Genome-Wide Identification of Susceptibility Alleles for Viral Infections through a Population Genetics Approach

Viruses have exerted a constant and potent selective pressure on human genes throughout evolution. We utilized the marks left by selection on allele frequency to identify viral infection-associated allelic variants. Virus diversity (the number of different viruses in a geographic region) was used to measure virus-driven selective pressure. Results showed an excess of variants correlated with virus diversity in genes involved in immune response and in the biosynthesis of glycan structures functioning as viral receptors; a significantly higher than expected number of variants was also seen in genes encoding proteins that directly interact with viral components. Genome-wide analyses identified 441 variants significantly associated with virus-diversity; these are more frequently located within gene regions than expected, and they map to 139 human genes. Analysis of functional relationships among genes subjected to virus-driven selective pressure identified a complex network enriched in viral products-interacting proteins. The novel approach to the study of infectious disease epidemiology presented herein may represent an alternative to classic genome-wide association studies and provides a large set of candidate susceptibility variants for viral infections.

[1]  Keyang Chen,et al.  Virion-associated Uracil DNA Glycosylase-2 and Apurinic/Apyrimidinic Endonuclease Are Involved in the Degradation of APOBEC3G-edited Nascent HIV-1 DNA* , 2007, Journal of Biological Chemistry.

[2]  N. Suttorp,et al.  Tumor necrosis factor-alpha-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability. , 2005, Blood.

[3]  Osamu Takeuchi,et al.  Genetic analysis of resistance to viral infection , 2007, Nature Reviews Immunology.

[4]  A. Srinivasan,et al.  Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses , 2008, Proceedings of the National Academy of Sciences.

[5]  佐野 晃之.  Regulation of the innate immune response by threonine-phosphatase of eyes absent and the characterization of their phosphatase activity , 2012 .

[6]  Matthew D. Dyer,et al.  The Landscape of Human Proteins Interacting with Viruses and Other Pathogens , 2008, PLoS pathogens.

[7]  Anushya Muruganujan,et al.  Applications for protein sequence–function evolution data: mRNA/protein expression analysis and coding SNP scoring tools , 2006, Nucleic Acids Res..

[8]  S. Nagata,et al.  Regulation of the innate immune response by threonine-phosphatase of Eyes absent , 2009, Nature.

[9]  James H. Brown,et al.  Response to Comment on "Global Biodiversity, Biochemical Kinetics, and the Energetic-Equivalence Rule" , 2003, Science.

[10]  G. Crabtree,et al.  Identification of a putative regulator of early T cell activation genes. , 1988, Science.

[11]  J. Marth,et al.  Structural and Mechanistic Features of Protein O Glycosylation Linked to CD8+ T-Cell Apoptosis , 2006, Molecular and Cellular Biology.

[12]  Matteo Fumagalli,et al.  Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions , 2009, The Journal of experimental medicine.

[13]  David B. Witonsky,et al.  Adaptations to Climate in Candidate Genes for Common Metabolic Disorders , 2008, PLoS genetics.

[14]  T. Horan,et al.  CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues1 , 2006, The Journal of Immunology.

[15]  T. Bergström,et al.  Herpes simplex virus type 1 glycoprotein C is necessary for efficient infection of chondroitin sulfate-expressing gro2C cells. , 2002, The Journal of general virology.

[16]  Pardis C Sabeti,et al.  Genome-wide detection and characterization of positive selection in human populations , 2007, Nature.

[17]  M. Clerici,et al.  Genetic correlates of protection against HIV infection: the ally within , 2009, Journal of internal medicine.

[18]  F. Balloux,et al.  Pathogen-Driven Selection and Worldwide HLA Class I Diversity , 2005, Current Biology.

[19]  T. Yamamura,et al.  Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines , 2008, Proceedings of the National Academy of Sciences.

[20]  Y. Berthiaume,et al.  Dexamethasone inhibits the action of TNF on ENaC expression and activity. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[21]  L. Quintana-Murci,et al.  Natural selection has driven population differentiation in modern humans , 2008, Nature Genetics.

