DOCSLIB.ORG

Genome-Wide Detection of Natural Selection in African Americans Pre- and Post-Admixture

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genome-Wide Detection of Natural Selection in African Americans Pre- and Post-Admixture Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Method Genome-wide detection of natural selection in African Americans pre- and post-admixture Wenfei Jin,1 Shuhua Xu,1,6 Haifeng Wang,2 Yongguo Yu,3 Yiping Shen,4,5 Bailin Wu,4,5 and Li Jin1,4,6 1Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 2Chinese National Human Genome Center, Shanghai 201203, China; 3Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; 4Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China; 5Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal single nucleotide poly- morphisms (SNPs) genotyped in 5210 individuals and conducted a genome-wide search for selection signals in 1890 AfA. Several genomic regions showing an excess of African or European ancestry, which were considered the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre- and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF). Interestingly, many selection-candidate genes identified by the new approach were associated with AfA-specific high- risk diseases such as prostate cancer and hypertension, suggesting an important role these disease-related genes might have played in adapting to a new environment. CD36 and HBB, whose mutations confer a degree of protection against malaria, were also located in the highly differentiated regions between AAF and IAF. Further analysis showed that the frequencies of alleles protecting against malaria in AAF were lower than those in IAF, which is consistent with the relaxed selection pressure of malaria in the New World. There is no overlap between the top candidate genes detected by the two approaches, indicating the different environmental pressures AfA experienced pre- and post-population admixture. We suggest that the new approach is reasonably powerful and can also be applied to other admixed populations such as Latinos and Uyghurs. [Supplemental material is available for this article.] Although the vast majority of human genetic variations evolve might reflect the natural selection since the two split. In this case, neutrally, some parts, however, have been shaped by natural se- we used African Americans, a well-studied admixed population, as lection (Kimura 2003; Balaresque et al. 2007). Studies on recent the object of our study. natural selection have led to the discovery of genes showing African Americans (AfA) are residents of the United States population differences in adapting to pathogens, diet, climate, and with partial recent Sub-Saharan African ancestry. The majority of other environmental challenges. These discoveries have greatly them are descendents of the Africans, probably 500,000 to 650,000 enriched our understanding about the origins and also the evolu- in number, who were forcibly brought to North America during the tionary history of the human species, identified many genes with Middle Passage (Thomas 1999; Zakharia et al. 2009). However, important biological functions, and will lead to further elucidation many of those captive Africans died either during the Atlantic of the genetic basis of some human diseases (Balaresque et al. 2007; shipment to America due to the severe conditions, or soon upon Nielsen et al. 2007; Sabeti et al. 2007; Hancock et al. 2008; Akey their arrival in the New World as a result of exposure to foreign 2009). The recent availability of high-density SNPs has provided pathogens and/or the poor living conditions. Although the exact essential resources for genome-wide detection of natural selection, amount of life lost in this process remains a mystery, it may equal especially in ethnically well-defined populations with little ad- or exceed the actual amount enslaved (Stannard 1993). Therefore, mixture (Sabeti et al. 2007; Barreiro et al. 2008; Akey 2009). Al- the high mortality of AfA in the whole slavery era could be attributed though there have been several studies on recently admixed pop- to the overwhelming environmental challenges. These persistent ulations (Tang et al. 2007; Basu et al. 2008; Bryc et al. 2010), no selection pressures might make the frequencies of ‘‘beneficial’’ alleles study so far has particularly investigated the locus-specific pop- increase continually, which should lead to higher population differ- ulation differentiation between the ancestral components of an entiation between African components of ancestry in AfA and in- admixed population and its ancestral parental population, which digenous Africans at these loci, in contrast to those