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Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes.

ABSTRACT: Human endogenous retroviruses (HERVs) are ancient sequences integrated in the germ line cells and vertically transmitted through the offspring constituting about 8 % of our genome. In time, HERVs accumulated mutations that compromised their coding capacity. A prominent exception is HERV-W locus 7q21.2, producing a functional Env protein (Syncytin-1) coopted for placental syncytiotrophoblast formation. While expression of HERV-W sequences has been investigated for their correlation to disease, an exhaustive description of the group composition and characteristics is still not available and current HERV-W group information derive from studies published a few years ago that, of course, used the rough assemblies of the human genome available at that time. This hampers the comparison and correlation with current human genome assemblies.In the present work we identified and described in detail the distribution and genetic composition of 213 HERV-W elements. The bioinformatics analysis led to the characterization of several previously unreported features and provided a phylogenetic classification of two main subgroups with different age and structural characteristics. New facts on HERV-W genomic context of insertion and co-localization with sequences putatively involved in disease development are also reported.The present work is a detailed overview of the HERV-W contribution to the human genome and provides a robust genetic background useful to clarify HERV-W role in pathologies with poorly understood etiology, representing, to our knowledge, the most complete and exhaustive HERV-W dataset up to date.

SUBMITTER: Grandi N

PROVIDER: S-EPMC5016936 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes.

Grandi Nicole N Cadeddu Marta M Blomberg Jonas J Tramontano Enzo E

Retrovirology 20160909 1

<h4>Background</h4>Human endogenous retroviruses (HERVs) are ancient sequences integrated in the germ line cells and vertically transmitted through the offspring constituting about 8 % of our genome. In time, HERVs accumulated mutations that compromised their coding capacity. A prominent exception is HERV-W locus 7q21.2, producing a functional Env protein (Syncytin-1) coopted for placental syncytiotrophoblast formation. While expression of HERV-W sequences has been investigated for their correla ...[more]

PMID: 27613107

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Project description:BackgroundHuman endogenous retroviruses (HERVs) represent the inheritance of ancient germ-line cell infections by exogenous retroviruses and the subsequent transmission of the integrated proviruses to the descendants. ERVs have the same internal structure as exogenous retroviruses. While no replication-competent HERVs have been recognized, some retain up to three of four intact ORFs. HERVs have been classified before, with varying scope and depth, notably in the RepBase/RepeatMasker system. However, existing classifications are bewildering. There is a need for a systematic, unifying and simple classification. We strived for a classification which is traceable to previous classifications and which encompasses HERV variation within a limited number of clades.ResultsThe human genome assembly GRCh 37/hg19 was analyzed with RetroTector, which primarily detects relatively complete Class I and II proviruses. A total of 3173 HERV sequences were identified. The structure of and relations between these proviruses was resolved through a multi-step classification procedure that involved a novel type of similarity image analysis ("Simage") which allowed discrimination of heterogeneous (noncanonical) from homogeneous (canonical) HERVs. Of the 3173 HERVs, 1214 were canonical and segregated into 39 canonical clades (groups), belonging to class I (Gamma- and Epsilon-like), II (Beta-like) and III (Spuma-like). The groups were chosen based on (1) sequence (nucleotide and Pol amino acid), similarity, (2) degree of fit to previously published clades, often from RepBase, and (3) taxonomic markers. The groups fell into 11 supergroups. The 1959 noncanonical HERVs contained 31 additional, less well-defined groups. Simage analysis revealed several types of mosaicism, notably recombination and secondary integration. By comparing flanking sequences, LTRs and completeness of gene structure, we deduced that some noncanonical HERVs proliferated after the recombination event. Groups were further divided into envelope subgroups (altogether 94) based on sequence similarity and characteristic "immunosuppressive domain" motifs. Intra and inter(super)group, as well as intraclass, recombination involving envelope genes ("env snatching") was a common event. LTR divergence indicated that HERV-K(HML2) and HERVFC had the most recent integrations, HERVL and HUERSP3 the oldest.ConclusionsA comprehensive HERV classification and characterization approach was undertaken. It should be applicable for classification of all ERVs. Recombination was common among HERV ancestors.

Project description:Processed pseudogenes result from reverse transcribed mRNAs. In general, because processed pseudogenes lack promoters, they are no longer functional from the moment they are inserted into the genome. Subsequently, they freely accumulate substitutions, insertions and deletions. Moreover, the ancestral structure of processed pseudogenes could be easily inferred using the sequence of their functional homologous genes. Owing to these characteristics, processed pseudogenes represent good neutral markers for studying genome evolution. Recently, there is an increasing interest for these markers, particularly to help gene prediction in the field of genome annotation, functional genomics and genome evolution analysis (patterns of substitution). For these reasons, we have developed a method to annotate processed pseudogenes in complete genomes. To make them useful to different fields of research, we stored them in a nucleic acid database after having annotated them. In this work, we screened both mouse and human complete genomes from ENSEMBL to find processed pseudogenes generated from functional genes with introns. We used a conservative method to detect processed pseudogenes in order to minimize the rate of false positive sequences. Within processed pseudogenes, some are still having a conserved open reading frame and some have overlapping gene locations. We designated as retroelements all reverse transcribed sequences and more strictly, we designated as processed pseudogenes, all retroelements not falling in the two former categories (having a conserved open reading or overlapping gene locations). We annotated 5823 retroelements (5206 processed pseudogenes) in the human genome and 3934 (3428 processed pseudogenes) in the mouse genome. Compared to previous estimations, the total number of processed pseudogenes was underestimated but the aim of this procedure was to generate a high-quality dataset. To facilitate the use of processed pseudogenes in studying genome structure and evolution, DNA sequences from processed pseudogenes, and their functional reverse transcribed homologs, are now stored in a nucleic acid database, HOPPSIGEN. HOPPSIGEN can be browsed on the PBIL (Pole Bioinformatique Lyonnais) World Wide Web server (http://pbil.univ-lyon1.fr/) or fully downloaded for local installation.

Dataset Information

Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes.

Publications

Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes.

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