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The characterisation of three types of genes that overlie copy number variable regions.

Woodwark C, Bateman A - PLoS ONE (2011)

Bottom Line: Looking into possible mechanisms for the regulation of gene expression we found that type I genes have a significant paucity of genes regulated by miRNAs and are not significantly enriched for monoallelically expressed genes.Type III genes, on the other hand, have a significant excess of genes regulated by miRNAs and are enriched for genes that are monoallelically expressed.Many diseases and genomic disorders are associated with CNVs so a better understanding of the different ways genes are associated with normal CNVs will help focus on candidate genes in genome wide association studies.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. cara@sanger.ac.uk

ABSTRACT

Background: Due to the increased accuracy of Copy Number Variable region (CNV) break point mapping, it is now possible to say with a reasonable degree of confidence whether a gene (i) falls entirely within a CNV; (ii) overlaps the CNV or (iii) actually contains the CNV. We classify these as type I, II and III CNV genes respectively.

Principal findings: Here we show that although type I genes vary in copy number along with the CNV, most of these type I genes have the same expression levels as wild type copy numbers of the gene. These genes must, therefore, be under homeostatic dosage compensation control. Looking into possible mechanisms for the regulation of gene expression we found that type I genes have a significant paucity of genes regulated by miRNAs and are not significantly enriched for monoallelically expressed genes. Type III genes, on the other hand, have a significant excess of genes regulated by miRNAs and are enriched for genes that are monoallelically expressed.

Significance: Many diseases and genomic disorders are associated with CNVs so a better understanding of the different ways genes are associated with normal CNVs will help focus on candidate genes in genome wide association studies.

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Frequency distribution graphs of expression ratios.Expression ratio distribution for the same individuals and the same expression data as analysed by Schuster-Böckler et al. [4]. Only type I genes based on the CNV coordinates from Conrad et. al. [1] were used.
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pone-0014814-g002: Frequency distribution graphs of expression ratios.Expression ratio distribution for the same individuals and the same expression data as analysed by Schuster-Böckler et al. [4]. Only type I genes based on the CNV coordinates from Conrad et. al. [1] were used.

Mentions: The expression ratio analysis of Schuster-Böckler et al. [4] was repeated with the Conrad et al. [1] CNV data set using only the type I genes. As figure 2 shows, despite the increased accuracy of these CNVs most genes, whether duplicated or deleted, have expression levels very similar to the wild type expression level (expression ratio of one) with a difference in means of just 0.026 between them. This may be seen more clearly in figure 3, which shows the expression ratios plotted for each type I gene. The graphs for both the duplicated and deleted genes show that most genes have an expression ratio of one (the straight horizontal stretch of the graph) with only a few genes at either end of the graph that have expression ratios that differ greatly from one. Similar shaped graphs are also produced for type II and III genes (Supplemental figure S1) which would imply that the copy number of the gene does not affect the expression of type I genes as only parts of the type II and III genes vary in copy number not the whole gene. This apparent lack of correlation of gene dosage on expression levels suggests that the type I genes must be under tight homeostatic regulation that somehow compensates for gene dosage. Although, the whole of type II and III CNV genes do not vary in copy number, their expression ratios do vary in a similar way to type I genes so may also require dosage compensation mechanisms to cover the affects of disrupted alleles or missing regulatory regions.


The characterisation of three types of genes that overlie copy number variable regions.

Woodwark C, Bateman A - PLoS ONE (2011)

Frequency distribution graphs of expression ratios.Expression ratio distribution for the same individuals and the same expression data as analysed by Schuster-Böckler et al. [4]. Only type I genes based on the CNV coordinates from Conrad et. al. [1] were used.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102654&req=5

pone-0014814-g002: Frequency distribution graphs of expression ratios.Expression ratio distribution for the same individuals and the same expression data as analysed by Schuster-Böckler et al. [4]. Only type I genes based on the CNV coordinates from Conrad et. al. [1] were used.
Mentions: The expression ratio analysis of Schuster-Böckler et al. [4] was repeated with the Conrad et al. [1] CNV data set using only the type I genes. As figure 2 shows, despite the increased accuracy of these CNVs most genes, whether duplicated or deleted, have expression levels very similar to the wild type expression level (expression ratio of one) with a difference in means of just 0.026 between them. This may be seen more clearly in figure 3, which shows the expression ratios plotted for each type I gene. The graphs for both the duplicated and deleted genes show that most genes have an expression ratio of one (the straight horizontal stretch of the graph) with only a few genes at either end of the graph that have expression ratios that differ greatly from one. Similar shaped graphs are also produced for type II and III genes (Supplemental figure S1) which would imply that the copy number of the gene does not affect the expression of type I genes as only parts of the type II and III genes vary in copy number not the whole gene. This apparent lack of correlation of gene dosage on expression levels suggests that the type I genes must be under tight homeostatic regulation that somehow compensates for gene dosage. Although, the whole of type II and III CNV genes do not vary in copy number, their expression ratios do vary in a similar way to type I genes so may also require dosage compensation mechanisms to cover the affects of disrupted alleles or missing regulatory regions.

Bottom Line: Looking into possible mechanisms for the regulation of gene expression we found that type I genes have a significant paucity of genes regulated by miRNAs and are not significantly enriched for monoallelically expressed genes.Type III genes, on the other hand, have a significant excess of genes regulated by miRNAs and are enriched for genes that are monoallelically expressed.Many diseases and genomic disorders are associated with CNVs so a better understanding of the different ways genes are associated with normal CNVs will help focus on candidate genes in genome wide association studies.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. cara@sanger.ac.uk

ABSTRACT

Background: Due to the increased accuracy of Copy Number Variable region (CNV) break point mapping, it is now possible to say with a reasonable degree of confidence whether a gene (i) falls entirely within a CNV; (ii) overlaps the CNV or (iii) actually contains the CNV. We classify these as type I, II and III CNV genes respectively.

Principal findings: Here we show that although type I genes vary in copy number along with the CNV, most of these type I genes have the same expression levels as wild type copy numbers of the gene. These genes must, therefore, be under homeostatic dosage compensation control. Looking into possible mechanisms for the regulation of gene expression we found that type I genes have a significant paucity of genes regulated by miRNAs and are not significantly enriched for monoallelically expressed genes. Type III genes, on the other hand, have a significant excess of genes regulated by miRNAs and are enriched for genes that are monoallelically expressed.

Significance: Many diseases and genomic disorders are associated with CNVs so a better understanding of the different ways genes are associated with normal CNVs will help focus on candidate genes in genome wide association studies.

Show MeSH