Functional and Evolutionary Significance of Human MicroRNA Seed Region Mutations

Hill, Christopher G.; Jabbari, Neda; Matyunina, Lilya V.; McDonald, John F.

doi:10.1371/journal.pone.0115241

Cited by 39 publications

(28 citation statements)

References 22 publications

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“…There is a high functional cost of even single nucleotide changes within seed regions, which is consistent with their high sequence conservation among miRNA families both within and between species and suggests processes that may underlie the evolution of miRNA regulatory control (Hill et al, 2014). The target specificity determined by the seed has evolutionary and biological implications because single nucleotide polymorphisms in canonical miRNA binding sites would affect miRNA-mediated regulations, a notion supported also by experimental data (Afonso-Grunz and Muller, 2015;Vosa et al, 2015).The canonical 7nt seed can be divided into several types (Ellwanger et al, 2011).…”

Section: Seed-involving Interactionssupporting

confidence: 52%

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

Pačes

Nič²,

Novotný³

et al. 2017

EFS3

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This report is the outcome of an EFSA procurement aiming at investigating and summarising the state of knowledge on (I) the mode-of-action of dsRNA and miRNA pathways, (II) the potential for nontarget gene regulation by dsRNA-derived siRNAs or miRNAs, (III) the determination of siRNA pools in plant tissues and the importance of individual siRNAs for silencing. The report is based on a comprehensive and systematic literature search, starting with the identification and retrieval of~190,000 publications related to the research area and further filtered down with keywords to produce focused collections used for subsequent screening of titles and abstracts. The report is comprised of an (I) Introduction to the field of small RNAs, (II) a Data and Methodologies section containing strategies used for literature search and study selection, and (III) the Results of the literature review organized according to the three main procurement tasks. The outcome of the first task reviews dsRNA and miRNA pathways in mammals (including humans), birds, fish, arthropods, annelids, molluscs, nematodes, and plants. Eight taxon-dedicated chapters are based on~1,400 cumulative references chosen from~10,000 inspected titles and abstracts. We review conserved and divergent aspects of small RNA pathways and dsRNA responses in animals and plants including structure and function of key proteins as well as four basic mechanisms: genome-encoded posttranscriptional regulations (miRNA), degradation of RNAs by short interfering RNA pools generated from long dsRNA (RNAi), transcriptional silencing, and sequence-independent responses to dsRNA. The outcome of the second task focuses on base pairing between small RNAs and their target RNAs and predictability of biological effects of small RNAs in animals and plants. The outcome of the last task reviews methodology, siRNA pools, and movement of small RNAs in plants. Potential transfer of small RNAs between species and circulating miRNAs in mammals is described in the final chapter.

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Section: Seed-involving Interactionssupporting

confidence: 52%

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

Pačes

Nič²,

Novotný³

et al. 2017

EFS3

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“…The mutation profile of the mature sequences confirmed the pattern found by Wheeler et al (154; see also 55, 58), as the same two regions of the mature sequence - the seed region (positions 2-8) and the 3′ complementarity region (positions 13-16) - showed few instances of nucleotide substitutions compared with positions 1, 10-12, and 17-22 (Figure 6a, bottom). The frequency of substitutions in the seed region was effectively zero, with only ten changes seen in the 29,007 positions analyzed, confirming the functional importance of this region of the molecule (11, 60, 69, 152), and calling into question the long-term evolutionary importance of non-canonical interactions between miRNAs and target mRNAs (65, 134). …”

Section: Nucleotide Substitution Rates Of Mature Versus Star Sequencesmentioning

confidence: 69%

A Uniform System for the Annotation of Vertebrate microRNA Genes and the Evolution of the Human microRNAome

Fromm¹,

et al. 2015

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Although microRNAs (miRNAs) are among the most intensively studied molecules of the past 20 years, determining what is and what is not a miRNA has not been straightforward. Here, we present a uniform system for the annotation and nomenclature of miRNA genes. We show that fewer than a third of the 1,881 human miRBase entries, and only approximately 16% of the 7,095 metazoan miRBase entries, are robustly supported as miRNA genes. Furthermore, we show that the human repertoire of miRNAs has been shaped by periods of intense miRNA innovation, and that mature gene products show a very different tempo and mode of sequence evolution than star products. We establish a new open access database -- MirGeneDB (http://mirgenedb.org) -- to catalog this set of robustly supported miRNAs, which complements the efforts of miRBase, but differs from it by annotating the mature versus star products, and by imposing an evolutionary hierarchy upon this curated and consistently named repertoire.

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“…Therefore, investigation of the relationship between genetic variants in noncoding genomic regions and gene function may help to improve our knowledge about the associations between genotypes and phenotypes. Previous studies in miRNA variation reported a high conservation of human miRNAs [Saunders et al., ; Quach et al., ]; and although several examples showing the association of miRNA genetic variants with disease have already been described [Jazdzewski et al., ; Hoffman et al., ; Jazdzewski et al., ; Xu et al., ; Xu et al., ; Lopez‐Valenzuela et al., ; Soldà et al., ; Chen et al., ; Fu et al., ; Hrdlickova et al., ; Wan et al., ; Xu et al., ; Zhou et al., ], there is still little information on the functional consequences that these genetic changes may have [Duan et al., ; Jazdzewski et al., ; Jazdzewski et al., ; Lopez‐Valenzuela et al., ; Ghanbari et al., ; Hill et al., ]. Here, we analyzed global genetic variation in miRNA regions among human populations and look for the functional differences between allele variants of three common miRNA SNVs that had repeatedly been associated with different types of cancer.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Genetic Variation: From Population Analysis to Functional Implications of Three Allele Variants Associated with Cancer

et al. 2016

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Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants associated with cancer (rs2910164:C > G in MIR146A, rs11614913:C > T in MIR196A2, and rs3746444:A > G in both MIR499A and MIR499B). We found differences in the expression between alleles and in the regulation of several genes involved in cancer, such as TP53, KIT, CDH1, CLH, and TERT, which may result in changes in regulatory networks related to tumorigenesis. Furthermore, luciferase-based assays showed that MIR499A could be regulating the cadherin CDH1 and the cell adhesion molecule CLH1 in an allele-dependent fashion. A better understanding of the effect of microRNA variants associated with disease could be key in our way to a more personalized medicine.

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Functional and Evolutionary Significance of Human MicroRNA Seed Region Mutations

Cited by 39 publications

References 22 publications

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

A Uniform System for the Annotation of Vertebrate microRNA Genes and the Evolution of the Human microRNAome

MicroRNA Genetic Variation: From Population Analysis to Functional Implications of Three Allele Variants Associated with Cancer

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