Frank Jacobs lab                                                                                                               

University of Amsterdam                                                                                                                   

The impact of retrotransposon invasions on the evolution of human gene regulatory networks

Retrotransposons are virus-derived mobile DNA elements that retained the capability to copy-paste themselves in the host genome, long after the initial attack of the virus and the insertion of the viral DNA into our genome. As a result, over 50% of the human genome is retrotransposon-derived, showing that mobile DNA elements have accumulated in our genome over the course of mammalian evolution.

Some recently emerged retrotransposon-families, such as LINE1 and SVA elements are still active in our genome and while new insertions can give rise to disease, they are an important source for genomic variability responsible for the continuing evolution of our genome. Even compared between the human and chimpanzee genomes, many thousands of species-specific retrotransposon insertions exist.  The viral-like gene-regulatory properties of retrotransposons can have significant effects on gene expression when insertions of these ‘mobile promoters’ or ‘mobile enhancers’ happen near genes. 

In previous work (Jacobs et al., 2014; Nature) we have found that two primate-specific KRAB zinc finger gene have recently evolved to repress the activity of SVA and L1PA retrotransposons. This study shows how our genome is in a continuous battle against retrotransposon invasions; an evolutionary arms race which explains the rapid expansion of KRAB zinc finger genes in primate genomes.

Classical example of an evolutionary arms race between predator and prey. Antelopes need to keep evolving to outrun or outsmart the cheetah which itself needs to keep evolving higher speed or better techniques in order to survive. In evolutionary biology, an evolutionary arms race is an evolutionary struggle between competing sets of co-evolving genes that develop adaptations and counter-adaptations against each other, resembling an arms race.

Intriguingly, the genome’s effort to silence retrotransposons also affects genes in the direct neighborhood of their insertion sites, suggesting that both retrotransposons and KRAB zinc finger genes become integrated in pre-existing gene regulation pathways and may therefore be an important source for the evolution of gene-regulatory novelties.

Currently, our lab investigates the extent to which human-lineage specific retrotransposon insertions and the KRAB zinc fingers that evolved to repress them have contributed to the evolution of neural gene-regulatory pathways and how these new regulatory properties relate to human neurological disease.

An evolutionary arms race between retrotransposons in our genome and the KRAB ZNF genes that co-evolve to counteract retrotransposon invasions, as we described for ZNF91 and SVA retrotransposons, and ZNF93 and L1 retrotransposons in the human genome (Jacobs et al., 2014).  After one of the many thousands suppressed retrotransposons manages to break free from the grip of its KRAB zinc finger gene repressor, it sparks another invasion of retrotransposons. This elicits a host genome response and other KRAB zinc finger genes, which are frequently formed by segmental duplications, are recruited and optimized to defend against the new invasion. Inevitably this in turn drives the evolution of newer families of retrotransposons, giving rise to a continuing evolutionary arms race.