No Evidence that MicroRNAs Coevolve with Genes Located in Copy Number Regions

Abstract

MicroRNAs (miRNAs) are a widespread class of regulatory noncoding RNAs with key roles in physiology and development, conferring robustness to noise in regulatory networks. Consistent with this buffering function, it was recently suggested that human miRNAs coevolve with genes in copy number regions (copy number variation [CNV] genes) to reduce dosage imbalance. Here, I compare miRNA regulation between CNV and non-CNV genes in four model organisms. miRNA regulation of CNV genes is elevated in human and fly but reduced in nematode and zebrafish. By analyzing 31 human CNV data sets, careful analysis of human and chimpanzee orthologs, resampling genes within species and comparing structural variant types, I show that the apparent coevolution between CNV genes and miRNAs is due to the strong dependency between 3'-untranslated region length and miRNA target prediction. Deciphering the interplay between CNVs and miRNAs will likely require a deeper understanding of how miRNAs are embedded in regulatory circuits.

Keywords: copy number variation; gene regulation; miRNA; regulatory networks; robustness.

Fig. 1.

Comparison of the mean number of miRNA regulators (left axis) and mean number of miRNA binding sites (right axis) predicted by TargetScan between CNV genes and non-CNV genes in four model organisms. CNV miRNA target genes have more miRNA regulators and target sites than non-CNV genes in human and fly. In contrast, non-CNV genes are regulated by more miRNAs and have more target sites than CNV genes in zebrafish and worm. Human: N_CNV = 16,060, N_non-CNV = 1,360; fly: N_CNV = 1,580, N_non-CNV = 10,170; worm: N_CNV = 731, N_non-CNV = 14,656; zebrafish: N_CNV = 2,787, N_non-CNV = 13,610; ***P < 0.0001, Wilcoxon rank-sum tests. Error bars represent ± 1 standard error of the mean.

Fig. 2.

The number of miRNAs per target gene is strongly correlated with the length of the 3′-UTR in human, fly, zebrafish, and worm (left panels). Lines represent the linear regressions between the number of miRNAs inferred by TargetScan and the 3′-UTR length for each target gene. CNV genes have on average longer 3′-UTRs than non-CNV genes in human and fly. In contrast, the mean 3′-UTR length is shorter for CNV genes than for non-CNV genes in worm and zebrafish (right panels). ***P < 0.0001.