evolved neutrally. Meanwhile, before Africans and Europeans migrated to the New World, their ancestral parental populations had evolved in- 6Corresponding authors. dependently in distinct environments for tens of thousands of E-mail [email protected]. years (Basu et al. 2008). The completely new environment in the E-mail [email protected]. Article published online before print. Article, supplemental material, and publi- New World constituted a challenge for both populations and the cation date are at http://www.genome.org/cgi/doi/10.1101/gr.124784.111. populations of their admixture. Therefore, it is very likely that 22:519–527 Ó 2012 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/12; www.genome.org Genome Research 519 www.genome.org Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Jin et al. some genomic regions in AfA show an excess of a particular an- of 88 CEU and 88 YRI (the phased parents of trios, presumably cestry as a result of selection pressures after the population admixture unrelated, from HapMap3 data) to represent their ancestral pa- (Tang et al. 2007; Basu et al. 2008). For example, there are various rental populations. The identical monomorphic SNPs in CEU and studies in detecting signatures of selection in AfA by examining ad- YRI samples were removed for they could not provide valuable mixture proportion using a small number of available loci (Workman information in the local ancestry inference. HAPMIX (Price et al. et al. 1963; Reed 1969; Blumberg and Hesser 1971; Adams and Ward 2009) was employed to estimate the locus-specific genetic contri- 1973; Long 1991). Recently, Bryc et al. (2010) identified three auto- butions of the ancestral parental populations to AfA (see Methods) somal regions showing excessive or reduced African ancestry (by at by taking 21.65% as the European contribution, as estimated by least three standard deviations [SD] of the mean) as natural selection FRAPPE. Based on the likelihood given by HAPMIX, generation since candidates based on ;500K SNPs genotyped in 365 AfA. admixture (l) was estimated to be l = 7 (an essentially hybrid iso- Here, we analyzed the genotype data from ;500,000 auto- lation model), which was similar to those based on other AfA data somal SNPs shared by 1890 AfA and 3320 non-AfA for detecting sets (Smith et al. 2004; Price et al. 2009). Detailed analysis showed the signatures of selection in AfA that were classified into pre- that l values for most individuals ranged from 1 to 12, and could be admixture and post-admixture according to the different envi- explained by a continuous-gene-flow (CGF) model (see Supple- ronments they experienced (Supplemental Fig. S1). Firstly, we de- mental Text and Supplemental Fig. S6). The locus-specific European tected the natural selections that were more likely to occur after ancestry proportion across the genome of AfA was estimated to be admixture by examining the genome-wide distribution of ancestry 21.68% 6 0.75% (mean 6 SD). The SD of locus-specific ancestral in AfA. Then we developed a new strategy by reconstructing an genetic contributions in this study is lower than those in any pre- ancestral African population (AAF) from inferred African compo- vious studies (Workman et al. 1963; Reed 1969; Blumberg and Hesser nents of ancestry in AfA and comparing it with indigenous African 1971; Tang et al. 2007; Basu et al. 2008; Bryc et al. 2010), which was populations (IAF) (Supplemental Fig. S2), which reflect natural not beyond our expectation since we used a much larger sample size. selection since the African ancestors of AfA left Africa (including The genomic regions showing excessive or reduced ancestry both pre- and post-admixture). Many candidate genes identified in the admixed population are likely to be signatures of natural se- by our new approach could explain the challenges that AfA and lection (Tang et al. 2007; Basu et al. 2008; Bryc et al. 2010; Oleksyk their ancestry had experienced. Thus we suggest that our new et al. 2010). The loci showing strong deviation of European an- approach is reasonably powerful and can also be applied to the cestry (3 SDs above or below the genome-wide average) were studies of other admixed populations. therefore identified as candidates of natural selection in this study. Four regions (2p22, 3q13, 6q26, 16q21) with excessive European Results influence and two regions (1p36, 2q37) with excessive African influence were observed in AfA genomes (Fig. 1). Each of the six African and European ancestries in AfA regions was significantly different from the genome-wide average À16 The populations from West Africa and Europe, who had undoubtedly of ancestral contributions (P < 2.2 3 10 , t-test).
