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A model for the roles of miRNAs in evolution and disease. (A) A representation of a skeletal element in an evolutionarily ancestral state, or a young or healthy condition. (B) A representation of a skeletal element in an evolutionarily derived state, or a senescent or diseased condition. (C) In the baseline condition, the mirn gene produces a given level of miR molecules, which bind to their target site with a certain affinity to allow a specific level of translation. (D) In the evolutionarily derived state, cis-acting enhancer mutations may decrease or increase (not shown) transcription of the mirn gene, which would lead to decreased (or increased, not shown) inhibition of the target mRNA and hence increased (or decreased, not shown) amounts of target protein, which could alter skeletal shape or function. Similar diminution of mirn expression could occur by stage specific changes in mirn transcription or epigenetic modifications. (E) Mutations accumulated during evolution could alter the miRNA recognition site on target mRNAs to increase or decrease binding, which could alter the amount of target protein produced compared to baseline. Altered protein levels could alter the morphologies or the relative rates of skeletal build-up or degradation by osteoblasts and osteoclasts.