Opposing functions of the plant < i > TOPLESS < /i > gene family during SNC1-mediated autoimmunity
by Christopher M. Garner, Benjamin J. Spears, Jianbin Su, Leland J. Cseke, Samantha N. Smith, Conner J. Rogan, Walter Gassmann Regulation of the plant immune system is important for controlling the specificity and amplitude of responses to pathogens and in preventing growth-inhibiting autoimmunity that leads to reductions in plant fitness. In previous work, we reported that SRFR1, a negative regulator of effector-triggere d immunity, interacts with SNC1 and EDS1. WhenSRFR1 is non-functional in the Arabidopsis accession Col-0,SNC1 levels increase, causing a cascade of events that lead to autoimmunity phenotypes. Previous w...
Source: PLoS Genetics - February 23, 2021 Category: Genetics & Stem Cells Authors: Christopher M. Garner Source Type: research

Molecular parallelisms between pigmentation in the avian iris and the integument of ectothermic vertebrates
by Pedro Andrade, Ma łgorzata A. Gazda, Pedro M. Araújo, Sandra Afonso, Jacob. A. Rasmussen, Cristiana I. Marques, Ricardo J. Lopes, M. Thomas P. Gilbert., Miguel Carneiro Birds exhibit striking variation in eye color that arises from interactions between specialized pigment cells named chromatophores. The types of chromatophores present in the avian iris are lacking from the integument of birds or mammals, but are remarkably similar to those found in the skin of ec tothermic vertebrates. To investigate molecular mechanisms associated with eye coloration in birds, we took advantage of a Mendelian mutation found in...
Source: PLoS Genetics - February 23, 2021 Category: Genetics & Stem Cells Authors: Pedro Andrade Source Type: research

Ancient and recent introgression shape the evolutionary history of pollinator adaptation and speciation in a model monkeyflower radiation ( < i > Mimulus < /i > section < i > Erythranth < /i > e)
In this study, we use genome-wide capture of nuclear gene sequences, plus skimming of organellar sequences, to investigate the phylogenomic s of monkeyflowers inMimulus sectionErythranthe (27 accessions from seven species). Taxa withinErythranthe, particularly the parapatric and putatively sister speciesM.lewisii (bee-pollinated) andM.cardinalis (hummingbird-pollinated), have been a model system for investigating the ecological genetics of speciation and adaptation for over five decades. Across>8000 nuclear loci, multiple methods resolve a predominant species tree in whichM.cardinalis groups with other hummingbird-polli...
Source: PLoS Genetics - February 22, 2021 Category: Genetics & Stem Cells Authors: Thomas C. Nelson Source Type: research

RNA-binding protein syncrip regulates starvation-induced hyperactivity in adult < i > Drosophila < /i >
by Wanhao Chi, Wei Liu, Wenqin Fu, Shengqian Xia, Ellie S. Heckscher, Xiaoxi Zhuang How to respond to starvation determines fitness. One prominent behavioral response is increased locomotor activities upon starvation, also known as Starvation-Induced Hyperactivity (SIH). SIH is paradoxical as it promotes food seeking but also increases energy expenditure. Despite its importance i n fitness, the genetic contributions to SIH as a behavioral trait remains unexplored. Here, we examined SIH in theDrosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association studies. We identified 23 significant l...
Source: PLoS Genetics - February 22, 2021 Category: Genetics & Stem Cells Authors: Wanhao Chi Source Type: research

Interdependent recruitment of CYC8/TUP1 and the transcriptional activator XYR1 at target promoters is required for induced cellulase gene expression in < i > Trichoderma reesei < /i >
by Lei Wang, Weixin Zhang, Yanli Cao, Fanglin Zheng, Guolei Zhao, Xinxing Lv, Xiangfeng Meng, Weifeng Liu Cellulase production in filamentous fungusTrichoderma reesei is highly responsive to various environmental cues involving multiple positive and negative regulators. XYR1 (Xylanase regulator 1) has been identified as the key transcriptional activator of cellulase gene expression inT.reesei. However, the precise mechanism by which XYR1 achieves transcriptional activation of cellulase genes is still not fully understood. Here, we identified the TrCYC8/TUP1 complex as a novel coactivator for XYR1 inT.reesei. CYC8/TUP1 is ...
Source: PLoS Genetics - February 19, 2021 Category: Genetics & Stem Cells Authors: Lei Wang Source Type: research

Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis
by Jonathan Lenz, Robert Liefke, Julianne Funk, Samuel Shoup, Andrea Nist, Thorsten Stiewe, Robert Schulz, Yumiko Tokusumi, Lea Albert, Hartmann Raifer, Klaus F örstemann, Olalla Vázquez, Tsuyoshi Tokusumi, Nancy Fossett, Alexander Brehm The generation of lineage-specific gene expression programmes that alter proliferation capacity, metabolic profile and cell type-specific functions during differentiation from multipotent stem cells to specialised cell types is crucial for development. During differentiation gene expression progra mmes are dynamically modulated by a complex interplay between sequence-specific ...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Jonathan Lenz Source Type: research

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency
by Ken Batai, Zuxi Cui, Amit Arora, Ebony Shah-Williams, Wenndy Hernandez, Maria Ruden, Courtney M. P. Hollowell, Stanley E. Hooker, Madhavi Bathina, Adam B. Murphy, Carolina Bonilla, Rick A. Kittles A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D v...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Ken Batai Source Type: research

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population
In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potent ially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmac...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Mullin Ho Chung Yu Source Type: research

Fruitless decommissions regulatory elements to implement cell-type-specific neuronal masculinization
by Margarita V. Brovkina, Rachel Duffi é, Abbigayl E. C. Burtis, E. Josephine Clowney In the fruit flyDrosophila melanogaster, male-specific splicing and translation of the Fruitless transcription factor (FruM) alters the presence, anatomy, and/or connectivity of>60 types of central brain neurons that interconnect to generate male-typical behaviors. While the indispensable function of FruM in sex-specific behavior has been understood for decades, the molecular mechanisms underlying its activity remain unknown. Here, we take a genome-wide, brain-wide approach to identifying regulatory elements whose activity depe...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Margarita V. Brovkina Source Type: research

RanBP2/Nup358 enhances miRNA activity by sumoylating Argonautes
by Qingtang Shen, Yifan E. Wang, Mathew Truong, Kohila Mahadevan, Jingze J. Wu, Hui Zhang, Jiawei Li, Harrison W. Smith, Craig A. Smibert, Alexander F. Palazzo Mutations in RanBP2 (also known as Nup358), one of the main components of the cytoplasmic filaments of the nuclear pore complex, contribute to the overproduction of acute necrotizing encephalopathy (ANE1)-associated cytokines. Here we report that RanBP2 represses the translation of theinterleukin 6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, theIL6 messenger ribonucleoprotein (mRNP...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Qingtang Shen Source Type: research

IAA3-Mediated repression of PIF proteins coordinates light and auxin signaling in < i > Arabidopsis < /i >
In this study, we identified a direct link between the light and a uxin signaling pathways mediated by the auxin transcriptional repressor IAA3 and light-controlled PIF transcription factors inArabidopsis. The gain-of-function mutation inIAA3 caused hyposensitivity to light, whereas disruption ofIAA3 led to an elongated hypocotyl under different light intensity conditions, indicating that IAA3 is required in light regulated hypocotyl growth. Genetic studies showed that the function of IAA3 in hypocotyl elongation is dependent on PIFs. Our data further demonstrated that IAA3 interacts with PIFsin vitro andin vivo, and it at...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Yulin Xi Source Type: research

Split versions of < i > Cleave and Rescue < /i > selfish genetic elements for measured self limiting gene drive
by Georg Oberhofer, Tobin Ivy, Bruce A. Hay Gene drive elements promote the spread of linked traits, providing methods for changing the composition or fate of wild populations. Drive mechanisms that are self-limiting are attractive because they allow control over the duration and extent of trait spread in time and space, and are reversible through natural selection as drive wanes. Self-sustainingCleave and Rescue (ClvR) elements include a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene, a tightly linked recoded version of the essential gene resistant to cleavage (the...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Georg Oberhofer Source Type: research

Zebrafish Ski7 tunes RNA levels during the oocyte-to-embryo transition
by Luis Enrique Cabrera-Quio, Alexander Schleiffer, Karl Mechtler, Andrea Pauli Post-transcriptional regulation of gene expression is crucial during the oocyte-to-embryo transition, a highly dynamic process characterized by the absence of nuclear transcription. Thus, changes to the RNA content are solely dependent on RNA degradation. Although several mechanisms that promote R NA decay during embryogenesis have been identified, it remains unclear which machineries contribute to remodeling the maternal transcriptome. Here, we focused on the degradation factor Ski7 in zebrafish. Homozygousski7 mutant fish had higher proporti...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Luis Enrique Cabrera-Quio Source Type: research

