Osteocalcin promotes bone mineralization but is not a hormone
by Stavros C. Manolagas (Source: PLoS Genetics)
Source: PLoS Genetics - June 2, 2020 Category: Genetics & Stem Cells Authors: Stavros C. Manolagas Source Type: research

Integrins regulate epithelial cell shape by controlling the architecture and mechanical properties of basal actomyosin networks
by Carmen Santa-Cruz Mateos, Andrea Valencia-Exp ósito, Isabel M. Palacios, María D. Martín-Bermudo Forces generated by the actomyosin cytoskeleton are key contributors to many morphogenetic processes. The actomyosin cytoskeleton organises in different types of networks depending on intracellular signals and on cell-cell and cell-extracellular matrix (ECM) interactions. However, actomyosin netwo rks are not static and transitions between them have been proposed to drive morphogenesis. Still, little is known about the mechanisms that regulate the dynamics of actomyosin networks during morphogenesis. Th...
Source: PLoS Genetics - June 1, 2020 Category: Genetics & Stem Cells Authors: Carmen Santa-Cruz Mateos Source Type: research

Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape
by Xueliang Lyu, Qian Yang, Lin Li, Yunkun Dang, Zhipeng Zhou, She Chen, Yi Liu Codon usage bias is a universal feature of all genomes and plays an important role in regulating protein expression levels. Modification of adenosine to inosine at the tRNA anticodon wobble position (I34) by adenosine deaminases (ADATs) is observed in all eukaryotes and has been proposed to explai n the correlation between codon usage and tRNA pool. However, how the tRNA pool is affected by I34 modification to influence codon usage-dependent gene expression is unclear. UsingNeurospora crassa as a model system, by combining molecular, biochemic...
Source: PLoS Genetics - June 1, 2020 Category: Genetics & Stem Cells Authors: Xueliang Lyu Source Type: research

Scalable probabilistic PCA for large-scale genetic variation data
We present ProPCA, a highly scalable method based on a probabilistic generative model, which computes the top PCs on genetic variation data efficiently. We applied ProPCA to compute the top five PCs on genotype data from the UK Bioban k, consisting of 488,363 individuals and 146,671 SNPs, in about thirty minutes. To illustrate the utility of computing PCs in large samples, we leveraged the population structure inferred by ProPCA within White British individuals in the UK Biobank to identify several novel genome-wide signals of re cent putative selection including missense mutations inRPGRIP1L andTLR4. (Source: PLoS Genetics)
Source: PLoS Genetics - May 29, 2020 Category: Genetics & Stem Cells Authors: Aman Agrawal Source Type: research

Yeast mismatch repair components are required for stable inheritance of gene silencing
by Qian Liu, Xuefeng Zhu, Michelle Lindstr öm, Yonghong Shi, Ju Zheng, Xinxin Hao, Claes M. Gustafsson, Beidong Liu Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locusHMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1...
Source: PLoS Genetics - May 29, 2020 Category: Genetics & Stem Cells Authors: Qian Liu Source Type: research

< i > Saccharomyces cerevisiae < /i > Mus81-Mms4 prevents accelerated senescence in telomerase-deficient cells
In this study, we useS.cerevisiae to evaluate the contribution of the conserved Mus81-Mms4 endonuclease in telomerase-deficient yeast cells that maintain their telomeres by mechanisms akin to human ALT. Similar to human cells, we find that yeast Mus81 readily localizes to telomeres and its activity is important for viability after initial loss of telomerase. Interestingly, our analysis reveals that yeast Mus81 is not required for the survival of cells undergoing recombination-mediated telomere lengthening,i.e. for ALT itself. Rather we infer from genetic analysis that Mus81-Mms4 facilitates telomere replication during time...
Source: PLoS Genetics - May 29, 2020 Category: Genetics & Stem Cells Authors: Erin K. Schwartz Source Type: research

