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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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-S, 2025. "Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64609-2
    DOI: 10.1038/s41467-025-64609-2
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    References listed on IDEAS

    as
    1. Nikolaos M. R. Lykoskoufis & Evarist Planet & Halit Ongen & Didier Trono & Emmanouil T. Dermitzakis, 2024. "Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Parithi Balachandran & Isha A. Walawalkar & Jacob I. Flores & Jacob N. Dayton & Peter A. Audano & Christine R. Beck, 2022. "Transposable element-mediated rearrangements are prevalent in human genomes," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Elena V. Linardopoulou & Eleanor M. Williams & Yuxin Fan & Cynthia Friedman & Janet M. Young & Barbara J. Trask, 2005. "Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication," Nature, Nature, vol. 437(7055), pages 94-100, September.
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