[22]  A. Srinivasan,et al.  Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin , 2008, Nature Biotechnology.

[23]  N. Rosenberg,et al.  Standardized Subsets of the HGDP‐CEPH Human Genome Diversity Cell Line Panel, Accounting for Atypical and Duplicated Samples and Pairs of Close Relatives , 2006, Annals of human genetics.

[24]  N. Reich,et al.  The early expressed HIV-1 genes regulate DNMT1 expression , 2008, Epigenetics.

[25]  Christian Gautier,et al.  VirHostNet: a knowledge base for the management and the analysis of proteome-wide virus–host interaction networks , 2008, Nucleic Acids Res..

[26]  E. Argyris,et al.  The perlecan heparan sulfate proteoglycan mediates cellular uptake of HIV-1 Tat through a pathway responsible for biological activity. , 2004, Virology.

[27]  A. Chakravarti,et al.  Differential Susceptibility to Hypertension Is Due to Selection during the Out-of-Africa Expansion , 2005, PLoS genetics.

[28]  E. Argyris,et al.  Human Immunodeficiency Virus Type 1 Enters Primary Human Brain Microvascular Endothelial Cells by a Mechanism Involving Cell Surface Proteoglycans Independent of Lipid Rafts , 2003, Journal of Virology.

[29]  K. Campbell,et al.  Old World and Clade C New World Arenaviruses Mimic the Molecular Mechanism of Receptor Recognition Used by α-Dystroglycan's Host-Derived Ligands , 2007, Journal of Virology.

[30]  Ari Helenius,et al.  Virus entry by macropinocytosis , 2009, Nature Cell Biology.

[31]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[32]  R. Albert.  Scale-free networks in cell biology , 2005, Journal of Cell Science.

[33]  M. Day,et al.  Human polyomavirus BKV transcriptionally activates DNA methyltransferase 1 through the pRb/E2F pathway , 2006, Oncogene.

[34]  John Novembre,et al.  Spatial patterns of variation due to natural selection in humans , 2009, Nature Reviews Genetics.

[35]  Marijan Gerencer,et al.  Identification of HIV-1 protease cleavage site in human C1-inhibitor. , 2004, Virus research.

[36]  David I. Smith,et al.  Role for the p53 homologue p73 in E2F-1-induced apoptosis , 2000, Nature.

[37]  F. Chan,et al.  Functional redundancy of the Nur77 and Nor‐1 orphan steroid receptors in T‐cell apoptosis , 1997, The EMBO journal.

[38]  P. Gasque,et al.  Neuroinvasion by pathogens: a key role of the complement system. , 2002, Molecular immunology.

[39]  G. Pfeifer,et al.  3-Methyladenine-DNA Glycosylase (MPG Protein) Interacts with Human RAD23 Proteins* , 2000, The Journal of Biological Chemistry.

[40]  C. Drouet,et al.  Hepatitis C virus NS3 serine protease interacts with the serpin C1 inhibitor , 1999, FEBS letters.

[41]  R. J. Cho,et al.  Transcription, genomes, function. , 2000, Trends in genetics : TIG.

[42]  T. Stehle,et al.  The Polyomaviridae: Contributions of virus structure to our understanding of virus receptors and infectious entry , 2009, Virology.

[43]  J. Casanova,et al.  Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases , 2007, Nature Immunology.

[44]  R. Jaenisch,et al.  DNA Methylation by DNA Methyltransferase 1 Is Critical for Effector CD8 T Cell Expansion1 , 2006, The Journal of Immunology.

[45]  M. Norval,et al.  The Effect of Ultraviolet Radiation on Human Viral Infections , 2006, Photochemistry and photobiology.

[46]  A. E. Hirsh,et al.  Evolutionary Rate in the Protein Interaction Network , 2002, Science.

[47]  Andrew Meade,et al.  Assembly rules for protein networks derived from phylogenetic-statistical analysis of whole genomes , 2007, BMC Evolutionary Biology.

[48]  M. Campbell,et al.  PANTHER: a library of protein families and subfamilies indexed by function. , 2003, Genome research.

