An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons.

Abstract

SummaryThroughout evolution, primate genomes have been modified by waves of retrotransposon insertions1,2,3. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. In mouse embryonic stem cells (mESCs), transcriptional silencing of retrotransposons requires TRIM28 (KAP1) and it’s repressive complex, which can be recruited to target sites by KRAB zinc finger proteins such as murine-specific ZFP809 which binds to integrated murine leukemia virus DNA elements and recruits KAP1 to repress them4,5. KZNF genes are one of the fastest growing gene families in primates and this expansion is hypothesized to enable primates to respond to newly emerged retrotransposons6,7. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA)8 and Long Interspersed Nuclear Element-1 (L1)9, is unknown. We find that two primate-specific KZNF genes rapidly evolved to repress these two distinct retrotransposon families shortly after they began to spread in our ancestral genome. ZNF91 underwent a series of structural changes 8-12 MYA that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until ~12.5 MYA when the L1PA3-subfamily escaped ZNF93’s restriction through purge of the ZNF93 binding site. Our data support a model where KZNF gene expansion limits the activity of newly emerged retrotransposon classes, and this is followed by mutations in these retrotransposons to evade repression, a cycle of events that could explain the rapid expansion of lineage-specific KZNF genes.