A novel role for Dun1 in the regulation of origin firing upon hyper-acetylation of H3K56
by Lihi Gershon, Martin Kupiec During DNA replication newly synthesized histones are incorporated into the chromatin of the replicating sister chromatids. In the yeastSaccharomyces cerevisiae new histone H3 molecules are acetylated at lysine 56. This modification is carefully regulated during the cell cycle, and any disruption of this process is a source of genomic instability. Here we show that the protein kinase Dun1 is necessary in order to maintain viability in the absence of the histone deacetylases Hst3 and Hst4, which remove the acetyl moiety from histone H3. This lethality is not due to the well-characterized role...
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Lihi Gershon Source Type: research

Correction: Demographic history shaped geographical patterns of deleterious mutation load in a broadly distributed Pacific Salmon
by Quentin Rougemont, Jean-S ébastien Moore, Thibault Leroy, Eric Normandeau, Eric B. Rondeau, Ruth E. Withler, Donald M. Van Doornik, Penelope A. Crane, Kerry A. Naish, John Carlos Garza, Terry D. Beacham, Ben F. Koop, Louis Bernatchez (Source: PLoS Genetics)
Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Quentin Rougemont Source Type: research

Lhx6 regulates canonical Wnt signaling to control the fate of mesenchymal progenitor cells during mouse molar root patterning
In this study, we find that Lhx6 labels a subpopulation of root progenitor cells in the apical dental mesenchyme, which is closely associated with furcation development. Loss of Lhx6 leads to furcation and root number defects, indicating that Lhx6 is a key root patterning regulator. Among the multiple cellular events regulated by Lhx6 is the odontoblast fate commitment of progenitor cells, which it controls in a cell-autonomous manner. Specifically,Lhx6 loss leads to elevated expression of the Wnt antagonistSfrp2 and down-regulation of Wnt signaling in the furcation region, while overactivation of Wnt signaling in Lhx6+ pr...
Source: PLoS Genetics - February 17, 2021 Category: Genetics & Stem Cells Authors: Jinzhi He Source Type: research

Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for < i > RB1 < /i > -deficient cells
by Andrey A. Parkhitko, Arashdeep Singh, Sharon Hsieh, Yanhui Hu, Richard Binari, Christopher J. Lord, Sridhar Hannenhalli, Colm J. Ryan, Norbert Perrimon TheRB1 tumor suppressor is recurrently mutated in a variety of cancers including retinoblastomas, small cell lung cancers, triple-negative breast cancers, prostate cancers, and osteosarcomas. Finding new synthetic lethal (SL) interactions withRB1 could lead to new approaches to treating cancers with inactivatedRB1. We identified 95 SL partners ofRB1 based on aDrosophila screen for genetic modifiers of the eye phenotype caused by defects in theRB1 ortholog,Rbf1. We valid...
Source: PLoS Genetics - February 16, 2021 Category: Genetics & Stem Cells Authors: Andrey A. Parkhitko Source Type: research

LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability
by Jiao-Xiang Wu, Kun-Yan He, Zhuang-Zhuang Zhang, Yu-Lan Qu, Xian-Bin Su, Yi Shi, Na Wang, Lan Wang, Ze-Guang Han The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show thatLzp deletion inhibited very low-density lipoprotein (VLDL) ...
Source: PLoS Genetics - February 16, 2021 Category: Genetics & Stem Cells Authors: Jiao-Xiang Wu Source Type: research

Genomic rearrangements generate hypervariable mini-chromosomes in host-specific isolates of the blast fungus
by Thorsten Langner, Adeline Harant, Luis B. Gomez-Luciano, Ram K. Shrestha, Angus Malmgren, Sergio M. Latorre, Hern án A. Burbano, Joe Win, Sophien Kamoun Supernumerary mini-chromosomes–a unique type of genomic structural variation–have been implicated in the emergence of virulence traits in plant pathogenic fungi. However, the mechanisms that facilitate the emergence and maintenance of mini-chromosomes across fungi remain poorly understood. In the blast fungusMagnaporthe oryzae (Syn.Pyricularia oryzae), mini-chromosomes have been first described in the early 1990s but, until very recently, have been o...
Source: PLoS Genetics - February 16, 2021 Category: Genetics & Stem Cells Authors: Thorsten Langner Source Type: research

