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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
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
First
  • 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
slide4

Genomics of insect metamorphosis

  • 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
drosophia development
Drosophia development
  • 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
drosophila
Drosophila
  • It was possible to pull out tissue-specific developmental programs
    • Could verify this with mutants (critical for first model systems)
c elegans
C. elegans
  • 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.
differences in experiments
Differences in experiments/
  • 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?
examination of germline specific transcripts in c elegans
Examination of germline-specific transcripts in C. elegans
  • 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?
surprises in the c elegans story
Surprises in the C. elegans story?
  • 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.
is it possible to study behavior at this level
Is it possible to study behavior at this level?
  • 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
genomics in model systems to study human disease
Genomics in model systems to study human disease
  • 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
more disease models
More disease models
  • 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
regulatory networks
Regulatory networks
  • 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”
genome wide analysis of transcription factor binding site interactions
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.
be careful
Be careful
  • 9 transcription factors govern the yeast cell cycle (?)
  • Look at what these bind
  • Only 213 of 800 cell cycle genes are boudn by these.
comparative genomics
Comparative genomics
  • Can sequence important regions of closely related species to understand regulatory regions (Lander in Nature/Johnston in Science)
future
Future
  • 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
neurospora genome
Neurospora genome
  • 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.
neurospora
Neurospora -
  • 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
genome papers
Genome papers
  • 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
webpages
Webpages
  • All genome projects have a webpage:
  • http://www-genome.wi.mit.edu/.
  • www.tigr.org
  • Also see webpages for this class (GOLD)