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes
by Marco Gr ündl, Susanne Walz, Laura Hauf, Melissa Schwab, Kerstin Marcela Werner, Susanne Spahr, Clemens Schulte, Hans Michael Maric, Carsten P. Ade, Stefan Gaubatz The Hippo signalling pathway and its central effector YAP regulate proliferation of cardiomyocytes and growth of the heart. Using genetic models in mice we show that the increased proliferation of embryonal and postnatal cardiomyocytes due to loss of the Hippo-signaling component SAV1 depends on t he Myb-MuvB (MMB) complex. Similarly, proliferation of postnatal cardiomyocytes induced by constitutive active YAP requires MMB. Genome studies revealed that ...
Source: PLoS Genetics - May 29, 2020 Category: Genetics & Stem Cells Authors: Marco Gr ündl Source Type: research

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution
by Christian D. Huber, Bernard Y. Kim, Kirk E. Lohmueller Comparative genomic approaches have been used to identify sites where mutations are under purifying selection and of functional consequence by searching for sequences that are conserved across distantly related species. However, the performance of these approaches has not been rigorously evaluated under population genetic models. Further, short-lived functional elements may not leave a footprint of sequence conservation across many species. We use simulations to study how one measure of conservation, the Genomic Evolutionary Rate Profiling (GERP) score, relates to ...
Source: PLoS Genetics - May 29, 2020 Category: Genetics & Stem Cells Authors: Christian D. Huber Source Type: research

An osteocalcin-deficient mouse strain without endocrine abnormalities
by Cassandra R. Diegel, Steven Hann, Ugur M. Ayturk, Jennifer C. W. Hu, Kyung-eun Lim, Casey J. Droscha, Zachary B. Madaj, Gabrielle E. Foxa, Isaac Izaguirre, VAI Vivarium and Transgenics Core, Noorulain Paracha, Bohdan Pidhaynyy, Terry L. Dowd, Alexander G. Robling, Matthew L. Warman, Bart O. Williams Osteocalcin (OCN), the most abundant noncollagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient m ouse allele (Osc–) i...
Source: PLoS Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Cassandra R. Diegel Source Type: research

Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass
by Takeshi Moriishi, Ryosuke Ozasa, Takuya Ishimoto, Takayoshi Nakano, Tomoka Hasegawa, Toshihiro Miyazaki, Wenguang Liu, Ryo Fukuyama, Yuying Wang, Hisato Komori, Xin Qin, Norio Amizuka, Toshihisa Komori The strength of bone depends on bone quantity and quality. Osteocalcin (Ocn) is the most abundant noncollagenous protein in bone and is produced by osteoblasts. It has been previously claimed that Ocn inhibits bone formation and also functions as a hormone to regulate insulin secretion in the panc reas, testosterone synthesis in the testes, and muscle mass. We generated Ocn-deficient (Ocn–/–) mice by deleting...
Source: PLoS Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Takeshi Moriishi Source Type: research

The domesticated transposase ALP2 mediates formation of a novel Polycomb protein complex by direct interaction with MSI1, a core subunit of Polycomb Repressive Complex 2 (PRC2)
by Christos N. Velanis, Pumi Perera, Bennett Thomson, Erica de Leau, Shih Chieh Liang, Ben Hartwig, Alex F örderer, Harry Thornton, Pedro Arede, Jiawen Chen, Kimberly M. Webb, Serin Gümüs, Geert De Jaeger, Clinton A. Page, C. Nathan Hancock, Christos Spanos, Juri Rappsilber, Philipp Voigt, Franziska Turck, Frank Wellmer, Justin Goodrich A large fraction of plant genomes is composed of transposable elements (TE), which provide a potential source of novel genes through “domestication”–the process whereby the proteins encoded by TE diverge in sequence, lose their ability to catalyse transposi...
Source: PLoS Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Christos N. Velanis Source Type: research

The genomic landscape of metastasis in treatment-na ïve breast cancer models
by Christina Ross, Karol Szczepanek, Maxwell Lee, Howard Yang, Tinghu Qiu, Jack Sanford, Kent Hunter Metastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumor development and progression, the role of genetic alteration in the metastatic process is not well-understood. The theory of tumor evolution postulated by Peter Nowell in 1976 has yet to be proven in the context of metastasis. Therefore, in order to investigate how somatic evolu...
Source: PLoS Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Christina Ross Source Type: research

