Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line

Abstract

The inbred mouse is an invaluable model for human biology and disease. Nevertheless, when considering genetic mechanisms of variation and disease, it is important to appreciate the significant differences in the spectra of spontaneous mutations that distinguish these species. While insertions of transposable elements are responsible for only approximately 0.1% of de novo mutations in humans, the figure is 100-fold higher in the laboratory mouse. This striking difference is largely due to the ongoing activity of mouse endogenous retroviral elements. Here we briefly review mouse endogenous retroviruses (ERVs) and their influence on gene expression, analyze mechanisms of interaction between ERVs and the host cell, and summarize the variety of mutations caused by ERV insertions. The prevalence of mouse ERV activity indicates that the genome of the laboratory mouse is presently behind in the "arms race" against invasion.

Figure 1. Mutagenic Mechanisms of IAP and ETn Insertions

IAP and ETn insertions were classified by their mechanism of gene disruption. Well documented instances of aberrant transcription initiation (5'-terminus) and polyadenylation (3'-terminus) were counted, as well as aberrant splicing and exon skipping (internal disruption). Insertions that cause gene disruption by multiple mechanisms (Table S1) were counted once in each relevant class.

Figure 2. Common Effects of ETn and IAP Insertions on Gene Expression

(A) ETn effects on gene transcript processing. The most common patterns of aberrant transcript processing caused by ETns in gene introns are shown. The natural LTR polyadenylation (polyA) site and a second cryptic polyadenylation site in the internal region, along with four cryptic splice acceptors (SA) and a donor site (SD), are involved in most cases. The number of such cases is an underestimate, since several reports lack sufficient detail of aberrant transcripts. In some cases, several aberrant forms have been found. Boxes denote gene exons, thin lines denote introns, and thick lines denote spliced mRNAs, with direction of transcription from left to right. For clarity, cryptic splice acceptor sites in the 3' LTR are not shown since no documented splicing events involving these sites were found. Intronic mutagenic ETns and the affected gene are most often found in the same orientation (15 of 16 cases). (B) IAP promoter effects on gene transcription. Ectopic gene expression driven by an antisense promoter in the 5' LTR of an IAP has been reported in eight cases. In some cases, the IAP is located a significant distance upstream of the gene.

Figure 3. Host Restriction and Silencing of ERVs/LTRs

Blocks to various stages of the retroviral or LTR retroelement life cycle are depicted as are silencing mechanisms affecting activity of integrated elements. Examples of restriction genes and silencing mechanisms: receptor block, Fv4; uncoating block, Trim5; reverse transcription/trafficking block, APOBEC3 and Fv1; transcription block, CpG methylation; and RNA processing block, Nxf1 and RNAi. See text and Table 2 for more details and other examples. An ERV or LTR element within an intron is shown to illustrate common gene-disruptive effects of such sequences through introduction of polyadenylation sites, promoters, and splice donor and acceptor sites. Spliced RNA is depicted with dashed lines. A normal gene transcript driven by the native promoter (P) is shown below the gene. A full-length retroviral transcript, which could be packaged for further rounds of retrotransposition or retroviral infection, is shown above the gene locus. Various potential aberrant or chimeric transcripts are shown above.