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The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses.

Lukic S, Nicolas JC, Levine AJ - Cell Death Differ. (2013)

Bottom 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.Many of these zinc-finger genes exist in clusters associated with human chromosome 19.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)).

View Article: PubMed Central - PubMed

Affiliation: Simons Center for Systems Biology, Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.

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)).

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Distribution of similar C2H2 zinc-finger domains on chromosome 19. Each zinc-finger sequence was assigned to one of eight different clusters based on a hierarchical clustering analysis (see ‘Analysis of C2H2 motifs in Materials and Methods'). Each of these clusters is represented by a different color: orange, red, violet, green, yellow, gray, light blue and magenta. We used the sequence divergence between pairs of zinc-fingers as the similarity metric in this analysis. The density associated with each cluster was normalized such that the total mass is one, and it is represented with a particular color in the figure. We found that five clusters of zinc-fingers are highly localized on particular regions of chromosome 19 (orange, red, violet, green and yellow). This supports the hypothesis that local duplications generated by unequal crossover events have been responsible for the expansion of clusters of C2H2 zinc-fingers
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fig4: Distribution of similar C2H2 zinc-finger domains on chromosome 19. Each zinc-finger sequence was assigned to one of eight different clusters based on a hierarchical clustering analysis (see ‘Analysis of C2H2 motifs in Materials and Methods'). Each of these clusters is represented by a different color: orange, red, violet, green, yellow, gray, light blue and magenta. We used the sequence divergence between pairs of zinc-fingers as the similarity metric in this analysis. The density associated with each cluster was normalized such that the total mass is one, and it is represented with a particular color in the figure. We found that five clusters of zinc-fingers are highly localized on particular regions of chromosome 19 (orange, red, violet, green and yellow). This supports the hypothesis that local duplications generated by unequal crossover events have been responsible for the expansion of clusters of C2H2 zinc-fingers

Mentions: We classified all the C2H2 zinc-fingers on chromosome 19 using their sequence similarity. We found that similar C2H2 sequences cluster together around one of six major clusters in chromosome 19 (see Figure 4 and Materials and Methods). We found a strong positive correlation between sequence divergence and physical distance. This is consistent with the hypothesis that the expansion of clusters on chromosome 19 has been driven by local duplications associated with unequal crossover events.


The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses.

Lukic S, Nicolas JC, Levine AJ - Cell Death Differ. (2013)

Distribution of similar C2H2 zinc-finger domains on chromosome 19. Each zinc-finger sequence was assigned to one of eight different clusters based on a hierarchical clustering analysis (see ‘Analysis of C2H2 motifs in Materials and Methods'). Each of these clusters is represented by a different color: orange, red, violet, green, yellow, gray, light blue and magenta. We used the sequence divergence between pairs of zinc-fingers as the similarity metric in this analysis. The density associated with each cluster was normalized such that the total mass is one, and it is represented with a particular color in the figure. We found that five clusters of zinc-fingers are highly localized on particular regions of chromosome 19 (orange, red, violet, green and yellow). This supports the hypothesis that local duplications generated by unequal crossover events have been responsible for the expansion of clusters of C2H2 zinc-fingers
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921586&req=5

fig4: Distribution of similar C2H2 zinc-finger domains on chromosome 19. Each zinc-finger sequence was assigned to one of eight different clusters based on a hierarchical clustering analysis (see ‘Analysis of C2H2 motifs in Materials and Methods'). Each of these clusters is represented by a different color: orange, red, violet, green, yellow, gray, light blue and magenta. We used the sequence divergence between pairs of zinc-fingers as the similarity metric in this analysis. The density associated with each cluster was normalized such that the total mass is one, and it is represented with a particular color in the figure. We found that five clusters of zinc-fingers are highly localized on particular regions of chromosome 19 (orange, red, violet, green and yellow). This supports the hypothesis that local duplications generated by unequal crossover events have been responsible for the expansion of clusters of C2H2 zinc-fingers
Mentions: We classified all the C2H2 zinc-fingers on chromosome 19 using their sequence similarity. We found that similar C2H2 sequences cluster together around one of six major clusters in chromosome 19 (see Figure 4 and Materials and Methods). We found a strong positive correlation between sequence divergence and physical distance. This is consistent with the hypothesis that the expansion of clusters on chromosome 19 has been driven by local duplications associated with unequal crossover events.

Bottom 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.Many of these zinc-finger genes exist in clusters associated with human chromosome 19.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)).

View Article: PubMed Central - PubMed

Affiliation: Simons Center for Systems Biology, Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.

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)).

Show MeSH
Related in: MedlinePlus