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • The Role of Cdep in the Embryonic Morphogenesis of Drosophila Melanogaster
    The Role of Cdep in the Embryonic Morphogenesis of Drosophila melanogaster Dissertation zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer.nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von Anne Morbach Geboren am 05. August 1984 in Nordhausen, Deutschland Eingereicht am 30. Oktober 2015 Die Dissertation wurde in der Zeit von April 2012 bis Oktober 2015 im Max-Planck-Institut für molekulare Zellbiologie und Genetik angefertigt Gutachter: Prof. Dr. Elisabeth Knust Prof. Dr. Christian Dahmann Now, here, you see, it takes all the running you can do, to keep in the same place. Lewis Carroll, Through the Looking-Glass I Contents List of Figures V List of Tables VII Abstract IX List of Abbreviations XI 1 Introduction 1 1.1 Epithelial cell polarity . 1 1.1.1 Cellularization and formation of the primary epithelium . 1 1.1.1.1 Establishment of epithelial polarity and adhesion . 2 1.1.2 The epithelial polarity network . 3 1.1.3 Cell-cell adhesion . 5 1.1.3.1 Adherens junctions . 5 1.1.3.2 Septate junctions . 6 1.2 Epithelial movements in Drosophila embryonic morphogenesis . 6 1.2.1 Epithelial tube formation during Drosophila embryogenesis . 7 1.2.2 Coordinated migration of epithelial sheets during Dros. embryogenesis 7 1.2.2.1 FERM domain proteins in epithelial migration . 9 1.2.2.2 Cdep . 10 1.3 Mutagenesis with the CRISPR/Cas9 system . 12 2 Aim of My PhD Thesis Work 15 3 Preliminary Work 17 4 Results 19 4.1 A screen for novel regulators in Drosophila embryonic morphogenesis .
    [Show full text]
  • Transcriptomic and Proteomic Profiling Provides Insight Into
    BASIC RESEARCH www.jasn.org Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy † † ‡ Peidi Liu,* Emelie Lassén,* Viji Nair, Celine C. Berthier, Miyuki Suguro, Carina Sihlbom,§ † | † Matthias Kretzler, Christer Betsholtz, ¶ Börje Haraldsson,* Wenjun Ju, Kerstin Ebefors,* and Jenny Nyström* *Department of Physiology, Institute of Neuroscience and Physiology, §Proteomics Core Facility at University of Gothenburg, University of Gothenburg, Gothenburg, Sweden; †Division of Nephrology, Department of Internal Medicine and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; ‡Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan; |Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; and ¶Integrated Cardio Metabolic Centre, Karolinska Institutet Novum, Huddinge, Sweden ABSTRACT IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type–specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell–positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell–positive standard genes.
    [Show full text]
  • Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis
    The Journal of Neuroscience, July 8, 2020 • 40(28):5413–5430 • 5413 Development/Plasticity/Repair Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis Victor Danelon,1* Ron Goldner,2* Edward Martinez,1 Irena Gokhman,2 Kimberly Wang,1 Avraham Yaron,2 and Tracy S. Tran1 1Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, and 2Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel Diverse neuronal populations with distinct cellular morphologies coordinate the complex function of the nervous system. Establishment of distinct neuronal morphologies critically depends on signaling pathways that control axonal and dendritic devel- opment. The Sema3A-Nrp1/PlxnA4 signaling pathway promotes cortical neuron basal dendrite arborization but also repels axons. However, the downstream signaling components underlying these disparate functions of Sema3A signaling are unclear. Using the KRK-AAA novel PlxnA4 knock-in male and female mice, generated by CRISPR/cas9, we show here that the KRK motif in the PlxnA4 cytoplasmic domain is required for Sema3A-mediated cortical neuron dendritic elaboration but is dispensable for inhibitory axon guidance. The RhoGEF FARP2, which binds to the KRK motif, shows identical functional specificity as the KRK motif in the PlxnA4 receptor. We find that Sema3A activates the small GTPase Rac1, and that Rac1 activity is required for dendrite elaboration but not axon growth cone collapse. This work identifies a novel Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signaling pathway that specifi- cally controls dendritic morphogenesis but is dispensable for repulsive guidance events. Overall, our results demonstrate that the divergent signaling output from multifunctional receptor complexes critically depends on distinct signaling motifs, highlighting the modular nature of guidance cue receptors and its potential to regulate diverse cellular responses.
