Evolutionary arms race within primate genomes

An ongoing battle between KRAB zinc finger genes to control the invasion of mobile DNA elements has driven the evolution of greater complexity of primate genomes.

HFSP Long-Term Fellow Frank Jacobs and colleagues
authored on Mon, 03 November 2014

For millions of years, a type of mobile DNA elements called retrotransposons have been copy-pasting themselves into the genomes of our ancestral species. Throughout mammalian evolution there have been numerous waves of retrotransposon insertions, characterized by periods where retrotransposons could spread through our genome until something managed to stop their invasion. The threat of uncontrolled activity of mobile DNA elements to genome-integrity has forced the host-genome to come up with mechanisms to prevent jumping events. Our study reveals an evolutionary arms race between retrotransposons and the genes that evolved to repress them. An arms race with ourselves, driving genomes to become increasingly complex as they evolve mechanisms to fight off ever-changing elements of their own DNA.

Figure: John C.W. Carroll, Gladstone Institutes at UCSF

Important pioneering work by the labs of Stephen Goff, James Thomas and Didier Trono suggested a while ago that KRAB zinc finger proteins, together with their co-repressor protein KAP1, may be important components of this host-defense mechanism against retroviral and retrotransposon attacks on mammalian genomes. The human genome contains more than 400 KRAB zinc finger genes, of which 170 are present only in primates. We hypothesized that the unusual expansion of KRAB zinc finger genes in primates is the result of an evolutionary pressure on primate species to make new KRAB zinc-finger genes. We took the challenge to identify the genes that evolved to repress two classes of primate-specific retrotransposons, SVA and LINE1 (L1PA) elements, which have been active throughout great ape evolution and contributed significantly to primate genome evolution.

We found that SVA elements, a type of retrotransposons that has been invading our genome for the last 12-18 million years, is controlled by the primate-specific KRAB zinc finger gene ZNF91. The gene encoding ZNF91 itself had emerged in our ancestor’s genome a little while before, but has undergone dramatic structural changes between 8 -12 million years ago, changes that enabled it to repress SVAs. As proof for this, we showed that reconstructed ancestral versions of ZNF91, or ZNF91 genes present in macaque and orangutan, ZNF91 versions that predated the dramatic structural evolution of the ZNF91 gene, were not able to repress SVA.

Furthermore, we found ZNF93 was able to repress primate-specific L1PA elements. Surprisingly, however, it could only repress a subset of L1PA elements, the subtypes that invaded our genome between 12 -25 million years ago. Interestingly, ZNF93 was not able to repress L1PA subtypes that emerged later in our genome, including the currently active form of L1, L1Hs. The explanation for this is that the most recently evolved L1PA-subtypes lack a short segment of DNA to which ZNF93 can bind. The L1PA lineage had ‘dumped’ this sequence about 12.5 million years ago and without the binding site, these L1PA retrotransposons managed to evade repression by ZNF93. Interestingly, when the missing sequence was put back into one of the shorter L1PA elements, the L1PA element was better at jumping. However, it also made it hypersensitive to ZNF93 repression. So even though the sequence helps with jumping activity, losing it gives the retrotransposon an advantage by allowing it to escape repression by ZNF93.

What we describe in this study is just a snap-shot of a never-ending race. KRAB zinc finger genes have been rapidly expanding and evolving in mammalian genomes, which makes sense because the retrotransposons themselves are continuously evolving to escape this repression. When retrotransposons manage to evade repression, the host cannot allow the KRAB zinc finger gene in charge of repressing the old element to co-evolve with this change as it would release the repression of the old elements. In addition, we show that KRAB zinc fingers get co-opted by the host and become heavily integrated into existing gene-regulatory networks, and may have become essential for normal cellular functioning. So instead, a new KRAB zinc finger gene needs to step up to the challenge and rapidly evolve to become the repressor of the newly emerged retrotransposon subtype, driving the genome and gene regulatory networks to a progressively more complex state.

Reference

An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. F.M.J. Jacobs, D. Greenberg, N. Nguyen, M. Haeussler, A. Ewing, S. Katzman, B. Paten, S.R. Salama, D. Haussler.  Nature, http://dx.doi.org/10.1038/nature13760

Pubmed link