The developmental genetic architecture of vocabulary skills during the first three years of life: Capturing emerging associations with later-life reading and cognition
by Ellen Verhoef, Chin Yang Shapland, Simon E. Fisher, Philip S. Dale, Beate St Pourcain Individual differences in early-life vocabulary measures are heritable and associated with subsequent reading and cognitive abilities, although the underlying mechanisms are little understood. Here, we (i) investigate the developmental genetic architecture of expressive and receptive vocabulary in early-life and (ii) assess timing of emerging genetic associations with mid-childhood verbal and non-verbal skills. We studied longitudinally assessed early-life vocabulary measures (15–38 months) and later-life verbal and non-verbal s...
Source: PLoS Genetics - February 12, 2021 Category: Genetics & Stem Cells Authors: Ellen Verhoef Source Type: research

Intermedilysin cytolytic activity depends on heparan sulfates and membrane composition
This study shows that membrane-targeting toxins combined with genetic screening can identify the genes involved in biological membrane composition and metab olism. (Source: PLoS Genetics)
Source: PLoS Genetics - February 12, 2021 Category: Genetics & Stem Cells Authors: Gediminas Drabavicius Source Type: research

Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells
by Yoshitaka Furuta, Omar Pena-Ramos, Zao Li, Lucia Chiao, Zheng Zhou Intracellular Ca2+ level is under strict regulation through calcium channels and storage pools including the endoplasmic reticulum (ER). Mutations in certain ion channel subunits, which cause mis-regulated Ca2+ influx, induce the excitotoxic necrosis of neurons. In the nematodeCaenorhabditis elegans, dominant mutations in the DEG/ENaC sodium channel subunit MEC-4 induce six mechanosensory (touch) neurons to undergo excitotoxic necrosis. These necrotic neurons are subsequently engulfed and digested by neighboring hypodermal cells. We previously reported ...
Source: PLoS Genetics - February 11, 2021 Category: Genetics & Stem Cells Authors: Yoshitaka Furuta Source Type: research

The impact of global and local Polynesian genetic ancestry on complex traits in Native Hawaiians
In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D. (Source: PLoS Genetics)
Source: PLoS Genetics - February 11, 2021 Category: Genetics & Stem Cells Authors: Hanxiao Sun Source Type: research

CRMP/UNC-33 organizes microtubule bundles for KIF5-mediated mitochondrial distribution to axon
by Ying-Chun Chen, Hao-Ru Huang, Chia-Hao Hsu, Chan-Yen Ou Neurons are highly specialized cells with polarized cellular processes and subcellular domains. As vital organelles for neuronal functions, mitochondria are distributed by microtubule-based transport systems. Although the essential components of mitochondrial transport including motors and cargo a daptors are identified, it is less clear how mitochondrial distribution among somato-dendritic and axonal compartment is regulated. Here, we systematically study mitochondrial motors, including four kinesins, KIF5, KIF17, KIF1, KLP-6, and dynein, and transport regulators...
Source: PLoS Genetics - February 11, 2021 Category: Genetics & Stem Cells Authors: Ying-Chun Chen Source Type: research

Hybrid seed incompatibility in < i > Capsella < /i > is connected to chromatin condensation defects in the endosperm
In this study, we investigated the molecular events accompanying seed failure in hybrids of the closely related species pairCapsella rubella andC.grandiflora. Mapping of QTL for the underlying cause of hybrid incompatibility inCapsella identified three QTL that were close to pericentromeric regions. We investigated whether there are specific changes in heterochromatin associated with interspecific hybridizations and found a strong reduction of chromatin condensation in the endosperm, connected with a strong loss of CHG and CHH methylation and random loss of a single chromosome. Consistent with reduced DNA methylation in th...
Source: PLoS Genetics - February 11, 2021 Category: Genetics & Stem Cells Authors: Katarzyna Dziasek Source Type: research

