Retroviral Elements and Their Hosts: Insertional Mutagenesis in the Mouse Germ Line

Maksakova, Irina A.; Romanish, Mark T.; Gagnier, Liane; Dunn, Catherine A.; Lagemaat, Louie N. van de; Mager, Dixie L.

doi:10.1371/journal.pgen.0020002

Cited by 321 publications

(428 citation statements)

References 124 publications

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“…A functional env gene thus might inhibit proliferation through reinfection. In addition, retrotransposition simply might be a more efficient way to generate new integrations into germline cells (27), circumventing the requirement for survival in a hostile extracellular environment and evading some innate antiviral defenses [e.g., tetherin, a membrane-bound protein that inhibits the replication of enveloped viruses by tethering budding virus to the cell-surface (37-39)]. That retrotransposing ERVs are more common than reinfecting ones is consistent with ERVs as a group being rarer than the entirely retrotransposing Long Interspersed Nuclear Elements (LINEs) in the mouse and human genomes (2,3).…”

Section: Discussionmentioning

confidence: 99%

Env-less endogenous retroviruses are genomic superspreaders

Magiorkinis

Gifford

Katzourakis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

124

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Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and therefore are a unique combination of pathogen and selfish genetic element. Some ERV lineages proliferate by infecting germline cells, as do typical retroviruses, whereas others lack the env gene required for virions to enter cells and thus behave like retrotransposons. We wished to know what factors determined the relative abundance of different ERV lineages, so we analyzed ERV loci recovered from 38 mammal genomes by in silico screening. By modeling the relationship between proliferation and replication mechanism in detail within one group, the intracisternal A-type particles (IAPs), and performing simple correlations across all ERV lineages, we show that when ERVs lose the env gene their proliferation within that genome is boosted by a factor of ∼30. We also show that ERV abundance follows the Pareto principle or 20/80 rule, with ∼20% of lineages containing 80% of the loci. This rule is observed in many biological systems, including infectious disease epidemics, where commonly ∼20% of the infected individuals are responsible for 80% of onward infection. We thus borrow simple epidemiological and ecological models and show that retrotransposition and loss of env is the trait that leads endogenous retroviruses to becoming genomic superspreaders that take over a significant proportion of their host's genome. E ndogenous retroviruses (ERVs) proliferate by the repeated integration of new viral sequences into their host's germline (1), integrations which can become fixed in the host population and have led to ERV sequences (loci) comprising 8-10% of the human and mouse genomes (2, 3) (this number also includes nonautonomous LTR-retrotransposons, which we do not analyze here). These loci form phylogenetically distinct lineages traditionally called "families" (4) (unrelated to the general use of this term in taxonomy), each of which is the result of the expansion of a founder infection of the organism's germline that can have occurred more than ∼100 million years ago (5).ERVs can replicate both as transposable elements (TEs) and viruses. Some lineages copy by an entirely intracellular mechanism and are functionally indistinguishable from the class of TEs called LTR-retrotransposons, whereas others copy within the host germline using cell reinfection in the same manner as the copying within somatic cells of exogenous retroviruses (XRVs) (6). We refer to these replication mechanisms as "retrotransposition" and "reinfection," respectively. Whether an ERV is reinfecting or retrotransposing can be determined by the integrity of its env gene, which produces the protein on the surface of the viral particle that is responsible for cell entry. We can assume that an ERV lineage with a functional env is reinfecting, whereas an ERV lineage with a disintegrated env is retrotransposing (whether reinfection can include germline cells in other host individuals of the same or other species is not known). Some retroviruses w...

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Section: Discussionmentioning

confidence: 99%

Env-less endogenous retroviruses are genomic superspreaders

Magiorkinis

Gifford

Katzourakis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

124

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“…Although human ERVs do not show signs of recent activity (Moyes et al, 2007), mouse ERVs are still causing de novo deleterious mutations and provide a significant source of strain-specific insertional polymorphisms (Zhang et al, 2008). In spite of the scarcity of elements with full coding potential, the retroviral-like intracisternal A particle (IAP) and the MusD/Early Transposon (ETn) families are still responsible for approximately 10% of spontaneous mutations in inbred mice (Maksakova et al, 2006. Using ex vivo assays, a few transpositioncompetent elements have been shown to efficiently mobilize the impotent members of their own family in trans, providing an alternative strategy for de novo insertions (Ribet et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

2010

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Retrotransposable elements comprise around 50% of the mammalian genome. Their activity represents a constant threat to the host and has prompted the development of adaptive control mechanisms to protect genome architecture and function. To ensure their propagation, retrotransposons have to mobilize in cells destined for the next generation. Accordingly, these elements are particularly well suited to transcriptional networks associated with pluripotent and germinal states in mammals. The relaxation of epigenetic control that occurs in the early developing germline constitutes a dangerous window in which retrotransposons can escape from host restraint and massively expand. What could be observed as risky behavior may turn out to be an insidious strategy developed by germ cells to sense retrotransposons and hold them back in check. Herein, we review recent insights that have provided a detailed picture of the defense mechanisms that concur toward retrotransposon silencing in mammalian genomes, and in particular in the germline. In this lineage, retrotransposons are hit at multiple stages of their life cycle, through transcriptional repression, RNA degradation and translational control. An organized cross-talk between PIWIinteracting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories provides this potent and multilayered response to retrotransposon unleashing in early germ cells.

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“…A subset of these intracellular parasites, including long terminal repeat (LTR) and LINE1 elements, maintain the ability to retrotranspose, thus representing an ongoing threat to genome integrity (Maksakova et al 2006;Jern and Coffin 2008). Numerous transcriptional and post-transcriptional silencing pathways have evolved to suppress expression of retrotransposons (Wolf and Goff 2008).…”

mentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

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Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at approximately embryonic day 15.5 (E15.5) in prospermatogonia. Earlier in germline development, the genome, including most retrotransposons, is progressively demethylated. Young ERVK and ERV1 elements, however, retain intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low-input ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) method. Although these repressive histone modifications are found predominantly on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated long terminal repeats (LTRs) and LINE1 elements. Germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of both marks and DNA methylation at H3K9me3-enriched retrotransposon families. Strikingly, Setdb1 knockout E13.5 PGCs show concomitant derepression of many marked ERVs, including intracisternal A particle (IAP), ETn, and ERVK10C elements, and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male E13.5 PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline.

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Retroviral Elements and Their Hosts: Insertional Mutagenesis in the Mouse Germ Line

Cited by 321 publications

References 124 publications

Env-less endogenous retroviruses are genomic superspreaders

Env-less endogenous retroviruses are genomic superspreaders

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

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