Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice

Melania Bruno (), Sharaf M. Farhana, Apratim Mitra, Kevin Costello, Dawn E. Watkins-Chow, Glennis A. Logsdon, Craig W. Gambogi, Beth L. Dumont, Ben E. Black, Thomas M. Keane, Anne C. Ferguson-Smith, Ryan K. Dale and Todd S. Macfarlan ()
Additional contact information
Melania Bruno: National Institutes of Health
Sharaf M. Farhana: National Institutes of Health
Apratim Mitra: National Institutes of Health
Kevin Costello: Downing Street
Dawn E. Watkins-Chow: National Institutes of Health
Glennis A. Logsdon: University of Pennsylvania
Craig W. Gambogi: University of Pennsylvania
Beth L. Dumont: The Jackson Laboratory
Ben E. Black: University of Pennsylvania
Thomas M. Keane: Hinxton
Anne C. Ferguson-Smith: Downing Street
Ryan K. Dale: National Institutes of Health
Todd S. Macfarlan: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs in human and mice have been found to repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. Whether new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a 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 Chromosome 4 reveals parallel expansion and diversification of this locus in different mouse strains (C57BL/6 J, 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.

Date: 2025
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DOI: 10.1038/s41467-025-64609-2

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