Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline

Abstract

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline.

Fig. 1

Structure of the major mammalian retrotransposons. Mouse and human examples of the three different classes of mammalian retrotransposon (LINE, SINE, LTR) are shown. Transcription regulatory regions are indicated with filled rectangles, and the main protein coding regions with open rectangles. Transcriptional start sites are shown with an arrow. Some LTR retrotransposons, e.g. IAP, have lost the env gene present in their infectious progenitors [241]. LTR long terminal repeat

Fig. 2

Overview of the mouse germline cycle. Schematic overview of germ cell development in mice. Pluripotent cells are indicated in italicised text and germ cells in bold text. DNA is passed between germ cells and pluripotent cells through the generations in a germline cycle (green arrows). Differentiation into somatic tissues is indicated by grey arrows. The level of DNA methylation at different stages of development is indicated by the level of shading

Fig. 3

Retrotransposon suppression mechanisms. A schematic overview of a generalised retrotransposon life cycle encompassing transcription, RNA export, translation, assembly, nuclear import, and de novo integration is shown. Specific elements can show some variation in this process, e.g. RNA from non-autonomous SINE retrotransposons is not translated, and uses LINE-1-encoded proteins to catalyse their integration. Also, the mechanism of integration differs between LINE-1 and LTR retrotransposons. Genes involved in suppressing retrotransposons at specific stages of their life cycle in germ cells and pluripotent cells are indicated

Fig. 4

Expression patterns and mutant phenotypes of germline genome defence genes. The stages of spermatogenesis are indicated along the top of the diagram, and expression patterns of the indicated germline genome defence genes are indicated by blue bars. The stages at which mutant mice are reported to have defects in progression through spermatogenesis are indicated with crosses