Developmental functional genomics and the neurospora genome
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Developmental functional genomics and the Neurospora genome. Outline methods to gind genome-wide maps of develomental processes. What to do after the genome is done? What data do you need? What models do you need to be able to build?. First.

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Outline methods to gind genome wide maps of develomental processes l.jpg
Outline methods to gind genome-wide maps of develomental processes

  • What to do after the genome is done?

  • What data do you need?

  • What models do you need to be able to build?

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First processes

  • Describe the developing system in terms of gene expression

    • Can be used to assign genes to functional groups

    • Set baselines for perturbation experiments

    • Example: insect metamorphosis – an integrated set of developmental processes controlled by a transcriptional hierarchy that coordinates the action of hundreds of genes

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Genomics of insect metamorphosis processes

  • Microarray analysis revealed that 13% of assayed transcripts displayed significant changes in the first 30 hours of metamorphosis.

  • They found coordinate changes in groups of genes that provided insight into the dynamics of the process

    • Ecdysone levels up – glycolysis down

    • Metamorphosis onset- muscle-related transcripts are down

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Drosophia development processes

  • Comparison of expression patterns showed that embryogenesis and metamorphosis were more similar than other growth stages (insight into how complex organisms develop).

    • It may be easier to study one phase than the other – so here is the logic for doing it.

    • It may be possible to differentiate the effects of the same genes on the two processes

  • 40% of genes differed between sexes and most of this was in the germline

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Drosophila processes

  • It was possible to pull out tissue-specific developmental programs

    • Could verify this with mutants (critical for first model systems)

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C. elegans processes

  • Time course from early embryogenesis to adulthood

    • Do they know what effect growth medium has?

  • 22% of the transcripts showed significant change over this time course

  • Less evolutionarily conserved genes tend to be expressed later in life than highly conserved genes.

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Differences in experiments/ processes

  • 6 or 8 timepoints were used for C. elegans, whereas 80 were used for Drosophila

  • Suggest that these developmental studies are not necessary for other organisms in which tissues can be easily dissected. What do you think?

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Examination of germline-specific transcripts in C. elegans processes

  • Used germline mutant + wild type to identify these

  • 1416 (12%) were germline enriched

    • 258 oocyte enriched

    • 650 sperm enriched

    • 508 germline enriched

  • Identities indicate that posttranslational mechanisms play an important part in sperm

    • Kinses, phosphatases

  • Is this enough information for you? What would you do next? What questions would you ask?

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Surprises in the C. elegans story? processes

  • Germiline-specific genes were not on the X chromosome

  • There is no doubt more information in these datasets that will be mined in the future – if you know about them.

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Is it possible to study behavior at this level? processes

  • Some Drosophila behaviors are under circadian control

    • Found 134 transcripts that are cyclic

    • 25% have no known function

  • Geotaxis (moving with or against gravity, polygenic trait

    • Found several hundred differentially expressed genes

    • Found three genes that when mutated resulted in geotaxis defects

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Genomics in model systems to study human disease processes

  • Leptin knockout mice vs wild type

    • Found 2000 detectably expressed genes and 450 were significantly different in mutant obese mice and wild type.

    • Added leptin back to ob mice to distinguish specific effects of leptin

    • Identified a transcription factor downregulated by leptin that regulates fatty-acid biosynthesis

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More disease models processes

  • MS

  • Retinal diseases -mouse

    • Identified 396 genes, looked for rod-specific expresion. Human orthologs exist for 237. In all, 86 of the newly identified genes correspond to 37 different disease loci

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Regulatory networks processes

  • How can multiple types of information be integrated?

  • Modules – multiple, adjacent cis-regulatory elements

  • “Building the core of the regulatory circuitry by determining the relationships between cis-regulatory sequences, regulatory proteins, and gene expression seems a first step in delineating developmental networks”

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Genome-wide analysis of transcription –factor/binding-site interactions

  • ChIP (chromatin immunoprecipitation) – identify what genes transcription factors are interacting with. (Cross-link binding proteins to DNA. Shear DNA and IP. Label and hybridize DNA to identify genes to which factors are bound.

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Be careful interactions

  • 9 transcription factors govern the yeast cell cycle (?)

  • Look at what these bind

  • Only 213 of 800 cell cycle genes are boudn by these.

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Comparative genomics interactions

  • Can sequence important regions of closely related species to understand regulatory regions (Lander in Nature/Johnston in Science)

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Future interactions

  • Localization and processing of RNA

  • Post translational modifications

  • Integration of data “data currently being generated is..systematic but also superficial.”

  • Much of the data leads to speculative discorse

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Neurospora genome interactions

  • There are many of these types of papers.

  • Sequence a genome, assemble it (this is an enormous amount of work) – then come up with the beginning of analyses that says this was worth doing.

  • 40 megabases – a little over 2X yeast.

  • 10K genes, only 25% fewer than Drosophila and almost 2X that of yeast.

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Neurospora - interactions

  • Intro gives the placement of this organism – why is it important?

  • >20-fold sequence coverage

  • Have 958 sequence contigs, with 97% of the sequence in the largest 44 contigs

  • 41% of the genes aren’t found in other organisms

  • Important organism for studying epigenetics

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Genome papers interactions

  • What is there?

    • Sequence information

    • Genes

    • Pathways

    • Potential utility of the sequence

    • Comparative analysis with other genomes

    • Some researchers continue sequence analyses others move to functional genomics

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Webpages interactions

  • All genome projects have a webpage:



  • Also see webpages for this class (GOLD)