SNPs in human miRNA genes affect biogenesis and function. Rna

Department of Molecular Biology, City of Hope National Medical Center, Duarte, California 91010, USA.
RNA (Impact Factor: 4.94). 08/2009; 15(9):1640-51. DOI: 10.1261/rna.1560209
Source: PubMed


MicroRNAs (miRNAs) are 21-25-nucleotide-long, noncoding RNAs that are involved in translational regulation. Most miRNAs derive from a two-step sequential processing: the generation of pre-miRNA from pri-miRNA by the Drosha/DGCR8 complex in the nucleus, and the generation of mature miRNAs from pre-miRNAs by the Dicer/TRBP complex in the cytoplasm. Sequence variation around the processing sites, and sequence variations in the mature miRNA, especially the seed sequence, may have profound affects on miRNA biogenesis and function. In the context of analyzing the roles of miRNAs in Schizophrenia and Autism, we defined at least 24 human X-linked miRNA variants. Functional assays were developed and performed on these variants. In this study we investigate the affects of single nucleotide polymorphisms (SNPs) on the generation of mature miRNAs and their function, and report that naturally occurring SNPs can impair or enhance miRNA processing as well as alter the sites of processing. Since miRNAs are small functional units, single base changes in both the precursor elements as well as the mature miRNA sequence may drive the evolution of new microRNAs by altering their biological function. Finally, the miRNAs examined in this study are X-linked, suggesting that the mutant alleles could be determinants in the etiology of diseases.

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Available from: Jinong Feng,
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    • "Accepted April 27, 2015. 1 Corresponding author: within seed regions (mir-seed-SNP), would be expected to exhibit a complex biological effect (Sun et al., 2009). "
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    ABSTRACT: MicroRNA (miRNA) is a class of noncoding RNA important in posttranscriptional regulation of target genes. The regulation mechanism requires complementarity between target mRNA and the miRNA region responsible for their recognition and binding, also called the seed region. It has been estimated that each miRNA targets approximately 200 genes and genetic variability of miRNA genes has been associated with phenotypic variation and disease susceptibility in humans, livestock species, and model organisms. Polymorphisms in miRNA genes especially within the seed region could therefore represent biomarkers for phenotypic traits important in livestock animals. Using the updated Version 5.0 of our previously developed bioinformatics tool miRNA SNiPer we assembled polymorphic miRNA genes in chicken. Out of 740 miRNA genes 263 were polymorphic, among them 77 had SNPs located within the mature region, and 29 of them within the miRNA seed region. Because several polymorphisms in databases result from sequencing errors, we performed experimental validation of polymorphisms located within 4 selected miRNA genes in chicken (gga-mir-1614, -1644, -1648, and -1657). We confirmed the presence of nine polymorphisms and identified 3 additional novel polymorphisms within primary miRNA regions in chicken representing 3 layer-type breeds, one layer-type hybrid, and one meat-type intercrossed population. The developed catalog of mir-SNPs in chicken can serve researchers as a starting point for association studies dealing with poultry production traits and designing functional experiments. © The Author 2015. Published by Oxford University Press on behalf of Poultry Science Association.
    Poultry Science 07/2015; 94(9). DOI:10.3382/ps/pev170 · 1.67 Impact Factor
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    • "The variant was predicted to alter the secondary structure around the Drosha processing site . Functional validation showed that the variant results in increased expression of pre - miR - 510 , miR - 510 - 5p , and miR - 510 - 3p ( Feng et al . , 2009 ; Sun et al . , 2009 ) . A variant affecting Dicer processing is rs546098287 , located within the seed sequence of miR - 96 - 3p . This variant was identified as the causative mutation in an Italian family with non - syndromic hearing loss ( Soldà et al . , 2012 ) . Two segregating point mutations in miR - 96 - 5p were previously identified in two Spanish f"
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    ABSTRACT: Citation: Cammaerts S, Strazisar M, De Rijk P and Del Favero J (2015) Genetic variants in microRNA genes: impact on microRNA expression, function, and disease. Front. Genet. 6:186. MicroRNAs (miRNAs) are important regulators of gene expression and like any other gene, their coding sequences are subject to genetic variation. Variants in miRNA genes can have profound effects on miRNA functionality at all levels, including miRNA transcription, maturation, and target specificity, and as such they can also contribute to disease. The impact of variants in miRNA genes is the focus of the present review. To put these effects into context, we first discuss the requirements of miRNA transcripts for maturation. In the last part an overview of available databases and tools and experimental approaches to investigate miRNA variants related to human disease is presented.
    Frontiers in Genetics 05/2015; 6. DOI:10.3389/fgene.2015.00186
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    • "By binding to the different target gene regions, that is, 3 0 -untranslated region (3 0 UTR), 5 0 UTR, promoter or coding sequences, they repress or activate translation (reviewed in [Kunej et al. 2012]). The crucial binding location for translational regulation resides in the mature miRNA sequence, more accurately within the nucleotides 2–7 or 2–8 from the 5 0 end of the miRNA, called the seed region (Sun et al. 2009). "
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    ABSTRACT: MicroRNAs are currently being extensively studied due to their important role as post-transcriptional regulators. During miRNA biogenesis, precursors undergo two cleavage steps performed by Drosha-DGCR8 (Microprocessor) cleaving of pri-miRNA to produce pre-miRNA and Dicer-mediated cleaving to create mature miRNA. Genetic variants within human miRNA regulome have been shown to influence miRNA expression, target interaction and to affect the phenotype. In this study, we reviewed the literature, existing bioinformatics tools and catalogs associated with polymorphic miRNA regulome, and organized them into four categories: (1) polymorphisms located within miRNA genes (miR-SNPs), (2) transcription factor-binding sites/miRNA regulatory regions (miR-rSNPs), (3) miRNA target sites (miR-TS-SNPs), and 4. miRNA silencing machinery (miR-SM-SNPs). Since the miR-SM-SNPs have not been systematically studied yet, we have collected polymorphisms associated with miRNA silencing machinery. We have developed two catalogs containing genetic variability within: (1) genes encoding three main catalytic components of the silencing machinery, DROSHA, DGCR8, and DICER1; (2) miRNA genes itself, overlapping Drosha and Dicer cleavage sites. The developed resource of polymorphisms is available online ( and will be useful for further functional studies and development of biomarkers associated with diseases and phenotypic traits.
    09/2014; 3(1). DOI:10.1002/mgg3.110
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