    [Show full text]
  • Alternate-Locus Aware Variant Calling in Whole Genome Sequencing Marten Jäger1,2, Max Schubach1, Tomasz Zemojtel1,Knutreinert3, Deanna M
    Jäger et al. Genome Medicine (2016) 8:130 DOI 10.1186/s13073-016-0383-z RESEARCH Open Access Alternate-locus aware variant calling in whole genome sequencing Marten Jäger1,2, Max Schubach1, Tomasz Zemojtel1,KnutReinert3, Deanna M. Church4 and Peter N. Robinson1,2,3,5,6* Abstract Background: The last two human genome assemblies have extended the previous linear golden-path paradigm of the human genome to a graph-like model to better represent regions with a high degree of structural variability. The new model offers opportunities to improve the technical validity of variant calling in whole-genome sequencing (WGS). Methods: We developed an algorithm that analyzes the patterns of variant calls in the 178 structurally variable regions of the GRCh38 genome assembly, and infers whether a given sample is most likely to contain sequences from the primary assembly, an alternate locus, or their heterozygous combination at each of these 178 regions. We investigate 121 in-house WGS datasets that have been aligned to the GRCh37 and GRCh38 assemblies. Results: We show that stretches of sequences that are largely but not entirely identical between the primary assembly and an alternate locus can result in multiple variant calls against regions of the primary assembly. In WGS analysis, this results in characteristic and recognizable patterns of variant calls at positions that we term alignable scaffold-discrepant positions (ASDPs). In 121 in-house genomes, on average 51.8 ± 3.8 of the 178 regions were found to correspond best to an alternate locus rather than the primary assembly sequence, and filtering these genomes with our algorithm led to the identification of 7863 variant calls per genome that colocalized with ASDPs.
    [Show full text]
  • A Set of Regulatory Genes Co-Expressed in Embryonic Human Brain Is Implicated in Disrupted Speech Development
    Molecular Psychiatry https://doi.org/10.1038/s41380-018-0020-x ARTICLE A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development 1 1 1 2 3 Else Eising ● Amaia Carrion-Castillo ● Arianna Vino ● Edythe A. Strand ● Kathy J. Jakielski ● 4,5 6 7 8 9 Thomas S. Scerri ● Michael S. Hildebrand ● Richard Webster ● Alan Ma ● Bernard Mazoyer ● 1,10 4,5 6,11 6,12 13 Clyde Francks ● Melanie Bahlo ● Ingrid E. Scheffer ● Angela T. Morgan ● Lawrence D. Shriberg ● Simon E. Fisher 1,10 Received: 22 September 2017 / Revised: 3 December 2017 / Accepted: 2 January 2018 © The Author(s) 2018. This article is published with open access Abstract Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, CHD3 SETD1A WDR5 fi 1234567890();,: we discovered de novo mutations, implicating genes, including , and . In other probands, we identi ed novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.
    [Show full text]
  • A Draft Map of the Human Proteome
    ARTICLE doi:10.1038/nature13302 A draft map of the human proteome Min-Sik Kim1,2, Sneha M. Pinto3, Derese Getnet1,4, Raja Sekhar Nirujogi3, Srikanth S. Manda3, Raghothama Chaerkady1,2, Anil K. Madugundu3, Dhanashree S. Kelkar3, Ruth Isserlin5, Shobhit Jain5, Joji K. Thomas3, Babylakshmi Muthusamy3, Pamela Leal-Rojas1,6, Praveen Kumar3, Nandini A. Sahasrabuddhe3, Lavanya Balakrishnan3, Jayshree Advani3, Bijesh George3, Santosh Renuse3, Lakshmi Dhevi N. Selvan3, Arun H. Patil3, Vishalakshi Nanjappa3, Aneesha Radhakrishnan3, Samarjeet Prasad1, Tejaswini Subbannayya3, Rajesh Raju3, Manish Kumar3, Sreelakshmi K. Sreenivasamurthy3, Arivusudar Marimuthu3, Gajanan J. Sathe3, Sandip Chavan3, Keshava K. Datta3, Yashwanth Subbannayya3, Apeksha Sahu3, Soujanya D. Yelamanchi3, Savita Jayaram3, Pavithra Rajagopalan3, Jyoti Sharma3, Krishna R. Murthy3, Nazia Syed3, Renu Goel3, Aafaque A. Khan3, Sartaj Ahmad3, Gourav Dey3, Keshav Mudgal7, Aditi Chatterjee3, Tai-Chung Huang1, Jun Zhong1, Xinyan Wu1,2, Patrick G. Shaw1, Donald Freed1, Muhammad S. Zahari2, Kanchan K. Mukherjee8, Subramanian Shankar9, Anita Mahadevan10,11, Henry Lam12, Christopher J. Mitchell1, Susarla Krishna Shankar10,11, Parthasarathy Satishchandra13, John T. Schroeder14, Ravi Sirdeshmukh3, Anirban Maitra15,16, Steven D. Leach1,17, Charles G. Drake16,18, Marc K. Halushka15, T. S. Keshava Prasad3, Ralph H. Hruban15,16, Candace L. Kerr19{, Gary D. Bader5, Christine A. Iacobuzio-Donahue15,16,17, Harsha Gowda3 & Akhilesh Pandey1,2,3,4,15,16,20 The availability of human genome sequence has transformed biomedical research over the past decade. However, an equiv- alent map for the human proteome with direct measurements of proteins and peptides does not exist yet. Here we present a draft map of the human proteome using high-resolution Fourier-transform mass spectrometry.