Insights into the regulation of human CNV-miRNAs from the view of their target genes

Abstract

Background: microRNAs (miRNAs) represent a class of small (typically 22 nucleotides in length) non-coding RNAs that can degrade their target mRNAs or block their translation. Recent research showed that copy number alterations of miRNAs and their target genes are highly prevalent in cancers; however, the evolutionary and biological functions of naturally existing copy number variable miRNAs (CNV-miRNAs) among individuals have not been studied extensively throughout the genome.

Results: In this study, we comprehensively analyzed the properties of genes regulated by CNV-miRNAs, and found that CNV-miRNAs tend to target a higher average number of genes and prefer to synergistically regulate the same genes; further, the targets of CNV-miRNAs tend to have higher variability of expression within and between populations. Finally, we found the targets of CNV-miRNAs are more likely to be differentially expressed among tissues and developmental stages, and participate in a wide range of cellular responses.

Conclusions: Our analyses of CNV-miRNAs provide new insights into the impact of copy number variations on miRNA-mediated post-transcriptional networks. The deeper interpretation of patterns of gene expression variation and the functional characterization of CNV-miRNAs will help to broaden the current understanding of the molecular basis of human phenotypic diversity.

Figure 1

Synergistic regulation of CNV-miRNAs. (A) Schematic representation of five genes regulated by both CNV-miRNA-α and CNV-miRNA-β. (B) Distribution of genes affected by two pseudo-CNV-miRNAs in 1000 simulations. The arrow on the right hand side represents the observed number of targets of two CNV-miRNAs. (C) Distribution of genes targeted by the two non-independent CNV-miRNAs in 1,000 random simulations. (D) Distribution of CNV-miRNAs as a result of dosage-balance from synergistic regulation.

Figure 2

Expression variability of target genes within four human populations. This figure shows the comparison of the coefficient of variation calculated from the gene expression profiles in (A) YRI, (B) CEU, (C) CHB, and (D) JPT populations.

Figure 3

MAFs of SNPs in UTRs of target genes regulated exclusively by CNV-miRNAs or non-CNV-miRNAs. This figure shows the comparison of MAFs of SNPs in (A) YRI, (B) CEU, (C) CHB, and (D) JPT populations. In each sub-figure, the left panel shows the comparison of MAFs in the 5^′UTRs, the right panel shows the comparison of MAFs in the 3^′UTRs.

Figure 4

Expression variability of target genes between four human populations. (A) The plot of expression intensities of the genes in the YRI and CEU population, the red dots represent the genes that show CEU- and YRI-specific significantly differential expression intensities. (B) Number distribution of the differentially expressed genes in six population pairs selected from four ethnic populations. (C) Comparison of proportion of genes differentially expressed in the genes that are regulated exclusively by either non-CNV-miRNAs, non-CNV-miRNAs and CNV-miRNAs, or CNV-miRNAs, respectively.

Figure 5

Comparison of the differential expression ratios of human genes. Expression variation was measured across 4,877 subset-versus-subset comparisons.

Figure 6

Functional differences based on GO terms between the genes regulated exclusively by CNV-miRNAs and the genes regulated exclusively by non-CNV-miRNAs. (A) Biological process groups that show a significantly higher percent of genes regulated exclusively by CNV-miRNAs. (B) Biological process groups that show a significantly higher percent of genes regulated exclusively by non-CNV-miRNAs. (C) Molecular function groups that show a significantly higher percent of genes regulated exclusively by CNV-miRNAs (D) Molecular function groups that show a significantly higher percent of genes regulated exclusively by non-CNV-miRNAs. N1 represents the number of genes with GO-annotation in genes exclusively regulated by CNV-miRNAs, N2 represents the number of genes with GO-annotation in genes exclusively regulated by non-CNV-miRNAs. P-values were calculated by Fisher’s exact two tailed test.

Figure 7

Schematic representation of the four paradigms used to explain co-evolution between CNVs and miRNAs. (A) A simple repression motif is involved where a miRNA reduces the expression of its target (T), the increased dosage due to CNV-duplication of the target (T) is balanced by the corresponding CNV-duplication of miRNA. (B) miRNA and its target (T) mutually buffer each other’s expression from perturbation in a negative feedback loop, the increased dosage due to CNV-duplication of the target (T) is buffered by the expression variation of the miRNA. (C) The CNV-duplication of some miRNAs compensate for the CNV-deletion of other miRNAs in balancing the dosage of their common target (T). (D) The common target (T) of two miRNAs is up-regulated in the cellular response to environmental factors; the intrinsic dosage-sensitivity of the target (T) makes the CNV-duplication of both the miRNA1 and miRNA2 become favorable. miRNA1 and miRNA2 represent two different miRNAs.