1) that is req...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Damien Garrido Source Type: research

Opposing functions of Fng1 and the Rpd3 HDAC complex in H4 acetylation in < i > Fusarium graminearum < /i >
In this study, we identified the ortholog of the human inhibitor of growth (ING1) gene inF.graminearum (FNG1) and found that it specifically interacts with the FgEsa1 HAT of the NuA4 complex. Deletion ofFNG1 led to severe growth defects and blocked conidiation, sexual reproduction, DON production, and plant infection. Thefng1 mutant was normal in H3 acetylation but significantly reduced in H4 acetylation. A total of 34 spontaneous suppressors offng1 with faster growth rate were isolated. Most of them were still defective in sexual reproduction and plant infection. Thirty two of them had mutations in orthologs of yeastRPD3,...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Hang Jiang Source Type: research

Folliculin variants linked to Birt-Hogg-Dub é syndrome are targeted for proteasomal degradation
In conclusion, we propose that most BHD-linkedFLCN missense variants and small in-frame deletions operate by causing misfolding and degradation of the FLCN protein, and that stabilization and resulting restoration of function may hold therapeutic potential of certain disease-linked variants. Our computational saturation scan encompassing both missense variants and single site deletions inFLCN may allow classification of rare FLCN variants of uncertain clinical significance. (Source: PLoS Genetics)
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Lene Clausen Source Type: research

< i > Gtsf1 < /i > is essential for proper female sex determination and transposon silencing in the silkworm, < i > Bombyx mori < /i >
In this study, we identified BmGTSF1 as a novel piRNA factor which participates inB.mori sex determination. We found thatBmGtsf1 has a distinct expression pattern compared toDrosophila and mouse. CRISPR/Cas9 induced mutation inBmGtsf1 resulted in partial sex reversal in genotypically female animals by shifting expression of the downstream targetsBmMasc andBmdsx to the male pattern. As levels ofFem piRNAs were substantially reduced in female mutants, we concluded thatBmGtsf1 plays a critical role in the biogenesis of the feminizing signal. We also demonstrated that BmGTSF1 physically interacted with BmSIWI, a protein previo...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Kai Chen Source Type: research

TOR Complex 2- independent mutations in the regulatory PIF pocket of Gad8 < sup > AKT1/SGK1 < /sup > define separate branches of the stress response mechanisms in fission yeast
In this study, we describe the isolation ofgad8 mutant alleles that bypass the requirement for TORC2 and reveal a separation of function of TORC2 and Gad8 under stress conditions. In particular, osmotic and nutritional stress responses appear to form a separate branch from genotoxic stress responses downstream of TORC2-Gad8. Interestingly, TORC2-independent mutations map into the regulatory PIF pocket of Gad8, a highly conserved motif in AGC kinases that regulates substrate binding in PDK1 (phosphoinositide dependent kinase-1) and kinase activity in several AGC kinases. Gad8 activation is thought to require a two-step mech...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Emese Pataki Source Type: research

NIGT1 family proteins exhibit dual mode DNA recognition to regulate nutrient response-associated genes in Arabidopsis
by Yoshiaki Ueda, Shohei Nosaki, Yasuhito Sakuraba, Takuya Miyakawa, Takatoshi Kiba, Masaru Tanokura, Shuichi Yanagisawa Fine-tuning of nutrient uptake and response is indispensable for maintenance of nutrient homeostasis in plants, but the details of underlying mechanisms remain to be elucidated. NITRATE-INDUCIBLE GARP-TYPE TRANSCRIPTIONAL REPRESSOR 1 (NIGT1) family proteins are plant-specific transcriptional repre ssors that function as an important hub in the nutrient signaling network associated with the acquisition and use of nitrogen and phosphorus. Here, by yeast two-hybrid assays, bimolecular fluorescence compleme...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Yoshiaki Ueda Source Type: research

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis
This study furthers the idea that Fe-S cluster homeostasis acts as a sensor of environmental conditions, and because its broad influence on cell metabolism, modifies the antibiotic resistance profile ofE.coli. (Source: PLoS Genetics)
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Audrey Gerstel Source Type: research

A spectrum of verticality across genes
by Falk S. P. Nagies, Julia Brueckner, Fernando D. K. Tria, William F. Martin Lateral gene transfer (LGT) has impacted prokaryotic genome evolution, yet the extent to which LGT compromises vertical evolution across individual genes and individual phyla is unknown, as are the factors that govern LGT frequency across genes. Estimating LGT frequency from tree comparisons is pr oblematic when thousands of genomes are compared, because LGT becomes difficult to distinguish from phylogenetic artefacts. Here we report quantitative estimates for verticality across all genes and genomes, leveraging a well-known property of phylogen...
Source: PLoS Genetics - November 2, 2020 Category: Genetics & Stem Cells Authors: Falk S. P. Nagies Source Type: research

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation
by Brendan Evano, Diljeet Gill, Irene Hernando-Herraez, Glenda Comai, Thomas M. Stubbs, Pierre-Henri Commere, Wolf Reik, Shahragim Tajbakhsh Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular mu scles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and li...
Source: PLoS Genetics - October 30, 2020 Category: Genetics & Stem Cells Authors: Brendan Evano Source Type: research