Exome-wide association study reveals largely distinct gene sets underlying specific resistance to dengue virus types 1 and 3 in < i > Aedes aegypti < /i >
by Laura B. Dickson, Sarah H. Merkling, Mathieu Gautier, Amine Ghozlane, Davy Jiolle, Christophe Paupy, Diego Ayala, Isabelle Moltini-Conclois, Albin Fontaine, Louis Lambrechts Although specific interactions between host and pathogen genotypes have been well documented in invertebrates, the identification of host genes involved in discriminating pathogen genotypes remains a challenge. In the mosquitoAedes aegypti, the main dengue virus (DENV) vector worldwide, statistical associations between host genetic markers and DENV types or strains were previously detected, but the host genes underlying this genetic specificity hav...
Source: PLoS Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Laura B. Dickson Source Type: research

The Mediator CDK8-Cyclin C complex modulates Dpp signaling in < i > Drosophila < /i > by stimulating Mad-dependent transcription
by Xiao Li, Mengmeng Liu, Xingjie Ren, Nicolas Loncle, Qun Wang, Rajitha-Udakara-Sampath Hemba-Waduge, Stephen H. Yu, Muriel Boube, Henri-Marc G. Bourbon, Jian-Quan Ni, Jun-Yuan Ji Dysregulation of CDK8 (Cyclin-Dependent Kinase 8) and its regulatory partner CycC (Cyclin C), two subunits of the conserved Mediator (MED) complex, have been linked to diverse human diseases such as cancer. Thus, it is essential to understand the regulatory network modulating the CDK8-CycC complex in both normal development and tumorigenesis. To identify upstream regulators or downstream effectors of CDK8, we performed a dominant modifier genet...
Source: PLoS Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Xiao Li Source Type: research

Correction: Rapidly evolving protointrons in < i > Saccharomyces < /i > genomes revealed by a hungry spliceosome
by Jason Talkish, Haller Igel, Rhonda J. Perriman, Lily Shiue, Sol Katzman, Elizabeth M. Munding, Robert Shelansky, John Paul Donohue, Manuel Ares Jr. (Source: PLoS Genetics)
Source: PLoS Genetics - May 27, 2020 Category: Genetics & Stem Cells Authors: Jason Talkish Source Type: research

Novel frameshift variant in < i > MYL2 < /i > reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy
by Sathiya N. Manivannan, Sihem Darouich, Aida Masmoudi, David Gordon, Gloria Zender, Zhe Han, Sara Fitzgerald-Butt, Peter White, Kim L. McBride, Maher Kharrat, Vidu Garg Hypertrophic cardiomyopathy (HCM) is characterized by the thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral val ve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift vari...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Sathiya N. Manivannan Source Type: research

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago
by Heini M. Natri, Katalina S. Bobowik, Pradiptajati Kusuma, Chelzie Crenna Darusallam, Guy S. Jacobs, Georgi Hudjashov, J. Stephen Lansing, Herawati Sudoyo, Nicholas E. Banovich, Murray P. Cox, Irene Gallego Romero Indonesia is the world’s fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide Cp...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Heini M. Natri Source Type: research

Multiple mechanisms regulate H3 acetylation of enhancers in response to thyroid hormone
by Stine M. Pr æstholm, Majken S. Siersbæk, Ronni Nielsen, Xuguang Zhu, Anthony Hollenberg, Sheue-yann Cheng, Lars Grøntved Hormone-dependent activation of enhancers includes histone hyperacetylation and mediator recruitment. Histone hyperacetylation is mostly explained by a bimodal switch model, where histone deacetylases (HDACs) disassociate from chromatin, and histone acetyl transferases (HATs) are recruited. This m odel builds on decades of research on steroid receptor regulation of transcription. Yet, the general concept of the bimodal switch model has not been rigorously tested genome wide. We hav...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Stine M. Pr æstholm Source Type: research

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the < i > Drosophila < /i > intestine
by Jakob von Frieling, Muhammed Naeem Faisal, Femke Sporn, Roxana Pfefferkorn, Stella Solveig Nolte, Felix Sommer, Philip Rosenstiel, Thomas Roeder Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We usedDrosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here,...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Jakob von Frieling Source Type: research

