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. 2005 Jun;1(1):e13.
doi: 10.1371/journal.pcbi.0010013. Epub 2005 Jun 24.

microRNA target predictions across seven Drosophila species and comparison to mammalian targets

Dominic Grün  1 , Yi-Lu Wang, David Langenberger, Kristin C Gunsalus, Nikolaus Rajewsky
Affiliations

microRNA target predictions across seven Drosophila species and comparison to mammalian targets

Dominic Grün et al. PLoS Comput Biol. 2005 Jun.

Abstract

microRNAs are small noncoding genes that regulate the protein production of genes by binding to partially complementary sites in the mRNAs of targeted genes. Here, using our algorithm PicTar, we exploit cross-species comparisons to predict, on average, 54 targeted genes per microRNA above noise in Drosophila melanogaster. Analysis of the functional annotation of target genes furthermore suggests specific biological functions for many microRNAs. We also predict combinatorial targets for clustered microRNAs and find that some clustered microRNAs are likely to coordinately regulate target genes. Furthermore, we compare microRNA regulation between insects and vertebrates. We find that the widespread extent of gene regulation by microRNAs is comparable between flies and mammals but that certain microRNAs may function in clade-specific modes of gene regulation. One of these microRNAs (miR-210) is predicted to contribute to the regulation of fly oogenesis. We also list specific regulatory relationships that appear to be conserved between flies and mammals. Our findings provide the most extensive microRNA target predictions in Drosophila to date, suggest specific functional roles for most microRNAs, indicate the existence of coordinate gene regulation executed by clustered microRNAs, and shed light on the evolution of microRNA function across large evolutionary distances. All predictions are freely accessible at our searchable Web site http://pictar.bio.nyu.edu.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Phylogenetic Tree of 12 Drosophila Species
Our datasets include 3′ UTRs for seven of these species: D. melanogaster, D. yakuba, D. erecta, D. ananassae, D. pseudoobscura, D. virilis, and D. mojavensis. Species underlined in solid red are present in set 1 and set 2. D. erecta (broken red line) is present only in set 2. Source: http://species.flybase.net/.
Figure 2
Figure 2. Signal-to-Noise Ratios of the PicTar Single Target Site Predictions
For both set 1 and set 2 the predicted number of anchor sites for 46 unique microRNAs, conserved in all flies, and corresponding randomized microRNAs (averaged over five cohorts) and the respective signal-to-noise ratio (indicated above the bars) are shown with and without using free energy filtering of anchor sites for UTRs with either masked and unmasked repeats. (A) Predictions for set 1 with anchor sites conserved in the melanogaster and obscura groups. (B) Predictions for set 1 with anchor sites conserved in all flies. (C) Predictions for set 2 with anchor sites conserved in the melanogaster and obscura groups. (D) Predictions for set 2 with anchor sites conserved in all flies.
Figure 3
Figure 3. Sensitivity and Specificity as a Function of PicTar Score
Shown is the average number of predicted targeted genes as a function of a PicTar score cutoff (discarding all target genes with a score below this cutoff) for three different PicTar settings (S1–S3; see Materials and Methods): (A) high-sensitivity setting (S1), (B) high-specificity setting (S2), and (C) medium sensitivity/medium specificity setting (S3). The signal-to-noise ratio also depends on the score cutoff and is indicated above the curve for certain cutoff values. All predictions for all settings can be accessed on the PicTar Web server (not filtered by score cutoffs).
Figure 4
Figure 4. Specificity of PicTar Predictions of Genes with Multiple Putative Target Sites
Number of unique genes as a function of the minimal number of anchor sites for 46 unique, conserved microRNAs and for randomized microRNAs (averaged over five cohorts). The ratio of these numbers, reflecting the specificity, is indicated above each bar.
Figure 5
Figure 5. Significant GO Terms among the Predicted Target Genes of All Single microRNAs and Clusters of Co-Expressed microRNAs
Significantly enriched GO terms for (A) “biological processes” and (B) “molecular function” ontologies. Shown are GO terms with p-values smaller than 0.1, corrected for multiple testing. Hierarchical clustering was performed separately for GO terms and microRNAs (see Materials and Methods).
Figure 6
Figure 6. Lengths Distribution of 3′ UTRs in Human and D. melanogaster
Data for set 1 and set 2 on a logarithmic scale. The distribution decays exponentially with increasing length in human much slower than in D. melanogaster. The average 3′ UTR lengths in human and D. melanogaster are approximately 900 and approximately 400 nucleotides, respectively.
Figure 7
Figure 7. Length Distribution of Repeat Elements in 3′ UTRs of Human and D. melanogaster
Data for set 1 on a logarithmic scale. The distribution peaks strongly for both species at a length of 11 nucleotides and decays exponentially for longer repeat elements in D. melanogaster. Up to a length of roughly 50 nucleotides, both distributions are very similar, while for longer elements the distribution for human no longer decays exponentially, but has a broad tail with another significant peak at a length of approximately 300 nucleotides.
Figure 8
Figure 8. Number of Predicted Target Genes for Homologous microRNAs between Mammals and Flies
Scatter plot for relative numbers of targeted genes predicted for homologous microRNAs in mammals and flies. The ratio of the number of predicted target genes of a microRNA and the average number of putative targeted genes per microRNA are plotted in mammals (y-axis) versus flies (x-axis). Conservation in flies included the melanogaster and obscura groups. Outliers (with a ratio of relative numbers of predicted target genes larger than 3.0 or smaller then 0.33) are circled. The microRNA identifiers refer to microRNAs annotated in D. melanogaster.
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