< i > Vestigial < /i > mediates the effect of insulin signaling pathway on wing-morph switching in planthoppers
by Jin-Li Zhang, Sheng-Jie Fu, Sun-Jie Chen, Hao-Hao Chen, Yi-Lai Liu, Xin-Yang Liu, Hai-Jun Xu Wing polymorphism is an evolutionary feature found in a wide variety of insects, which offers a model system for studying the evolutionary significance of dispersal. In the wing-dimorphic planthopperNilaparvata lugens, the insulin/insulin-like growth factor signaling (IIS) pathway acts as a ‘master signal’ that directs the development of either long-winged (LW) or short-winged (SW) morphs via regulation of the activity of Forkhead transcription factor subgroup O (NlFoxO). However, downstream effectors of the IIS &nd...
Source: PLoS Genetics - February 9, 2021 Category: Genetics & Stem Cells Authors: Jin-Li Zhang Source Type: research

VER/VEGF receptors regulate AMPA receptor surface levels and glutamatergic behavior
by Eric S. Luth, Molly Hodul, Bethany J. Rennich, Carmino Riccio, Julia Hofer, Kaitlin Markoja, Peter Juo Several intracellular trafficking pathways contribute to the regulation of AMPA receptor (AMPAR) levels at synapses and the control of synaptic strength. While much has been learned about these intracellular trafficking pathways, a major challenge is to understand how extracellular factors, such a s growth factors, neuropeptides and hormones, impinge on specific AMPAR trafficking pathways to alter synaptic function and behavior. Here, we identify the secreted ligand PVF-1 and its cognate VEGF receptor homologs, VER-1 ...
Source: PLoS Genetics - February 9, 2021 Category: Genetics & Stem Cells Authors: Eric S. Luth Source Type: research

IgH 3 ’ regulatory region increases ectopic class switch recombination
by Sandrine Le Noir, Am élie Bonaud, Bastien Hervé, Audrey Baylet, François Boyer, Sandrine Lecardeur, Zeliha Oruc, Christophe Sirac, Michel Cogné DNA lesions inflicted by activation-induced deaminase (AID) instrumentally initiate the processes reshaping immunoglobulin genes in mature B-cells, from local somatic hypermutation (SHM) to junctions of distant breaks during class switch recombination (CSR). It remains incompletely understood how these divergent outcomes of AID attacks are differentially and temporally focused, with CSR strictly occurring in the Ig heavy chain (IgH) locus while SHM c...
Source: PLoS Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Sandrine Le Noir Source Type: research

α-synuclein impairs autophagosome maturation through abnormal actin stabilization
by Souvarish Sarkar, Abby L. Olsen, Katja Sygnecka, Kelly M. Lohr, Mel B. Feany Vesicular trafficking defects, particularly those in the autophagolysosomal system, have been strongly implicated in the pathogenesis of Parkinson’s disease and related α-synucleinopathies. However, mechanisms mediating dysfunction of membrane trafficking remain incompletely understood. Using aDrosophila model of α-synuclein neurotoxicity with widespread and robust pathology, we find that human α-synuclein expression impairs autophagic flux in aging adult neurons. Genetic destabilization of the actin cytoskeleton rescue...
Source: PLoS Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Souvarish Sarkar Source Type: research

Systemic and local effect of the < i > Drosophila headcase < /i > gene and its role in stress protection of Adult Progenitor Cells
by Panagiotis Giannios, Jordi Casanova During the development of a holometabolous insect such asDrosophila, specific group of cells in the larva survive during metamorphosis, unlike the other larval cells, and finally give rise to the differentiated adult structures. These cells, also known as Adult Progenitor Cells (APCs), maintain their multipotent capacity, differentially respond to hormonal and nutritional signals, survive the intrinsic and environmental stress and respond to the final differentiation cues. However, not much is known about the specific molecular mechanisms that account for their unique characteristics...
Source: PLoS Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Panagiotis Giannios Source Type: research

Low immunogenicity of common cancer hot spot mutations resulting in false immunogenic selection signals
by Arne Claeys, Tom Luijts, Kathleen Marchal, Jimmy Van den Eynden Cancer is driven by somatic mutations that result in a cellular fitness advantage. This selective advantage is expected to be counterbalanced by the immune system when these driver mutations simultaneously lead to the generation of neoantigens, novel peptides that are presented at the cancer cell membrane via HLA molecules from the MHC complex. The presentability of these peptides is determined by a patient’s MHC genotype and it has been suggested that this results in MHC genotype-specific restrictions of the oncogenic mutational landscape. Here, we ...
Source: PLoS Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Arne Claeys Source Type: research