Intimate functional interactions between   < i > TGS1 < /i > and the < i > Smn < /i >  complex revealed by an analysis of the < i > Drosophila < /i > eye development
by Paolo Maccallini, Francesca Bavasso, Livia Scatolini, Elisabetta Bucciarelli, Gemma Noviello, Veronica Lisi, Valeria Palumbo, Simone D'Angeli, Stefano Cacchione, Giovanni Cenci, Laura Ciapponi, James G. Wakefield, Maurizio Gatti, Grazia Daniela Raffa Trimethylguanosine synthase 1 (TGS1) is a conserved enzyme that mediates formation of the trimethylguanosine cap on several RNAs, including snRNAs and telomerase RNA. Previous studies have shown that TGS1 binds the Survival Motor Neuron (SMN) protein, whose deficiency causes spinal muscular atroph y (SMA). Here, we analyzed the roles of theDrosophila orthologs of the human...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Paolo Maccallini Source Type: research

Glucose transporter 10 modulates adipogenesis via an ascorbic acid-mediated pathway to protect mice against diet-induced metabolic dysregulation
by Chung-Lin Jiang, Wei-Ping Jen, Chang-Yu Tsao, Li-Ching Chang, Chien-Hsiun Chen, Yi-Ching Lee The development of type 2 diabetes mellitus (T2DM) depends on interactions between genetic and environmental factors, and a better understanding of gene-diet interactions in T2DM will be useful for disease prediction and prevention. Ascorbic acid has been proposed to reduce the risk of T2DM. Howev er, the links between ascorbic acid and metabolic consequences are not fully understood. Here, we report that glucose transporter 10 (GLUT10) maintains intracellular levels of ascorbic acid to promote adipogenesis, white adipose tissu...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Chung-Lin Jiang Source Type: research

Congenital hearing impairment associated with peripheral cochlear nerve dysmyelination in glycosylation-deficient muscular dystrophy
by Shigefumi Morioka, Hirofumi Sakaguchi, Hiroaki Mohri, Mariko Taniguchi-Ikeda, Motoi Kanagawa, Toshiaki Suzuki, Yuko Miyagoe-Suzuki, Tatsushi Toda, Naoaki Saito, Takehiko Ueyama Hearing loss (HL) is one of the most common sensory impairments and etiologically and genetically heterogeneous disorders in humans. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. Aberrant gl ycosylation of α-dystroglycan causes at least eighteen subtypes of MD, now categorized as MD-dystroglycanopathy (MD-DG), with a wide spectrum of...
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Shigefumi Morioka Source Type: research

Correction: The persimmon genome reveals clues to the evolution of a lineage-specific sex determination system in plants
by Takashi Akagi, Kenta Shirasawa, Hideki Nagasaki, Hideki Hirakawa, Ryutaro Tao, Luca Comai, Isabelle M. Henry (Source: PLoS Genetics)
Source: PLoS Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Takashi Akagi Source Type: research

A copy number variant is associated with a spectrum of pigmentation patterns in the rock pigeon ( < i > Columba livia < /i > )
by Rebecca Bruders, Hannah Van Hollebeke, Edward J. Osborne, Zev Kronenberg, Emily Maclary, Mark Yandell, Michael D. Shapiro Rock pigeons (Columba livia) display an extraordinary array of pigment pattern variation. One such pattern, Almond, is characterized by a variegated patchwork of plumage colors that are distributed in an apparently random manner. Almond is a sex-linked, semi-dominant trait controlled by the classicalStipper (St) locus. Heterozygous males (ZStZ+ sex chromosomes) and hemizygous Almond females (ZStW) are favored by breeders for their attractive plumage. In contrast, homozygous Almond males (ZStZSt) dev...
Source: PLoS Genetics - May 20, 2020 Category: Genetics & Stem Cells Authors: Rebecca Bruders Source Type: research

Beyond SNP heritability: Polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model
We present a basic model, using detailed linkage disequilibrium structure from a reference panel of 11 million SNPs, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find mod el polygenicities (as a fraction of the reference panel) ranging from ≃ 2 × 10−5 to ≃ 4 × 10−3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching...
Source: PLoS Genetics - May 19, 2020 Category: Genetics & Stem Cells Authors: Dominic Holland Source Type: research

