Sequence reconstruction of young KRAB-zinc finger gene clusters reveals dynamics of their rapid evolution in mice

KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. However, it is not known how new KZFP genes emerge in response to new waves of ERV invasion. This is mostly because KZFP genes are organized in repeat-rich gene clusters that often still retain sequence gaps in reference genome assemblies, hindering comprehensive analysis of these loci.We leveraged on the mouse model to understand dynamics of new KZFP gene evolution. Using a combination of long-read sequencing technologies and genome assembly, we have generated a first detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes in a cluster on Mus musculus chr4 revealed parallel expansion and diversification of this locus in different mouse strains (C57BL6J, 129S1/SvImJ and CAST/EiJ) and species (Mus spretus and Mus pahari). Our data supports a model by which new ERV integrations within young KZFP gene clusters likely promoted recombination events leading to the emergence of new KZFPs that repress them. At the same time, ERVs also increased their numbers by duplication instead of retrotransposition alone, unraveling a new mechanism for ERV enrichment at these loci.