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.