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2
by Dana Lau-Corona, Woo Kyun Bae, Lothar Hennighausen, David J. Waxman Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormo ne secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly...
Source: PLoS Genetics - May 19, 2020 Category: Genetics & Stem Cells Authors: Dana Lau-Corona Source Type: research

Alternative splicing of < i > jnk1a < /i > in zebrafish determines first heart field ventricular cardiomyocyte numbers through modulation of hand2 expression
This study reveals a novel and critical requirement forJnk1 in heart development and highlights the importance of alternative splicing in vertebrate cardiac morphogenesis. Genetic pathways functioning throughjnk1 may be important in human heart malformations with left ventricular hypoplasia. (Source: PLoS Genetics)
Source: PLoS Genetics - May 18, 2020 Category: Genetics & Stem Cells Authors: Adrian Santos-Ledo Source Type: research

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal < i > ITPR1 < /i > as a novel locus influencing fetal growth during sensitive periods in pregnancy
by Fasil Tekola-Ayele, Cuilin Zhang, Jing Wu, Katherine L. Grantz, Mohammad L. Rahman, Deepika Shrestha, Marion Ouidir, Tsegaselassie Workalemahu, Michael Y. Tsai Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performedtrans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during p...
Source: PLoS Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Fasil Tekola-Ayele Source Type: research

The genetic architecture of the maize progenitor, teosinte, and how it was altered during maize domestication
by Qiuyue Chen, Luis Fernando Samayoa, Chin Jian Yang, Peter J. Bradbury, Bode A. Olukolu, Michael A. Neumeyer, Maria Cinta Romay, Qi Sun, Anne Lorant, Edward S. Buckler, Jeffrey Ross-Ibarra, James B. Holland, John F. Doebley The genetics of domestication has been extensively studied ever since the rediscovery of Mendel’s law of inheritance and much has been learned about the genetic control of trait differences between crops and their ancestors. Here, we ask how domestication has altered genetic architecture by comp aring the genetic architecture of 18 domestication traits in maize and its ancestor teosinte using m...
Source: PLoS Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Qiuyue Chen Source Type: research

Activation of cryptic splicing in bovine < i > WDR19 < /i > is associated with reduced semen quality and male fertility
by Maya Hiltpold, Guanglin Niu, Naveen Kumar Kadri, Danang Crysnanto, Zih-Hua Fang, Mirjam Spengeler, Fritz Schmitz-Hsu, Christian Fuerst, Hermann Schwarzenbacher, Franz R. Seefried, Frauke Seehusen, Ulrich Witschi, Angelika Schnieke, Ruedi Fries, Heinrich Bollwein, Krzysztof Flisikowski, Hubert Pausch Cattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomali...
Source: PLoS Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Maya Hiltpold Source Type: research

The temporal regulation of TEK contributes to pollen wall exine patterning
by Shuang-Xi Xiong, Qiu-Ye Zeng, Jian-Qiao Hou, Ling-Li Hou, Jun Zhu, Min Yang, Zhong-Nan Yang, Yue Lou Pollen wall consists of several complex layers which form elaborate species-specific patterns. In Arabidopsis, the transcription factor ABORTED MICROSPORE (AMS) is a master regulator of exine formation, and another transcription factor, TRANSPOSABLE ELEMENT SILENCING VIA AT-HOOK (TEK), specifies f ormation of the nexine layer. However, knowledge regarding the temporal regulatory roles of TEK in pollen wall development is limited. Here, TEK-GFP driven by theAMS promoter was prematurely expressed in the tapetal nuclei, le...
Source: PLoS Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Shuang-Xi Xiong Source Type: research

ASEP: Gene-based detection of allele-specific expression across individuals in a population by RNA sequencing
by Jiaxin Fan, Jian Hu, Chenyi Xue, Hanrui Zhang, Katalin Susztak, Muredach P. Reilly, Rui Xiao, Mingyao Li Allele-specific expression (ASE) analysis, which quantifies the relative expression of two alleles in a diploid individual, is a powerful tool for identifyingcis-regulated gene expression variations that underlie phenotypic differences among individuals. Existing methods for gene-level ASE detection analyze one individual at a time, therefore failing to account for shared information across individuals. Failure to accommodate such shared information not only reduces power, but also makes it difficult to interpret re...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Jiaxin Fan Source Type: research

