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Evidence for evolutionary and nonevolutionary forces shaping the distribution of human genetic variants near transcription start sites.

Scala G, Affinito O, Miele G, Monticelli A, Cocozza S - PLoS ONE (2014)

Bottom Line: We found that, in this 10 kb region, the distribution of variants depends on their frequency and on their localization relative to the TSS.We found a significant relationship between the distribution of rare variants and nucleosome occupancy scores.In conclusion, this study provides a novel and detailed view of the distribution of genomic variants around TSSs, providing insight into the forces that instigate and maintain variability in such critical regions.

View Article: PubMed Central - PubMed

Affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Dipartimento di Fisica, Università degli Studi di Napoli "Federico II", Naples, Italy; Istituto Nazionale di Fisica Nucleare, Sezione di Napoli, Naples, Italy.

ABSTRACT
The regions surrounding transcription start sites (TSSs) of genes play a critical role in the regulation of gene expression. At the same time, current evidence indicates that these regions are particularly stressed by transcription-related mutagenic phenomena. In this work we performed a genome-wide analysis of the distribution of single nucleotide polymorphisms (SNPs) inside the 10 kb region flanking human TSSs by dividing SNPs into four classes according to their frequency (rare, two intermediate classes, and common). We found that, in this 10 kb region, the distribution of variants depends on their frequency and on their localization relative to the TSS. We found that the distribution of variants is generally different for TSSs located inside or outside of CpG islands. We found a significant relationship between the distribution of rare variants and nucleosome occupancy scores. Furthermore, our analysis suggests that evolutionary (purifying selection) and nonevolutionary (biased gene conversion) forces both play a role in determining the relative SNP frequency around TSSs. Finally, we analyzed the potential pathogenicity of each class of variant using the Combined Annotation Dependent Depletion score. In conclusion, this study provides a novel and detailed view of the distribution of genomic variants around TSSs, providing insight into the forces that instigate and maintain variability in such critical regions.

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Positional effects of BVF values in the four SNP classes.The two standard error confidence intervals for the observed normalized BVF values (red-dashed lines) are plotted along with its neutral expectation (blue-dashed line) for CGI-TSS frequency classes (left panel) and nCGI-TSS frequency classes (right panel). A dot is placed over the bins whose difference between the observed mean BVF value and the neutral expectation is statistically significant. On the x-axis is the position of the bin relative to the TSS.
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pone-0114432-g001: Positional effects of BVF values in the four SNP classes.The two standard error confidence intervals for the observed normalized BVF values (red-dashed lines) are plotted along with its neutral expectation (blue-dashed line) for CGI-TSS frequency classes (left panel) and nCGI-TSS frequency classes (right panel). A dot is placed over the bins whose difference between the observed mean BVF value and the neutral expectation is statistically significant. On the x-axis is the position of the bin relative to the TSS.

Mentions: Figure 1 shows confidence intervals of BVF values for the four frequency classes for CGI-TSSs and nCGI-TSSs. We observed several peaks and/or depressions in the BVF distribution in several genomic positions. To evaluate if these possible positional effects on BVF values were statistically robust, we compared BVF confidence intervals with a simulated neutral model in which variants were uniformly distributed among different bins and different TSSs (see Materials and Methods).


Evidence for evolutionary and nonevolutionary forces shaping the distribution of human genetic variants near transcription start sites.

Scala G, Affinito O, Miele G, Monticelli A, Cocozza S - PLoS ONE (2014)

Positional effects of BVF values in the four SNP classes.The two standard error confidence intervals for the observed normalized BVF values (red-dashed lines) are plotted along with its neutral expectation (blue-dashed line) for CGI-TSS frequency classes (left panel) and nCGI-TSS frequency classes (right panel). A dot is placed over the bins whose difference between the observed mean BVF value and the neutral expectation is statistically significant. On the x-axis is the position of the bin relative to the TSS.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256220&req=5

pone-0114432-g001: Positional effects of BVF values in the four SNP classes.The two standard error confidence intervals for the observed normalized BVF values (red-dashed lines) are plotted along with its neutral expectation (blue-dashed line) for CGI-TSS frequency classes (left panel) and nCGI-TSS frequency classes (right panel). A dot is placed over the bins whose difference between the observed mean BVF value and the neutral expectation is statistically significant. On the x-axis is the position of the bin relative to the TSS.
Mentions: Figure 1 shows confidence intervals of BVF values for the four frequency classes for CGI-TSSs and nCGI-TSSs. We observed several peaks and/or depressions in the BVF distribution in several genomic positions. To evaluate if these possible positional effects on BVF values were statistically robust, we compared BVF confidence intervals with a simulated neutral model in which variants were uniformly distributed among different bins and different TSSs (see Materials and Methods).

Bottom Line: We found that, in this 10 kb region, the distribution of variants depends on their frequency and on their localization relative to the TSS.We found a significant relationship between the distribution of rare variants and nucleosome occupancy scores.In conclusion, this study provides a novel and detailed view of the distribution of genomic variants around TSSs, providing insight into the forces that instigate and maintain variability in such critical regions.

View Article: PubMed Central - PubMed

Affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Dipartimento di Fisica, Università degli Studi di Napoli "Federico II", Naples, Italy; Istituto Nazionale di Fisica Nucleare, Sezione di Napoli, Naples, Italy.

ABSTRACT
The regions surrounding transcription start sites (TSSs) of genes play a critical role in the regulation of gene expression. At the same time, current evidence indicates that these regions are particularly stressed by transcription-related mutagenic phenomena. In this work we performed a genome-wide analysis of the distribution of single nucleotide polymorphisms (SNPs) inside the 10 kb region flanking human TSSs by dividing SNPs into four classes according to their frequency (rare, two intermediate classes, and common). We found that, in this 10 kb region, the distribution of variants depends on their frequency and on their localization relative to the TSS. We found that the distribution of variants is generally different for TSSs located inside or outside of CpG islands. We found a significant relationship between the distribution of rare variants and nucleosome occupancy scores. Furthermore, our analysis suggests that evolutionary (purifying selection) and nonevolutionary (biased gene conversion) forces both play a role in determining the relative SNP frequency around TSSs. Finally, we analyzed the potential pathogenicity of each class of variant using the Combined Annotation Dependent Depletion score. In conclusion, this study provides a novel and detailed view of the distribution of genomic variants around TSSs, providing insight into the forces that instigate and maintain variability in such critical regions.

Show MeSH