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Genome Res. 2017 Mar;27(3):374-384. doi: 10.1101/gr.208900.116. Epub 2017 Jan 13.

Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation.

Roden C1,2,3,4, Gaillard J2,5, Kanoria S6, Rennie W6, Barish S4, Cheng J1,2,3, Pan W1,2,3, Liu J1,2,3, Cotsapas C1,7, Ding Y6, Lu J1,2,3,8.

Author information

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Yale Stem Cell Center and Yale Cancer Center, Yale University, New Haven, Connecticut 06520, USA.
Yale Center for RNA Science and Medicine, New Haven, Connecticut 06520, USA.
Graduate Program in Biological and Biomedical Sciences, Yale University, New Haven, Connecticut 06510, USA.
School of Medicine, Yale University, New Haven, Connecticut 06510, USA.
Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA.
Department of Neurology, Yale School of Medicine, New Haven, Connecticut 06511, USA.
Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, Connecticut 06520, USA.


Mature microRNAs (miRNAs) are processed from hairpin-containing primary miRNAs (pri-miRNAs). However, rules that distinguish pri-miRNAs from other hairpin-containing transcripts in the genome are incompletely understood. By developing a computational pipeline to systematically evaluate 30 structural and sequence features of mammalian RNA hairpins, we report several new rules that are preferentially utilized in miRNA hairpins and govern efficient pri-miRNA processing. We propose that a hairpin stem length of 36 ± 3 nt is optimal for pri-miRNA processing. We identify two bulge-depleted regions on the miRNA stem, located ∼16-21 nt and ∼28-32 nt from the base of the stem, that are less tolerant of unpaired bases. We further show that the CNNC primary sequence motif selectively enhances the processing of optimal-length hairpins. We predict that a small but significant fraction of human single-nucleotide polymorphisms (SNPs) alter pri-miRNA processing, and confirm several predictions experimentally including a disease-causing mutation. Our study enhances the rules governing mammalian pri-miRNA processing and suggests a diverse impact of human genetic variation on miRNA biogenesis.

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