A cross-disorder PRS-pheWAS of 5 major psychiatric disorders in UK Biobank
by Beate Leppert, Louise A. C. Millard, Lucy Riglin, George Davey Smith, Anita Thapar, Kate Tilling, Esther Walton, Evie Stergiakouli Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 300,000 participants from the UK Biobank to examine...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Beate Leppert Source Type: research

Depletion of Ric-8B leads to reduced mTORC2 activity
by Ma íra H. Nagai, Victor P. S. Xavier, Luciana M. Gutiyama, Cleiton F. Machado, Alice H. Reis, Elisa R. Donnard, Pedro A. F. Galante, Jose G. Abreu, William T. Festuccia, Bettina Malnic mTOR, a serine/threonine protein kinase that is involved in a series of critical cellular processes, can be found in two functionally distinct complexes, mTORC1 and mTORC2. In contrast to mTORC1, little is known about the mechanisms that regulate mTORC2. Here we show that mTORC2 activity is reduce d in mice with a hypomorphic mutation of the Ric-8B gene. Ric-8B is a highly conserved protein that acts as a non-canonical guanine nuc...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Ma íra H. Nagai Source Type: research

The phosphorelay BarA/SirA activates the non-cognate regulator RcsB in < i > Salmonella enterica < /i >
by Hubert Salvail, Eduardo A. Groisman To survive an environmental stress, organisms must detect the stress and mount an appropriate response. One way that bacteria do so is by phosphorelay systems that respond to a stress by activating a regulator that modifies gene expression. To ensure an appropriate response, a given regulator is t ypically activated solely by its cognate phosphorelay protein(s). However, we now report that the regulator RcsB is activated by both cognate and non-cognate phosphorelay proteins depending on the condition experienced by the bacteriumSalmonella enterica serovar Typhimurium. The RcsC and Rc...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Hubert Salvail Source Type: research

Copy number variants  and fixed duplications among 198 rhesus macaques ( < i > Macaca mulatta < /i > )
by Marina Bras ó-Vives, Inna S. Povolotskaya, Diego A. Hartasánchez, Xavier Farré, Marcos Fernandez-Callejo, Muthuswamy Raveendran, R. Alan Harris, Douglas L. Rosene, Belen Lorente-Galdos, Arcadi Navarro, Tomas Marques-Bonet, Jeffrey Rogers, David Juan The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However,...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Marina Bras ó-Vives Source Type: research

Polyploidy breaks speciation barriers in Australian burrowing frogs < i > Neobatrachus < /i >
We describe rapid speciation of diploidNeobatrachus species and show that the three independently originated polyploid species have tetrasomic or mixed inheritance. We document higher genetic diversity in tetraploids, resulting from widespread gene flow between the tetraploids, asymmetric inter-ploidy gene flow directed from sympatric diploids to tetraploids, and isolation of diploid species from each other. We also constructed models of ecologically suitable areas for each species to investigate the impact of climate on differing ploidy levels. These models suggest substantial change in suitable areas compared to past cli...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Polina Yu. Novikova Source Type: research

ASEP: Gene-based detection of allele-specific expression cross individuals in a population by RNA sequencing
by Jiaxin Fan, Jian Hu, Chenyi Xue, Hanrui Zhang, Katalin Susztak, Muredach P. Reilly, Rui Xiao, Mingyao Li Allele-specific expression (ASE) analysis, which quantifies the relative expression of two alleles in a diploid individual, is a powerful tool for identifyingcis-regulated gene expression variations that underlie phenotypic differences among individuals. Existing methods for gene-level ASE detection analyze one individual at a time, therefore failing to account for shared information across individuals. Failure to accommodate such shared information not only reduces power, but also makes it difficult to interpret re...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Jiaxin Fan Source Type: research

ALC1/eIF4A1-mediated regulation of < i > CtIP < /i > mRNA stability controls DNA end resection
by Fernando Mej ías-Navarro, Guillermo Rodríguez-Real, Javier Ramón, Rosa Camarillo, Pablo Huertas During repair of DNA double-strand breaks, resection of DNA ends influences how these lesions will be repaired. If resection is activated, the break will be channeled through homologous recombination; if not, it will be simply ligated using the non-homologous end-joining machinery. Regulation of r esection relies greatly on modulating CtIP, which can be done by modifying: i) its interaction partners, ii) its post-translational modifications, or iii) its cellular levels, by regulating transcription, splic...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Fernando Mej ías-Navarro Source Type: research

