Letter | Published:

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

Nature volume 516, pages 242245 (11 December 2014) | Download Citation

Abstract

Throughout 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, transcriptional silencing of retrotransposons requires KAP1 (also known as TRIM28) and its repressive complex, which can be recruited to target sites by KRAB zinc-finger (KZNF) proteins such as murine-specific ZFP809 which binds to integrated murine leukaemia 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. Here we show 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 million years ago that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until 12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93’s restriction through the removal 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.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

The data discussed in this publication have been deposited in the NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE60211.

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Acknowledgements

This work was supported by California Institute of Regenerative Medicine (CIRM) facility awards (FA1-00617, CL1-00506-1.2) and scholar awards (TG2-01157) to F.M.J.J. and D.G. and F.M.J.J. also received a Human Frontier Science Program Postdoctoral fellowship (LT000689). D.H. is an Investigator of the Howard Hughes Medical Institute. S.K. is supported by the California Institute for Quantitative Biosciences, A.D.E. was supported by TCGA U24 24010-443720, M.H. by EMBO ALTF 292-2011, and B.P. and N.N. by ENCODE U41HG004568. We thank F. Wianny and C. Dehay (Lyon University) for the LYON-ES1 macaque embryonic stem cells; M. Oshimura and T. Inoue (Tottori University) for the E14(hChr11) trans-chromosomic embryonic stem cells, N. Pourmand and the UCSC genome sequencing center; B. Nazario (UCSC Institute for the Biology of Stem Cells) for flow cytometry assistance; M. Batzer (LSU) and K. Han (Dankook University) for L1CER sequences; L. Carbone (OHSU) for gibbon genomic DNA; A. Smit (ISB, Seattle) for discussions on L1PA evolution; D. Segal (UC Davis) for advice on ZNF mutations; H. Kazazian, D. Hancks and J. Goodier (JHMI) for retrotransposition plasmids and advice; K. Tygi, C. Vizenor, J. Rosenkrantz, W. Novey, S. Kyane and B. Mylenek for technical assistance and the entire Haussler laboratory for discussions and support.

Author information

Author notes

    • Frank M. J. Jacobs
    •  & David Greenberg

    These authors contributed equally to this work.

    • Frank M. J. Jacobs
    • , David Greenberg
    •  & Adam D. Ewing

    Present addresses: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam 1098 XH, The Netherlands (F.M.J.J.); Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA (D.G.); Mater Research Institute, University of Queensland, Queensland 4101, Australia (A.D.E.).

Affiliations

  1. Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA

    • Frank M. J. Jacobs
    • , David Greenberg
    • , Ngan Nguyen
    • , Maximilian Haeussler
    • , Adam D. Ewing
    • , Sol Katzman
    • , Benedict Paten
    • , Sofie R. Salama
    •  & David Haussler
  2. Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, California 95064, USA

    • David Greenberg
  3. Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA

    • Ngan Nguyen
  4. Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, California 95064, USA

    • Sofie R. Salama
    •  & David Haussler

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Contributions

F.M.J.J., D.G., D.H. and S.R.S. designed and analysed the experiments. F.M.J.J. performed RNA-seq, ChIP-seq and reintroduction of primate ZNFs in trans-chromosomic mESCs; D.G. performed ZNF cloning, luciferase reporter and retrotransposition assays; N.N., D.G., A.D.E. and B.P. performed resequencing and analysis to complete the ZNF91 and ZNF93 loci in various primates; N.N. and B.P. reconstructed the evolutionary history of ZNF91 and ZNF93 ZNF domains; M.H. generated a Repeatmasker UCSC-Browser and hub, ZNF-binding site predictions and VNTR length analysis; S.K. processed and analysed RNA-seq and ChIP-seq data; A.D.E. analysed SVA numbers in great apes and SVA–gene-expression correlations. F.M.J.J., D.G., S.R.S. and D.H. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Haussler.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information 1

    This file contains construction details and associated primers and gene sequences for the plasmids used in this study.

  2. 2.

    Supplementary Information 2

    This file contains primers used for generating sequence data to fill in genome assembly gaps around ZNF91 and ZNF93 in various primate genomes.

  3. 3.

    Supplementary Information 3

    This file contains full multiple sequence alignment for ZNF91.

  4. 4.

    Supplementary Information 4

    This file contains full multiple sequence alignment for ZNF93.

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DOI

https://doi.org/10.1038/nature13760

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