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Insights into Functional Elements in Drosophila: From Experimentation to Computation

The Drosophila Encode Workshop held on December 4, 2004, explored the functional elements of the Drosophila genome through two sessions. Key topics included transcription initiation and termination, regulatory elements like promoters and enhancers, and alternative splicing through contributions from experts like Mark Yandell, Kevin White, and more. The discussions emphasized the importance of Drosophila as a model organism for human disease studies, and highlighted the integration of experimental and computational methods for better understanding gene function and regulation. Collaborations and new technologies were proposed to enhance research findings.

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Insights into Functional Elements in Drosophila: From Experimentation to Computation

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  1. Functional Elements DefinedExperimentally and Computationally Drosophila Encode Workshop Dec. 4, 2004

  2. Session 1: 10:45-12:15 • Transcripts • Protein-coding Mark Yandell (C), Kevin White (E) Transcription Start Michael Brent (C), Akilesh Pandey (E) Transcription Stop UTRs • Alternate Splicing Steve Mount (E) • Non-coding Ian Holmes(C), Eric Lai (E) tRNA, rRNAs, snoRNAs, microRNAs,

  3. Session 2: 1:15-2:45 • Regulatory elements • Promoters, DNase sensitivity Roger Hoskins (E) • Cis Regulatory Elements Mike Eisen (C), Sue Celniker (E) Enhancers, repressors, silencers, insulators, Transcription factor binding sites Conserved sequences of unknown function • Chromatin Modification Gary Karpen (E) • Origins of Replication Sites of Replication termination • Genetic variation and Gene Evolution Andy Clark (C), David Begun (E) • Wrap-up Gene Myers

  4. Experiments & Computation How accurate? Room for improvement? What inputs would help? Experiment Computation Experiment DNA sequencing cDNA/EST sequencing ChIP/chip DNAse hypersensitivity Assembly WG Alignment Protein Gene Prediction Cis-Module finding 5’ RACE RT-PCR Transposon Reporters How accurate? Scalability / HTP ? Cost/benefit analysis Validate vs. Refine? Cost/benefit analysis Why flies? Outputs: Information & Materials

  5. Why Flies? • “Flies are most like humans” • Gene features are the most similar to human • Have a tightly spaced ladder of species as for mammals • Lot’s of alternative splicing, complex cis-control. • Closest model for human diseases. • “Flies are easy to play with” • Compact genome • Short generation times, many labs, … • “Existing Resources” • Genomes of 12 species, 50 melanogaster individuals • More known enhancers than any other organism • Good array sets, many functional assays. • Many lines of mutational variants

  6. State of the Art • Coding Genes • Most protein genes located, remainder “unusual” • Refinement of model: 5’ + 3’ ends, splice junctions, alternate splicing possible • Comparative methods are improving, could improve more along with alignments. • Proteomics could further inform transcription • RNA Genes / The Transcriptome • Must have comparative data, look for correlated structure • High throughput validation. Not currently available. • Cis-Elements • Can predict core promoters sufficiently well to assist experimental validation • Enhancers are much, much harder: current need PWMs or • Lots of approaches possible: SELEX, ChIP/chip, Reporter “searches”

  7. State of the Art • Higher-Order Structure • Histone modification is important • Population Statistics and Disease Correlation • “Good” model for human disease studies, only viable model for understanding functional consequences of variation • Long standing pop-stat model

  8. The Basics Enable Comparative Informatics • Extend ladder with 1 or 2 out species • Finish some of the 12 (to some greater degree) • EST/cDNA sequencing of all of the 12 (level?) The Usual Suspects • RACE and/or rt-PCR verification of all coding genes. • Capped EST sequencing. • Junction arrays + tiling arrays • Continued refinement of annotation • Functional understanding of alternate transcription • Purification of every (most?) TF’s + SELEX • ChIP/chip of all TFs + Core promotor proteins • ChIP/chip of histone modification, DH-map on cell types

  9. Novel Components • MS/MS of the proteome (Pandey) • Complete annotation of the transcriptome (Mount, Lai, Holmes) • Dros-map + complex phenotype/genotype correlation project (Clark, Begun) • Recombinant libraries of all transcripts, all enhancers (Celniker, Bellen) • Time (Development stage) and space (cell type) for all the above

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