Correction:  Regulation of ATG4B Stability by RNF5 Limits Basal Levels of Autophagy and Influences Susceptibility to Bacterial Infection
by Ersheng Kuang, Cheryl Y. M. Okumura, Sharon Sheffy-Levin, Tal Varsano, Vincent Chih-Wen Shu, Jianfei Qi, Ingrid R. Niesman, Huei-Jiun Yang, Carlos L ópez-Otín, Wei Yuan Yang, John C. Reed, Limor Broday, Victor Nizet, Ze'ev A. Ronai (Source: PLoS Genetics)
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Ersheng Kuang Source Type: research

UVR8-mediated inhibition of shade avoidance involves HFR1 stabilization in Arabidopsis
by Eleni Tavridou, Emanuel Schmid-Siegert, Christian Fankhauser, Roman Ulm Sun-loving plants perceive the proximity of potential light-competing neighboring plants as a reduction in the red:far-red ratio (R:FR), which elicits a suite of responses called the “shade avoidance syndrome” (SAS). Changes in R:FR are primarily perceived by phytochrome B (phyB), whereas UV-B perceived by UV RESISTANCE LOCUS 8 (UVR8) elicits opposing responses to provide a counterbalance to SAS, including reduced shade-induced hypocotyl and petiole elongation. Here we show at the genome-wide level that UVR8 broadly suppresses shade-ind...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Eleni Tavridou Source Type: research

Dynamic genetic architecture of yeast response to environmental perturbation shed light on origin of cryptic genetic variation
by Yanjun Zan, Örjan Carlborg Cryptic genetic variation could arise from, for example, Gene-by-Gene (G-by-G) or Gene-by-Environment (G-by-E) interactions. The underlying molecular mechanisms and how they influence allelic effects and the genetic variance of complex traits is largely unclear. Here, we empirically explored the r ole of environmentally influenced epistasis on the suppression and release of cryptic variation by reanalysing a dataset of 4,390 haploid yeast segregants phenotyped on 20 different media. The focus was on 130 epistatic loci, each contributing to segregant growth in at least one environment and...
Source: PLoS Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Yanjun Zan Source Type: research

An EHBP-1-SID-3-DYN-1 axis promotes membranous tubule fission during endocytic recycling
by Jinghu Gao, Linyue Zhao, Qian Luo, Shuyao Liu, Ziyang Lin, Peixiang Wang, Xin Fu, Juan Chen, Hongjie Zhang, Long Lin, Anbing Shi The ACK family tyrosine kinase SID-3 is involved in the endocytic uptake of double-stranded RNA. Here we identified SID-3 as a previously unappreciated recycling regulator in theCaenorhabditis elegans intestine. The RAB-10 effector EHBP-1 is required for the endosomal localization of SID-3. Accordingly, animals with loss of SID-3 phenocopied the recycling defects observed inehbp-1 andrab-10 single mutants. Moreover, we detected sequential protein interactions between EHBP-1, SID-3, NCK-1, and...
Source: PLoS Genetics - May 8, 2020 Category: Genetics & Stem Cells Authors: Jinghu Gao Source Type: research

Separable, Ctf4-mediated recruitment of DNA Polymerase α for initiation of DNA synthesis at replication origins and lagging-strand priming during replication elongation
by Sarina Y. Porcella, Natasha C. Koussa, Colin P. Tang, Daphne N. Kramer, Priyanka Srivastava, Duncan J. Smith During eukaryotic DNA replication, DNA polymerase alpha/primase (Pol α) initiates synthesis on both the leading and lagging strands. It is unknown whether leading- and lagging-strand priming are mechanistically identical, and whether Pol α associates processively or distributively with the repli some. Here, we titrate cellular levels of Pol α inS.cerevisiae and analyze Okazaki fragments to study both replication initiation and ongoing lagging-strand synthesisin vivo. We observe that both Okazak...
Source: PLoS Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Sarina Y. Porcella Source Type: research

