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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Gene Expression Omnibus
The data discussed in this publication have been deposited in the NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE60211.
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.
Extended data figures
This file contains construction details and associated primers and gene sequences for the plasmids used in this study.
This file contains primers used for generating sequence data to fill in genome assembly gaps around ZNF91 and ZNF93 in various primate genomes.
This file contains full multiple sequence alignment for ZNF91.
This file contains full multiple sequence alignment for ZNF93.
About this article
Molecular Cell (2019)