An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons
Open accessAbstract
Throughout evolution primate genomes have been modified by waves of retrotransposon insertions. 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 them. 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 retrotransposons. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA) and long interspersed nuclear element 1 (L1), 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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Host defense mechanisms recognize retrotransposon DNA sequences and induce heterochromatization at these locations very early in development.
“Host defense mechanisms recognize retrotransposon DNA sequences in their genomes and induce heterochromatization at these locations very early in development23, 24, 25 (Fig. 3).”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [25]
The paper’s Abstract (page unavailable) describes KRAB zinc-finger proteins recognizing retrotransposon sequences and recruiting KAP1 to silence them in embryonic stem cells. It does not establish that this induces heterochromatization at those locations very early in development; the experiments described use cultured embryonic stem cells rather than tracking that process during development. (LLM, conf=0.83)
Experimental — accuracy not yet measuredKZFPs co-evolve with retrotransposons as part of an ongoing arms race.
“KZFPs, of which there are over 400 in the human genome, co-evolve with retrotransposons as part of an ongoing ‘arms race’25.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [25]
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- Authors
- Jacobs, F. M. J., Greenberg, D., Nguyen, N., Haeussler, M., Ewing, A. D., Katzman, S., Paten, B., Salama, S. R., & Haussler, D.
- Affiliations
- The University of Queensland (AU)
- University of California, Santa Cruz (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Haussler, David
- ORCID
- Venue
- Nature
- Published
- 2014-09-28
- Volume
- 516
- Issue
- 7530
- Pages
- 242-245
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4268317
- OpenAlex
- W2053117901
- Cited by
- 506
- References
- 45
- Citations by year
- 2026: 37 · 2025: 36 · 2024: 39 · 2023: 46 · 2022: 39 · 2021: 48 · 2020: 59 · 2019: 42 · 2018: 42 · 2017: 48 · 2016: 35 · 2015: 33 · 2014: 1
- FWCI
- 45.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (U54HG007990)
- National Cancer Institute (U24CA143858)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- KRAB zinc finger proteins, SVA retrotransposon, LINE-1 retrotransposons, retrotransposon silencing, arms race, gene family expansion, primate genome evolution, KAP1, transcriptional repression, transposable elements, human genome, mouse embryonic stem cells
- MeSH terms
- Animals, Base Sequence, Humans, Mutation, Primates, Zinc Fingers, Retroelements, Evolution, Molecular, Mice, Kruppel-Like Transcription Factors, Embryonic Stem Cells
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