Abstract
Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc-finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10−3).
Highlights
Target DNA locus domain, a central HP1
To quantify the frequency with which human Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is recruited to endogenous retroviral DNA, we analyzed a recently published ChIP-seq data set for KAP1.8 The authors determined the genomic location of KAP1 by means of chromatin immunoprecipitation of KAP1 followed by next-generation sequencing experiments performed on three different cell lines (human embryonic kidney 293 cells (HEK293), U2OS and K562 cells, see Materials and Methods)
3.6 Mbp were annotated as transposable elements (TEs), which include long terminal repeat (LTR) elements, DNA transposons, long interspersed nuclear element retrotransposons (LINEs) and short interspersed nuclear element retrotransposon (SINEs)
Summary
Target DNA locus domain (ring finger, two B-box zinc-fingers and a coiled coil), a central HP1. We argue in favor of a new model in which zinc-finger genes found in a continuous array on chromosome 19 undergo recombination generating CNVs and new genes whose proteins recognize novel DNA sequences, some of which are found in retrotransposons. Because those retrotransposons that are unchecked by recognition of a repressor zinc-finger can go on to kill the host, we expect to observe in present day organisms a good correspondence between zinc-finger genes that recognize and bind to those retrotransposons that have recently entered the human lineage (and survived). In a scenario in which the host population is producing a large reservoir of repressors with different DNA binding affinities do the offspring that inherit a new ERV have a significant chance to somatically silence it and reproduce at a reasonable rate
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