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Category: Clinical Microbiology
Mammalian Endogenous Retroviruses, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555819217/9781555819200_Chap47-1.gif /docserver/preview/fulltext/10.1128/9781555819217/9781555819200_Chap47-2.gifAbstract:
Mammalian genomes have accumulated millions of retrotransposed sequences during evolution. This material can be divided into long terminal repeat (LTR) retrotransposons that include the endogenous retroviruses (ERVs), as well as long and short retrotransposons lacking LTRs, known as LINEs and SINEs, respectively. ERVs are defined as inherited genetic elements closely resembling the proviruses formed following exogenous retrovirus infection. In this chapter we describe the discovery, classification, and origins of ERVs in mammals, consider cellular mechanisms that have evolved to control their expression, and discuss the biological consequences, both positive and negative from the host’s standpoint, of ERV inheritance.
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(A) Formation of ERVs. Exogenous retroviruses typically infect their host and spread to other individuals via horizontal transmission. When retroviruses infect and integrate into the genome of germ line cells, the provirus can be vertically transmitted and become endogenous to the host. ERVs can amplify in the host genome through reinfection or through intracellular retrotransposition (see text). (B) Basic structures of ERVs. Complete ERVs are essentially identical to the integrated proviruses of simple exogenous retroviruses; they contain two LTRs made up of unique 3′ (U3), repeat (R), and unique 5′ (U5) regions, a primer binding site (pbs) and polypurine tract (ppt), as well as a full complement of coding sequences (gag, pol, and env), splice donor (SD) and acceptor (SA) sites, and an RNA packaging signal (psi). “Slimmed down” ERVs are elements lacking coding sequences compared to a complete ERV—here illustrated with a deletion in env. “Substituted” ERVs are elements in which the ERV coding sequences have been replaced with nonviral sequences. “Solo LTRs” are single LTRs generated by homologous recombination between the two LTRs of a complete element.
ERV/LTR content in different species. Overall genomic fractions occupied by ERVs and solo LTRs in various species. Data were obtained from the RepeatMasker web site (http://www.repeatmasker.org/genomicDatasets/RMGenomicDatasets.html) and are updated from the original genome publications—for example, the human and mouse genome papers ( 18 , 19 ) due to a more-sensitive repeat detection.
Common ways in which retroviral insertions can affect genes. (A) Proviral elements are shown as thick lines, with arrows for the LTRs, and gene exons are numbered boxes with P showing the gene promoter. Retroviral elements inserted near genes can donate their LTR enhancers or promoters to affect gene expression. This mechanism occurs when new somatic retroviral insertions activate oncogenes. This mechanism also occurs in normal cells as an evolutionary adaptation and in mouse cells defective for LTR epigenetic silencing. This can occur even if only a solitary LTR remains. (B) When inserted in an intron, splice sites and polyA signals within ERVs can perturb splicing. Most of the documented germ line-detrimental ERV insertions in mice are due to this mechanism. (C) ERVs/LTRs located downstream of a gene or within an intron have the potential to promote antisense transcripts, possibly regulating the gene or causing premature polyadenylation. (D) Closely related LTRs/ERVs distributed across the genome (black triangles) that bind the same transcription factors can become exapted (shown as gray triangles) and regulate expression of sets of genes (gene A and C in this example), establishing a regulatory network.
Independent instances of ERV Env domestication involved in placenta formation. (A) Domestication of Env proteins (which have natural fusogenic properties) can promote the formation of multinucleated tissue, as occurs in the developing placenta. Env syncytin-like molecules are shown as balls binding to receptors. (B) Schematic evolutionary tree showing different instances of ERV Env domestication (shown as arrows): Syncytin-A and Syncytin-B ( 197 ), Syncytin-Ory1 ( 198 ), Syncytin-1 ( 146 ), Syncytin-2 ( 147 ), Syncytin-Rum1 ( 199 ), Fematrin-1 ( 200 ), Syncytin-Car1 ( 201 ), and Syncytin-Mar1 ( 202 ).