Limits...
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)).

Show MeSH

Related in: MedlinePlus

Deletion rate on chromosome 19. The orange probability density represents the empirical distribution of 3513 zinc-finger motifs on chromosome 19. The deletion rate was estimated using population frequency data of polymorphic deletions larger than 50 bp in 45 individuals of European ancestry (CEU from 1000 genomes project). We used the Watterson estimator (continuous horizontal line) and a refinement of the Watterson estimator (dashed horizontal line) built from the frequency spectrum of deletions (see ‘Deletion rate as a function of the genomic location' in Supplementary Information). We estimated the deletion rate on seven different regions of chromosome 19. These regions include six segments with a high density of zinc-finger motifs (peaks on 19p13.2, 19p13.11-19p.12, 19q13.11, 19q13.2, 19q13.33 and q13.41-q13.42) and the complementary region of chromosome 19. However, because of lack of sufficient data we could only estimate the rate on three segments: the complementary region, the peak on 19p13.11-19p.12 and the peak on q13.41-q13.42. The question marks in the plot denote the four segments where we could not estimate the deletion rate with confidence. The deletion rate is expressed in units of number of deletions (larger than 50 bp) per generation and per Giga-base (Gb)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3921586&req=5

fig5: Deletion rate on chromosome 19. The orange probability density represents the empirical distribution of 3513 zinc-finger motifs on chromosome 19. The deletion rate was estimated using population frequency data of polymorphic deletions larger than 50 bp in 45 individuals of European ancestry (CEU from 1000 genomes project). We used the Watterson estimator (continuous horizontal line) and a refinement of the Watterson estimator (dashed horizontal line) built from the frequency spectrum of deletions (see ‘Deletion rate as a function of the genomic location' in Supplementary Information). We estimated the deletion rate on seven different regions of chromosome 19. These regions include six segments with a high density of zinc-finger motifs (peaks on 19p13.2, 19p13.11-19p.12, 19q13.11, 19q13.2, 19q13.33 and q13.41-q13.42) and the complementary region of chromosome 19. However, because of lack of sufficient data we could only estimate the rate on three segments: the complementary region, the peak on 19p13.11-19p.12 and the peak on q13.41-q13.42. The question marks in the plot denote the four segments where we could not estimate the deletion rate with confidence. The deletion rate is expressed in units of number of deletions (larger than 50 bp) per generation and per Giga-base (Gb)

Mentions: An additional question that we explored is whether the expansion of clusters of zinc-fingers on human chromosome 19 is an ongoing phenomenon. To test this hypothesis, we estimated the current CNV formation rate along chromosome 19 using population genetics methods applied to human data (see Supplementary Information and Figure 5). Because it is not clear how to root CNVs with copy number larger than 2, the analysis was restricted to deletions. We applied two different estimators of the deletion rate (see Figure 5) to sequence data associated with 45 individuals of European ancestry.13 The inferred chromosome-wide deletion rate for deletions larger than 50 base pairs was 0.017–0.022 deletions per generation and per Giga-base. The deletion rate in only two of the six clustered regions with a high density of C2H2 zinc-fingers on chromosome 19 could be estimated because the other four regions did not have enough gene duplications to provide statistically significant results. Both estimators predicted that the deletion rate in the clusters located on 19p13.11-19p.12 and on 19q13.41-19q13.42 is about twofold higher than the background deletion rate.


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)

Deletion rate on chromosome 19. The orange probability density represents the empirical distribution of 3513 zinc-finger motifs on chromosome 19. The deletion rate was estimated using population frequency data of polymorphic deletions larger than 50 bp in 45 individuals of European ancestry (CEU from 1000 genomes project). We used the Watterson estimator (continuous horizontal line) and a refinement of the Watterson estimator (dashed horizontal line) built from the frequency spectrum of deletions (see ‘Deletion rate as a function of the genomic location' in Supplementary Information). We estimated the deletion rate on seven different regions of chromosome 19. These regions include six segments with a high density of zinc-finger motifs (peaks on 19p13.2, 19p13.11-19p.12, 19q13.11, 19q13.2, 19q13.33 and q13.41-q13.42) and the complementary region of chromosome 19. However, because of lack of sufficient data we could only estimate the rate on three segments: the complementary region, the peak on 19p13.11-19p.12 and the peak on q13.41-q13.42. The question marks in the plot denote the four segments where we could not estimate the deletion rate with confidence. The deletion rate is expressed in units of number of deletions (larger than 50 bp) per generation and per Giga-base (Gb)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Deletion rate on chromosome 19. The orange probability density represents the empirical distribution of 3513 zinc-finger motifs on chromosome 19. The deletion rate was estimated using population frequency data of polymorphic deletions larger than 50 bp in 45 individuals of European ancestry (CEU from 1000 genomes project). We used the Watterson estimator (continuous horizontal line) and a refinement of the Watterson estimator (dashed horizontal line) built from the frequency spectrum of deletions (see ‘Deletion rate as a function of the genomic location' in Supplementary Information). We estimated the deletion rate on seven different regions of chromosome 19. These regions include six segments with a high density of zinc-finger motifs (peaks on 19p13.2, 19p13.11-19p.12, 19q13.11, 19q13.2, 19q13.33 and q13.41-q13.42) and the complementary region of chromosome 19. However, because of lack of sufficient data we could only estimate the rate on three segments: the complementary region, the peak on 19p13.11-19p.12 and the peak on q13.41-q13.42. The question marks in the plot denote the four segments where we could not estimate the deletion rate with confidence. The deletion rate is expressed in units of number of deletions (larger than 50 bp) per generation and per Giga-base (Gb)
Mentions: An additional question that we explored is whether the expansion of clusters of zinc-fingers on human chromosome 19 is an ongoing phenomenon. To test this hypothesis, we estimated the current CNV formation rate along chromosome 19 using population genetics methods applied to human data (see Supplementary Information and Figure 5). Because it is not clear how to root CNVs with copy number larger than 2, the analysis was restricted to deletions. We applied two different estimators of the deletion rate (see Figure 5) to sequence data associated with 45 individuals of European ancestry.13 The inferred chromosome-wide deletion rate for deletions larger than 50 base pairs was 0.017–0.022 deletions per generation and per Giga-base. The deletion rate in only two of the six clustered regions with a high density of C2H2 zinc-fingers on chromosome 19 could be estimated because the other four regions did not have enough gene duplications to provide statistically significant results. Both estimators predicted that the deletion rate in the clusters located on 19p13.11-19p.12 and on 19q13.41-19q13.42 is about twofold higher than the background deletion rate.

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