Understanding Drosophila Development at the Molecular Level Gene Myers EECS, UCal, Berkeley.

Understanding Drosophila Development at Understanding Drosophila Development at the Molecular Levelthe Molecular Level

Gene MyersGene Myers

EECS, UCal, BerkeleyEECS, UCal, Berkeley

On Systems BiologyOn Systems Biology

The goal is to understand cells and organisms as molecular The goal is to understand cells and organisms as molecular systems. An objective that can be reached in the next 10-25 systems. An objective that can be reached in the next 10-25 years is the elucidation of the topology of the “circuit” years is the elucidation of the topology of the “circuit” diagram of a species’ cells.diagram of a species’ cells.

Rationale drug design will become a reality.Rationale drug design will become a reality.

We will be able to predictable modify systems at the cellular We will be able to predictable modify systems at the cellular level.level.

Accurately reconstruct 6-12 Drosophila genomes with a shotgun approach as Accurately reconstruct 6-12 Drosophila genomes with a shotgun approach as cost-efficiently as possible.cost-efficiently as possible.

Compare the Drosophila genomes to:Compare the Drosophila genomes to:

Understand evolution of whole genomesUnderstand evolution of whole genomes

Better predict the genes and regulatory signals within eachBetter predict the genes and regulatory signals within each

My Drosophila PlanMy Drosophila PlanSe

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Based on sequence anchor blocks

Courtesy Lisa Stubbs Courtesy Lisa Stubbs Oak Ridge National LaboratoryOak Ridge National Laboratory

Evolution as Genomic RearrangementsEvolution as Genomic Rearrangements

Given a ladder of 5-10 Drosophila genomes we should be able to Given a ladder of 5-10 Drosophila genomes we should be able to accurately discern most protein encoding genes, many RNA accurately discern most protein encoding genes, many RNA genes, and a host of regulatory signalsgenes, and a host of regulatory signals

Comparative Gene FindingComparative Gene Finding

sechellia mauritiana simulans melanogaster orena teissieri yakuba mimetica

0M10M20M30M40M

pseudoobscura

Find genes by requiring all HMM models Find genes by requiring all HMM models (ab initio)(ab initio), , trained for each genome on cDNA-discovered trained for each genome on cDNA-discovered (homology)(homology) genes, to be highly probable subject to genes, to be highly probable subject to the constraint that the encoded proteins are the constraint that the encoded proteins are consistent with the evolutionary relatedness of the consistent with the evolutionary relatedness of the species species (comparative)(comparative)..

Empirically validate all genes and their alternate splice forms.Empirically validate all genes and their alternate splice forms.

Measure (e.g. ChIP-chip) or infer from spatio-temporal expression, the cis-Measure (e.g. ChIP-chip) or infer from spatio-temporal expression, the cis-regulatory control of all genes and their transcription factor binding sites.regulatory control of all genes and their transcription factor binding sites.

Build a spatio-temporal model of Drosophila embryonic development and Build a spatio-temporal model of Drosophila embryonic development and associated regulatory-control “circuit”.associated regulatory-control “circuit”.

Dissect cellular complexes (pull-downs + MS) and signal cascades (in vitro Dissect cellular complexes (pull-downs + MS) and signal cascades (in vitro MS/MS)MS/MS)

My Drosophila PlanMy Drosophila PlanSe

quen

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ence

Parts

Lis

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Parts

Lis

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Mec

hani

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Mec

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Accurately reconstruct 6-12 Drosophila genomes with a shotgun approach as Accurately reconstruct 6-12 Drosophila genomes with a shotgun approach as cost-efficiently as possible.cost-efficiently as possible.

Compare the Drosophila genomes to:Compare the Drosophila genomes to:

Understand evolution of whole genomesUnderstand evolution of whole genomes

Better predict the genes and regulatory signals within eachBetter predict the genes and regulatory signals within each

Expression of Gene CG14897Expression of Gene CG14897

Stage 1: MaternalStage 1: Maternal

Stage 4: Pole PlasmStage 4: Pole Plasm

Stage 8: Neuroderm AnlageStage 8: Neuroderm Anlage

Stage 11: Stage 11: Protocerebrum Protocerebrum PrimordiumPrimordium

Stage 14: Embryonic Stage 14: Embryonic Central Nervous SystemCentral Nervous System

Affy expr. profile: 1Affy expr. profile: 1stst 12 hours 12 hours

Sea Urchin Endo-Meso TF “Circuit” (Davidson Lab, Caltech)Sea Urchin Endo-Meso TF “Circuit” (Davidson Lab, Caltech)

Some possibilitiesSome possibilities

Intuitive systems for scientific analysisIntuitive systems for scientific analysis

Modeling of molecular processes in multi-cellular systems.Modeling of molecular processes in multi-cellular systems.

New paradigms for architecting softwareNew paradigms for architecting software

Nano-exploration of the cellNano-exploration of the cell

Fully robotic molecular biology labFully robotic molecular biology lab