Homeodomain protein Six4 prevents the generation of supernumerary < i > Drosophila < /i > type II neuroblasts and premature differentiation of intermediate neural progenitors
by Rui Chen, Yanjun Hou, Marisa Connell, Sijun Zhu In order to boost the number and diversity of neurons generated from neural stem cells, intermediate neural progenitors (INPs) need to maintain their homeostasis by avoiding both dedifferentiation and premature differentiation. Elucidating how INPs maintain homeostasis is critical for understandin g the generation of brain complexity and various neurological diseases resulting from defects in INP development. Here we report that Six4 expressed inDrosophila type II neuroblast (NB) lineages prevents the generation of supernumerary type II NBs and premature differentiation o...
Source: PLoS Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Rui Chen Source Type: research

Regulation of < i > ddb2 < /i > expression in blind cavefish and zebrafish reveals plasticity in the control of sunlight-induced DNA damage repair
by Haiyu Zhao, Hongxiang Li, Juan Du, Giuseppe Di Mauro, Sebastian Lungu-Mitea, Nathalie Geyer, Daniela Vallone, Cristiano Bertolucci, Nicholas S. Foulkes We have gained considerable insight into the mechanisms which recognize and repair DNA damage, but how they adapt to extreme environmental challenges remains poorly understood. Cavefish have proven to be fascinating models for exploring the evolution of DNA repair in the complete absence of UV-ind uced DNA damage and light. We have previously revealed that the Somalian cavefishPhreatichthys andruzzii, lacks photoreactivation repair via the loss of light, UV and ROS-indu...
Source: PLoS Genetics - February 5, 2021 Category: Genetics & Stem Cells Authors: Haiyu Zhao Source Type: research

Glucocerebrosidase reduces the spread of protein aggregation in a < i > Drosophila melanogaster < /i > model of neurodegeneration by regulating proteins trafficked by extracellular vesicles
by Kathryn A. Jewett, Ruth E. Thomas, Chi Q. Phan, Bernice Lin, Gillian Milstein, Selina Yu, Lisa F. Bettcher, Fausto Carnevale Neto, Danijel Djukovic, Daniel Raftery, Leo J. Pallanck, Marie Y. Davis Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations inglucosidase,beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Kathryn A. Jewett Source Type: research

Multiple sensors provide spatiotemporal oxygen regulation of gene expression in a < i > Rhizobium < /i > -legume symbiosis
by Paul J. Rutten, Harrison Steel, Graham A. Hood, Vinoy K. Ramachandran, Lucie McMurtry, Barney Geddes, Antonis Papachristodoulou, Philip S. Poole Regulation by oxygen (O2) in rhizobia is essential for their symbioses with plants and involves multiple O2 sensing proteins. Three sensors exist in the pea microsymbiontRhizobium leguminosarum Rlv3841: hFixL, FnrN and NifA. At low O2 concentrations (1%) hFixL signals via FxkR to induce expression of the FixK transcription factor, which activates transcription of downstream genes. These includefixNOQP, encoding the high-affinitycbb3-type terminal oxidase used in symbiosis. In ...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Paul J. Rutten Source Type: research

ATF3 downmodulates its new targets IFI6 and IFI27 to suppress the growth and migration of tongue squamous cell carcinoma cells
In this study, we examined biopsies of tongue squamous cell carcinomas (TSCCs) and found that the nuclear expression level of ATF3 correlated negatively with the differentiation status of TSCCs, which was validated by analy sis of the ATGC database. By using gain- or loss- of function analyses of ATF3 in four different TSCC cell lines, we demonstrated that ATF3 negatively regulates the growth and migration of human TSCC cellsin vitro. RNA-seq analysis identified two new downstream targets of ATF3, interferon alpha inducible proteins 6 (IFI6) and 27 (IFI27), which were upregulated in ATF3-deleted cells and were downregulate...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Lin Xu Source Type: research

Creating artificial human genomes using generative neural networks
In this study, we demonstrated that deep generative adversarial networks (GANs) and restricted Boltzmann machines (RBMs) can be trained to learn the complex distributions of real genomic datasets and generate novel high-quality artificial genomes (AGs) with none to little privacy loss. We show that our generated AGs replicate characteristics of the source dataset such as allele frequencies, linkage disequilibrium, pairwise haplotype distances and population structure. Moreover, they can also inherit complex features such as signals of selection. To illustrate the promising outcomes of our meth od, we showed that imputation...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Burak Yelmen Source Type: research