[49]  N. Kjeldgaard,et al.  Gene structure and function of the 2′-5′-oligoadenylate synthetase family , 2000, Cellular and Molecular Life Sciences CMLS.

[50]  J. Wrammert,et al.  The Generation of Influenza-Specific Humoral Responses Is Impaired in ST6Gal I-Deficient Mice 1 , 2009, The Journal of Immunology.

[51]  Christopher J. Miller,et al.  HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages , 2003, Nature Medicine.

[52]  Michael R. Johnson,et al.  Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. , 2009, Human molecular genetics.

[53]  D. Lowy,et al.  Role of Heparan Sulfate in Attachment to and Infection of the Murine Female Genital Tract by Human Papillomavirus , 2008, Journal of Virology.

[54]  P. Spear,et al.  Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. , 2001, The Journal of clinical investigation.

[55]  Ingo Müller,et al.  Dendritic cells: functional aspects of glycosylation and lectins. , 2009, Human immunology.

[56]  Philippe Froguel,et al.  Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). , 2009, The Journal of infectious diseases.

[57]  Joseph K. Pickrell,et al.  The Role of Geography in Human Adaptation , 2009, PLoS genetics.

[58]  S. Ishikawa,et al.  Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. , 2009, Cancer research.

[59]  Jérôme Goudet,et al.  Going the distance: human population genetics in a clinal world. , 2007, Trends in genetics : TIG.

[60]  David Reich,et al.  The Case for Selection at CCR5-Δ32 , 2005, PLoS biology.

[61]  Jacques Fellay,et al.  A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1 , 2007, Science.

[62]  A. Fauci,et al.  The challenge of emerging and re-emerging infectious diseases , 2004, Nature.

[63]  Donna R. Maglott,et al.  Human immunodeficiency virus type 1, human protein interaction database at NCBI , 2008, Nucleic Acids Res..

[64]  H. Willison,et al.  Probing the cis interactions of the inhibitory receptor Siglec‐7 with α2,8‐disialylated ligands on natural killer cells and other leukocytes using glycan‐specific antibodies and by analysis of α2,8‐sialyltransferase gene expression , 2006, Journal of leukocyte biology.

[65]  C. Sherr,et al.  Tumor surveillance via the ARF-p53 pathway. , 1998, Genes & development.

[66]  Susana López,et al.  Role of sialic acids in rotavirus infection , 2006, Glycoconjugate Journal.

[67]  N. Heveker,et al.  HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165. , 2009, Blood.

[68]  David B. Witonsky,et al.  CYP3A variation and the evolution of salt-sensitivity variants. , 2004, American journal of human genetics.

[69]  M. Feldman,et al.  Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation , 2008 .

[70]  Neil Salkind.  Encyclopedia of Measurement and Statistics , 2006 .

[71]  M. Eisen.  Faculty Opinions recommendation of The case for selection at CCR5-Delta32. , 2005 .

[72]  K. Campbell,et al.  Posttranslational Modification of α-Dystroglycan, the Cellular Receptor for Arenaviruses, by the Glycosyltransferase LARGE Is Critical for Virus Binding , 2005, Journal of Virology.

[73]  H. van Loveren,et al.  Ultraviolet radiation, resistance to infectious diseases, and vaccination responses. , 2002, Methods.

[74]  A. Imberty,et al.  Microbial recognition of human cell surface glycoconjugates. , 2008, Current opinion in structural biology.

[75]  N. Bresolin,et al.  Widespread balancing selection and pathogen-driven selection at blood group antigen genes. , 2009, Genome research.

[76]  C. Sutherland,et al.  UL16-Binding Proteins, Novel MHC Class I-Related Proteins, Bind to NKG2D and Activate Multiple Signaling Pathways in Primary NK Cells , 2002, The Journal of Immunology.

[77]  M. Hochberg,et al.  Ecology Drives the Worldwide Distribution of Human Diseases , 2004, PLoS biology.

[78]  G. Crabtree,et al.  NFAT Signaling Choreographing the Social Lives of Cells , 2002, Cell.