CSAIL Publications and Digital Archive header
bullet Research Abstracts Home bullet CSAIL Digital Archive bullet Research Activities bullet CSAIL Home bullet

link to publications.csail.mit.edu link to www.csail.mit.edu horizontal line


Research Abstracts - 2007
horizontal line

horizontal line

vertical line
vertical line

Systematic Discovery and Characterization of Fly microRNAs Using 12 Drosophila Genomes

Alexander Stark, Pouya Kheradpour, Leopold Parts, Julius Brennecke, Graham Ruby, Gregory Hannon, David Bartel & Manolis Kellis

microRNAs (miRNAs) are short RNA genes that direct the inhibition of target messenger-RNA expression via complementary binding sites in the targets' 3' untranslated region (UTR) [1-8] . Currently, miRNAs are estimated to comprise 1%-5% of animal genes [2,9,10], making them one of the most abundant classes of regulators. In addition, an average miRNA may regulate hundreds of genes , so that a large fraction of all genes are miRNA targets [11-15]. It is thus desirable to obtain a comprehensive view on all miRNAs in an animal genome, especially as knowledge of the sequence alone can allow the identification of the physiologically relevant target genes.

We used the 12 recently sequenced Drosophila species [16] to study structural and evolutionary properties of miRNA hairpins. We found that several distinct signatures can guide the de-novo discovery of miRNAs, revealing more than 50 novel miRNA genes, many of which we validate experimentally. Several of the novel miRNAs are clustered in genomic loci, and likely to be transcribed from a single precursor. Our analysis finds several additional members of existing families, and also many novel families.

We also find distinct evolutionary signals for the precise annotation of the start position of mature miRNAs. This allows us to correct the annotation and strand of previously known miRNA genes, sometimes leading to drastic corrections in their target genes. For example, we correct the Hox miRNA miR-10, and reveal that the new annotation now has a highly conserved target site in the Hox genes ultrabithorax and abdominal-B, a regulatory relationship typical for Hox miRNAs in flies and vertebrates. When a precise signal for the miRNA start does not exist, we find that indeed experimental information suggests that multiple starts are used in practice; similarly, when both strands score highly according to our evolutionary models, we find that indeed a mature product is found from both strands.

Finally, we find that the performance scales with the total divergence between the species under consideration. The divergence of neutrally evolving sequence allowed the genome-wide de novo discovery of miRNAs in12 Drosophila genomes, and will serve as a model for similar studies in human as dozens of mammalian genomes become available.


[1] Ambros V (2004) The functions of animal microRNAs. Nature 431: 350-355.

[2] Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281-297.

[3] Plasterk RH (2006) Micro RNAs in Animal Development. Cell 124: 877-881.

[4] Lai EC (2003) microRNAs: Runts of the Genome Assert Themselves. Curr Biol 13: R925-936.

[5] Alvarez-Garcia I, Miska EA (2005) MicroRNA functions in animal development and human disease. Development 132: 4653-4662.

[6] Chen K, Rajewsky N (2007) The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 8: 93-103.

[7] Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20: 515-524.

[8] Zamore PD, Haley B (2005) Ribo-gnome: the big world of small RNAs. Science 309: 1519-1524.

[9] Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, et al. (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet.

[10] Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH, et al. (2005) Phylogenetic Shadowing and Computational Identification of Human microRNA Genes. Cell 120: 21-24.

[11] Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of MicroRNA-Target Recognition. PLoS Biol 3: e85.

[12] Grun D, Wang YL, Langenberger D, Gunsalus KC, Rajewsky N (2005) microRNA Target Predictions across Seven Drosophila Species and Comparison to Mammalian Targets. PLoS Comput Biol 1: e13.

[13] Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, et al. (2005) Combinatorial microRNA target predictions. Nat Genet 37: 495-500.

[14] Lewis BP, Burge CB, Bartel DP (2005) Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets. Cell 120: 15-20.

[15] Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, et al. (2005) Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature 434: 338-345.

[16] Consortium DCGSaA (2007) Initial comparative genomics analysis of 12 Drosophila genomes. Nature In preparation.


vertical line
vertical line
horizontal line

MIT logo Computer Science and Artificial Intelligence Laboratory (CSAIL)
The Stata Center, Building 32 - 32 Vassar Street - Cambridge, MA 02139 - USA
tel:+1-617-253-0073 - publications@csail.mit.edu