RAC1 controls progressive movement and competitiveness of mammalian spermatozoa
by Alexandra Amaral, Bernhard G. Herrmann Mammalian spermatozoa employ calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) signaling in generating flagellar beat. However, how sperm direct their movement towards the egg cells has remained elusive. Here we show that the Rho small G protein RAC1 plays an important role in controlling progressive motility, in particular average path velocity and linearity. Upon RAC1 inhibition of wild type sperm with the drug NSC23766, progressive movement is impaired. Moreover, sperm from mice homozygous for the genetically variantt-haplotype region (tw5/tw32), which are sterile, show ...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Alexandra Amaral Source Type: research

Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
by Kunling Huang, Yuchang Wu, Junha Shin, Ye Zheng, Alireza Fotuhi Siahpirani, Yupei Lin, Zheng Ni, Jiawen Chen, Jing You, Sunduz Keles, Daifeng Wang, Sushmita Roy, Qiongshi Lu Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we int roduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Kunling Huang Source Type: research

The Species-Specific Acquisition and Diversification of a K1-like Family of Killer Toxins in Budding Yeasts of the Saccharomycotina
by Lance R. Fredericks, Mark D. Lee, Angela M. Crabtree, Josephine M. Boyer, Emily A. Kizer, Nathan T. Taggart, Cooper R. Roslund, Samuel S. Hunter, Courtney B. Kennedy, Cody G. Willmore, Nova M. Tebbe, Jade S. Harris, Sarah N. Brocke, Paul A. Rowley Killer toxins are extracellular antifungal proteins that are produced by a wide variety of fungi, includingSaccharomyces yeasts. Although manySaccharomyces killer toxins have been previously identified, their evolutionary origins remain uncertain given that many of these genes have been mobilized by double-stranded RNA (dsRNA) viruses. A survey of yeasts from theSaccharomyces...
Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Lance R. Fredericks Source Type: research

Four families of folate-independent methionine synthases
by Morgan N. Price, Adam M. Deutschbauer, Adam P. Arkin Although most organisms synthesize methionine from homocysteine and methyl folates, some have “core” methionine synthases that lack folate-binding domains and use other methyl donors.In vitro, the characterized core synthases use methylcobalamin as a methyl donor, butin vivo, they probably rely on corrinoid (vitamin B12-binding) proteins. We identified four families of core methionine synthases that are distantly related to each other (under 30% pairwise amino acid identity). From the characterized enzymes, we identified the families MesA, which is found ...
Source: PLoS Genetics - February 3, 2021 Category: Genetics & Stem Cells Authors: Morgan N. Price Source Type: research

Histone modification dynamics at H3K27 are associated with altered transcription of < i > in planta < /i > induced genes in < i > Magnaporthe oryzae < /i >
by Wei Zhang, Jun Huang, David E. Cook Transcriptional dynamic in response to environmental and developmental cues are fundamental to biology, yet many mechanistic aspects are poorly understood. One such example is fungal plant pathogens, which use secreted proteins and small molecules, termed effectors, to suppress host immunity and p romote colonization. Effectors are highly expressedin planta but remain transcriptionally repressedex planta, but our mechanistic understanding of these transcriptional dynamics remains limited. We tested the hypothesis that repressive histone modification at H3-Lys27 underlies transcriptio...
Source: PLoS Genetics - February 3, 2021 Category: Genetics & Stem Cells Authors: Wei Zhang Source Type: research

Steroid hormone ecdysone deficiency stimulates preparation for photoperiodic reproductive diapause
by Shuang Guo, Zhong Tian, Qing-Wen Wu, Kirst King-Jones, Wen Liu, Fen Zhu, Xiao-Ping Wang Diapause, a programmed developmental arrest primarily induced by seasonal environmental changes, is very common in the animal kingdom, and found in vertebrates and invertebrates alike. Diapause provides an adaptive advantage to animals, as it increases the odds of surviving adverse conditions. In insects, individuals perceive photoperiodic cues and modify endocrine signaling to direct reproductive diapause traits, such as ovary arrest and increased fat accumulation. However, it remains unclear as to which endocrine factors are invol...
Source: PLoS Genetics - February 2, 2021 Category: Genetics & Stem Cells Authors: Shuang Guo Source Type: research

Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
by Joseph Farris, Md Suhail Alam, Arpitha Mysore Rajashekara, Kasturi Haldar Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We un ified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with newin silico tools for murine and human genome level-analyses, gatheredin vivo evidence from mice engineered with top-ranking attenuated and...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: Joseph Farris Source Type: research