Bidirectional crosstalk between Hypoxia-Inducible Factor and glucocorticoid signalling in zebrafish larvae
by Davide Marchi, Kirankumar Santhakumar, Eleanor Markham, Nan Li, Karl-Heinz Storbeck, Nils Krone, Vincent T. Cunliffe, Fredericus J. M. van Eeden In the last decadesin vitro studies highlighted the potential for crosstalk between Hypoxia-Inducible Factor-(HIF) and glucocorticoid-(GC) signalling pathways. However, how this interplay precisely occursin vivo is still debated. Here, we use zebrafish larvae (Danio rerio) to elucidate how and to what degree hypoxic signalling affects the endogenous glucocorticoid pathway andvice versa,in vivo. Firstly, our results demonstrate that in the presence of upregulated HIF signalling...
Source: PLoS Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Davide Marchi Source Type: research

Additive and mostly adaptive plastic responses of gene expression to multiple stress in < i > Tribolium castaneum < /i >
by Eva L. Koch, Fr édéric Guillaume Gene expression is known to be highly responsive to the environment and important for adjustment of metabolism but there is also growing evidence that differences in gene regulation contribute to species divergence and differences among locally adapted populations. However, most studies so far inv estigated populations when divergence had already occurred. Selection acting on expression levels at the onset of adaptation to an environmental change has not been characterized. Understanding the mechanisms is further complicated by the fact that environmental change is often m...
Source: PLoS Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Eva L. Koch Source Type: research

Accounting for long-range correlations in genome-wide simulations of large cohorts
We present a Wright-Fisher extension to msprime, and show that it produces more realistic distributions of IBD, LD, and ancestry proportions, while also addressing more subtle biases of the coalescent. Further, these extensions are more computationally efficient than state-of-the-art coalescent simulations when simulating long regions, including whole-genome data. For shorter regions, efficiency can be maintained via a hybrid model which simulates the recent past under the Wright-Fisher model and uses coa lescent simulations in the distant past. (Source: PLoS Genetics)
Source: PLoS Genetics - May 5, 2020 Category: Genetics & Stem Cells Authors: Dominic Nelson Source Type: research

Rare protein-altering variants in < i > ANGPTL7 < /i > lower intraocular pressure and protect against glaucoma
by Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Guhan Venkataraman, Susanna Lemmel ä, Joni A. Turunen, Robert R. Graham, Aki S. Havulinna, Markus Perola, Aarno Palotie, FinnGen , Mark J. Daly, Manuel A. Rivas Protein-altering variants that are protective against human disease providein vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-alte...
Source: PLoS Genetics - May 5, 2020 Category: Genetics & Stem Cells Authors: Yosuke Tanigawa Source Type: research

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei
by Shan Jiang, Katherine Williams, Xiangduo Kong, Weihua Zeng, Nam Viet Nguyen, Xinyi Ma, Rabi Tawil, Kyoko Yokomori, Ali Mortazavi FSHD is characterized by the misexpression ofDUX4 in skeletal muscle. AlthoughDUX4 upregulation is thought to be the pathogenic cause of FSHD,DUX4 is lowly expressed in patient samples, and analysis of the consequences ofDUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile ofDUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upreg...
Source: PLoS Genetics - May 4, 2020 Category: Genetics & Stem Cells Authors: Shan Jiang Source Type: research

Simultaneous SNP selection and adjustment for population structure in high dimensional prediction models
by Sahir R. Bhatnagar, Yi Yang, Tianyuan Lu, Erwin Schurr, JC Loredo-Osti, Marie Forest, Karim Oualkacha, Celia M. T. Greenwood Complex traits are known to be influenced by a combination of environmental factors and rare and common genetic variants. However, detection of such multivariate associations can be compromised by low statistical power and confounding by population structure. Linear mixed effects models (LMM) can account for correlations due to relatedness but have not been applicable in high-dimensional (HD) settings where the number of fixed effect predictors greatly exceeds the number of samples. False positiv...
Source: PLoS Genetics - May 4, 2020 Category: Genetics & Stem Cells Authors: Sahir R. Bhatnagar Source Type: research