title: Genomic determinants of the efficiency of internal ribosomal entry sites of viral and cellular origin.
abstract: Variation in cellular gene expression levels has been shown to be inherited. Expression is controlled at transcriptional and post-transcriptional levels. Internal ribosome entry sites (IRES) are used by viruses to bypass inhibition of cap-dependent translation, and by eukaryotic cells to control translation under conditions when protein synthesis is inhibited. We aimed at identifying genomic determinants of variability in IRES-mediated translation of viral [Encephalomyocarditis virus (EMCV)] and cellular IRES [X-linked inhibitor-of-apoptosis (XIAP) and c-myc]. Bicistronic lentiviral constructs expressing two fluorescent reporters were used to transduce laboratory and B lymphoblastoid cell lines [15 CEPH pedigrees (n = 205) and 50 unrelated individuals]. IRES efficiency varied according to cell type and among individuals. Control of IRES activity has a significant genetic component (h(2) of 0.47 and 0.36 for EMCV and XIAP, respectively). Quantitative linkage analysis identified a suggestive locus (LOD 2.35) on chromosome 18q21.2, and genome-wide association analysis revealed of a cluster of SNPs on chromosome 3, intronic to the FHIT gene, marginally associated (P = 5.9E-7) with XIAP IRES function. This study illustrates the in vitro generation of intermediate phenotypes by using cell lines for the evaluation of genetic determinants of control of elements such as IRES.
authors.affiliation: Institute of Microbiology, University Hospital Center, University of Lausanne, Switzerland.
authors.forename: Kayole
authors.initials: K
authors.lastname: Kazadi
authors.forename: Corinne
authors.initials: C
authors.lastname: Loeuillet
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Angela
authors.initials: A
authors.lastname: Ciuffi
authors.forename: Miguel
authors.initials: M
authors.lastname: Muñoz
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
mesh_terms: D020121:5' Untranslated Regions; D002460:Cell Line; D004686:Encephalomyocarditis virus / Q000235:genetics; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D040641:Quantitative Trait Loci; D012367:RNA, Viral / Q000737:chemistry; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D016271:Proto-Oncogene Proteins c-myc; D012367:RNA, Viral; D051636:X-Linked Inhibitor of Apoptosis Protein