Viruses mutate to evade host defences: once a topic for epidemiologists and virologists, the COVID-19 pandemic has turned the mutation rates of viruses into casual dinner conversation. As we encounter a new variant of SARS-CoV-2 in short intervals, a 2014 study led by David Haussler exemplified how transposons, which are virus-like genomic elements, evolve to escape host defence mechanisms, and how the host fights back with mutations of its own.

The study is of great importance as it shows the co-evolution of cellular defence mechanisms as a response to a genome invader. Different from an arms race with an external pathogen, different transposon escape routes are created within the same genome, which highlights that genomes are dynamically shaped instead of being static entities.

Jacobs et al. took advantage of a mouse–human hybrid cell line, which enables the screening of primate-specific factors that are responsible for the transcriptional silencing of human transposons in a mouse cellular environment. Using a candidate-based approach and reporter assays, they identified a specialized KRAB zinc-finger (KZNF) protein, ZNF91, as responsible for the silencing of SINE-VNTR-Alu (SVA) transposons. Tracing ZNF91 back in ancestral genomes showed that it has undergone structural changes in the lineage to humans to cope with the newly emerging SVA elements.

Similarly, ZNF93 was found to repress the activity of a primate-specific long interspersed nuclear element 1 (LINE1). Loss of the ZNF93-binding site on LINE1 about 12.5 million years ago led to a new wave of LINE1 expression and transposition in great ape genomes. Whereas ZNF91 represents the host genome taking the lead in the race, ZNF93 presents a remarkable escape of the transposons. This hide-and-seek play is central to genome evolution and speciation.

Jacobs et al. further showed that repression of retrotransposons by the host also affects the expression of nearby genes. Hence, it is crucial to consider the effects of retrotransposons when investigating the evolution of gene expression patterns of the host.

This hide-and-seek play is central to genome evolution and speciation

This type of arms race is probably not restricted to transcriptional silencing, as transposons are transcribed as parts of transcriptional units. Therefore, such transposon-derived transcripts should have evolved sequence features to escape processing by RNA maturation machineries. How and for what purpose these RNA-binding proteins come into contact with transposable elements embedded in the introns of protein-coding genes remains largely unclear.