A challenge for miRNA: multiple isomiRs in miRNAomics

• Current data support the conclusion that isomiRs are not random events.
• They have drawn attention for regulatory biological roles.
• IsomiRs from homologous/clustered miRNA loci have close relationships.
• The analysis at the miRNA and isomiR levels enriches miRNA studies.

Accumulating evidence suggests that a single microRNA (miRNA) locus can generate a series of sequences during miRNA maturation process. These multiple sequences, called miRNA variants, or isomiRs, have different lengths and different 5′ and 3′ ends. Some of these isomiRs are detected as varied nucleotides and 3′ additional non-template nucleotides. As physiological miRNA isoforms, they have drawn attention for possible regulatory biological roles. The present work mainly reviews miRNA/isomiR biogenesis, isomiR expression patterns, and functional and evolutionary implications, especially between isomiRs from homologous and clustered miRNA loci. The phenomenon of multiple isomiRs and their biological roles indicates that analysis performed at the miRNA and isomiR levels should be included in miRNA studies. This may enrich and complicate miRNA biogenesis and coding–non-coding RNA regulatory networks.