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • MAP17's Up-Regulation, a Crosspoint in Cancer and Inflammatory
    García-Heredia and Carnero Molecular Cancer (2018) 17:80 https://doi.org/10.1186/s12943-018-0828-7 REVIEW Open Access Dr. Jekyll and Mr. Hyde: MAP17’s up- regulation, a crosspoint in cancer and inflammatory diseases José M. García-Heredia1,2,3 and Amancio Carnero1,3* Abstract Inflammation is a common defensive response that is activated after different harmful stimuli. This chronic, or pathological, inflammation is also one of the causes of neoplastic transformation and cancer development. MAP17 is a small protein localized to membranes with a restricted pattern of expression in adult tissues. However, its expression is common in destabilized cells, as it is overexpressed both in inflammatory diseases and in cancer. MAP17 is overexpressed in most, if not all, carcinomas and in many tumors of mesenchymal origin, and correlates with higher grade and poorly differentiated tumors. This overexpression drives deep changes in cell homeostasis including increased oxidative stress, deregulation of signaling pathways and increased growth rates. Importantly, MAP17 is associated in tumors with inflammatory cells infiltration, not only in cancer but in various inflammatory diseases such as Barret’s esophagus, lupus, Crohn’s, psoriasis and COPD. Furthermore, MAP17 also modifies the expression of genes connected to inflammation, showing a clear induction of the inflammatory profile. Since MAP17 appears highly correlated with the infiltration of inflammatory cells in cancer, is MAP17 overexpression an important cellular event connecting tumorigenesis and inflammation? Keywords: MAP17, Cancer, Inflammatory diseases Background process ends when the activated cells undergo apoptosis in Inflammatory response is a common defensive process acti- a highly regulated process that finishes after pathogens and vated after different harmful stimuli, constituting a highly cell debris have been phagocytized [9].
    [Show full text]
  • Genomic and Transcriptome Analysis Revealing an Oncogenic Functional Module in Meningiomas
    Neurosurg Focus 35 (6):E3, 2013 ©AANS, 2013 Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas XIAO CHANG, PH.D.,1 LINGLING SHI, PH.D.,2 FAN GAO, PH.D.,1 JONATHAN RUssIN, M.D.,3 LIYUN ZENG, PH.D.,1 SHUHAN HE, B.S.,3 THOMAS C. CHEN, M.D.,3 STEVEN L. GIANNOTTA, M.D.,3 DANIEL J. WEISENBERGER, PH.D.,4 GAbrIEL ZADA, M.D.,3 KAI WANG, PH.D.,1,5,6 AND WIllIAM J. MAck, M.D.1,3 1Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California; 2GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China; 3Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California; 4USC Epigenome Center, Keck School of Medicine, University of Southern California, Los Angeles, California; 5Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, California; and 6Division of Bioinformatics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California Object. Meningiomas are among the most common primary adult brain tumors. Although typically benign, roughly 2%–5% display malignant pathological features. The key molecular pathways involved in malignant trans- formation remain to be determined. Methods. Illumina expression microarrays were used to assess gene expression levels, and Illumina single- nucleotide polymorphism arrays were used to identify copy number variants in benign, atypical, and malignant me- ningiomas (19 tumors, including 4 malignant ones). The authors also reanalyzed 2 expression data sets generated on Affymetrix microarrays (n = 68, including 6 malignant ones; n = 56, including 3 malignant ones).