The conserved transmembrane protein TMEM-39 coordinates with COPII to promote collagen secretion and regulate ER stress response
by Zhe Zhang, Shuo Luo, Guilherme Oliveira Barbosa, Meirong Bai, Thomas B. Kornberg, Dengke K. Ma Dysregulation of collagen production and secretion contributes to aging and tissue fibrosis of major organs. How procollagen proteins in the endoplasmic reticulum (ER) route as specialized cargos for secretion remains to be fully elucidated. Here, we report that TMEM39, an ER-localized transmembra ne protein, regulates production and secretory cargo trafficking of procollagen. We identify theC.elegans ortholog TMEM-39 from an unbiased RNAi screen and show that deficiency oftmem-39 leads to striking defects in cuticle collagen...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: Zhe Zhang Source Type: research

Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta
We report a homozygous p.(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta leading to early demise. p.R222 is a highly conserved residue located within the collagen interacting surface of HSP47. Binding assays show a significantly reduced affinity of HSP47-R222S for type I collagen. This altered interaction leads to posttranslational overmodification of type I collagen produced by dermal fibroblasts, with increased glycosylation and/or hydroxylation of lysine and proline residues as shown by mass spectrometry. Since we also observed a normal intracellular folding and secretion rate of type I coll...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: Delfien Syx Source Type: research

Increased dopaminergic neurotransmission results in ethanol dependent sedative behaviors in < i > Caenorhabditis elegans < /i >
by Pratima Pandey, Anuradha Singh, Harjot Kaur, Anindya Ghosh-Roy, Kavita Babu Ethanol is a widely used drug, excessive consumption of which could lead to medical conditions with diverse symptoms. Ethanol abuse causes dysfunction of memory, attention, speech and locomotion across species. Dopamine signaling plays an essential role in ethanol dependent behaviors in animals ra nging fromC.elegans to humans. We devised an ethanol dependent assay in which mutants in the dopamine autoreceptor,dop-2, displayed a unique sedative locomotory behavior causing the animals to move in circles while dragging the posterior half of their...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: Pratima Pandey Source Type: research

Acetyltransferase Enok regulates transposon silencing and piRNA cluster transcription
by Shih-Ying Tsai, Fu Huang The piRNA pathway is a highly conserved mechanism to repress transposon activation in the germline inDrosophila and mammals. This pathway starts from transcribing piRNA clusters to generate long piRNA precursors. The majority of piRNA clusters lack conventional promoters, and utilize heterochromatin- and HP1D/Rhino-dependent noncanonical mechanisms for transcription. However, information regarding the transcriptional regulation of piRNA clusters is limited. Here, we report that theDrosophila acetyltransferase Enok, which can activate transcription by acetylating H3K23, is critical for piRNA pro...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: Shih-Ying Tsai Source Type: research

Oscillating and stable genome topologies underlie hepatic physiological rhythms during the circadian cycle
by J érôme Mermet, Jake Yeung, Félix Naef The circadian clock drives extensive temporal gene expression programs controlling daily changes in behavior and physiology. In mouse liver, transcription factors dynamics, chromatin modifications, and RNA Polymerase II (PolII) activity oscillate throughout the 24-hour (24h) day, regulating the rh ythmic synthesis of thousands of transcripts. Also, 24h rhythms in gene promoter-enhancer chromatin looping accompany rhythmic mRNA synthesis. However, how chromatin organization impinges on temporal transcription and liver physiology remains unclear. Here, we applied...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: J érôme Mermet Source Type: research

Fitness landscape of a dynamic RNA structure
by Valerie W. C. Soo, Jacob B. Swadling, Andre J. Faure, Tobias Warnecke RNA structures are dynamic. As a consequence, mutational effects can be hard to rationalize with reference to a single static native structure. We reasoned that deep mutational scanning experiments, which couple molecular function to fitness, should capture mutational effects across multiple confo rmational states simultaneously. Here, we provide a proof-of-principle that this is indeed the case, using the self-splicing group I intron fromTetrahymena thermophila as a model system. We comprehensively mutagenized two 4-bp segments of the intron. These ...
Source: PLoS Genetics - February 1, 2021 Category: Genetics & Stem Cells Authors: Valerie W. C. Soo Source Type: research