    [Show full text]
  • Genome-Wide DNA Methylation Dynamics During Epigenetic
    Gómez‑Redondo et al. Clin Epigenet (2021) 13:27 https://doi.org/10.1186/s13148‑021‑01003‑x RESEARCH Open Access Genome‑wide DNA methylation dynamics during epigenetic reprogramming in the porcine germline Isabel Gómez‑Redondo1*† , Benjamín Planells1†, Sebastián Cánovas2,3, Elena Ivanova4, Gavin Kelsey4,5 and Alfonso Gutiérrez‑Adán1 Abstract Background: Prior work in mice has shown that some retrotransposed elements remain substantially methylated during DNA methylation reprogramming of germ cells. In the pig, however, information about this process is scarce. The present study was designed to examine the methylation profles of porcine germ cells during the time course of epigenetic reprogramming. Results: Sows were artifcially inseminated, and their fetuses were collected 28, 32, 36, 39, and 42 days later. At each time point, genital ridges were dissected from the mesonephros and germ cells were isolated through magnetic‑ activated cell sorting using an anti‑SSEA‑1 antibody, and recovered germ cells were subjected to whole‑genome bisulphite sequencing. Methylation levels were quantifed using SeqMonk software by performing an unbiased analysis, and persistently methylated regions (PMRs) in each sex were determined to extract those regions showing 50% or more methylation. Most genomic elements underwent a dramatic loss of methylation from day 28 to day 36, when the lowest levels were shown. By day 42, there was evidence for the initiation of genomic re‑methylation. We identifed a total of 1456 and 1122 PMRs in male and female germ cells, respectively, and large numbers of transpos‑ able elements (SINEs, LINEs, and LTRs) were found to be located within these PMRs. Twenty‑one percent of the introns located in these PMRs were found to be the frst introns of a gene, suggesting their regulatory role in the expression of these genes.
    [Show full text]
  • Egfr Activates a Taz-Driven Oncogenic Program in Glioblastoma
    EGFR ACTIVATES A TAZ-DRIVEN ONCOGENIC PROGRAM IN GLIOBLASTOMA by Minling Gao A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 ©2020 Minling Gao All rights reserved Abstract Hyperactivated EGFR signaling is associated with about 45% of Glioblastoma (GBM), the most aggressive and lethal primary brain tumor in humans. However, the oncogenic transcriptional events driven by EGFR are still incompletely understood. We studied the role of the transcription factor TAZ to better understand master transcriptional regulators in mediating the EGFR signaling pathway in GBM. The transcriptional coactivator with PDZ- binding motif (TAZ) and its paralog gene, the Yes-associated protein (YAP) are two transcriptional co-activators that play important roles in multiple cancer types and are regulated in a context-dependent manner by various upstream signaling pathways, e.g. the Hippo, WNT and GPCR signaling. In GBM cells, TAZ functions as an oncogene that drives mesenchymal transition and radioresistance. This thesis intends to broaden our understanding of EGFR signaling and TAZ regulation in GBM. In patient-derived GBM cell models, EGF induced TAZ and its known gene targets through EGFR and downstream tyrosine kinases (ERK1/2 and STAT3). In GBM cells with EGFRvIII, an EGF-independent and constitutively active mutation, TAZ showed EGF- independent hyperactivation when compared to EGFRvIII-negative cells. These results revealed a novel EGFR-TAZ signaling axis in GBM cells. The second contribution of this thesis is that we performed next-generation sequencing to establish the first genome-wide map of EGF-induced TAZ target genes.
    [Show full text]