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Model organism genetics and human disease With an emphasis on….. APOYG!

Model organism genetics and human disease With an emphasis on….. APOYG!. 1,000 Myr. 500 Myr. 80 Myr. Mammalian Biology. Human Biology. Multicellular Biology. The “Security Council”. Unicellular Biology. Model Organisms. 6,000. Not so many genes!. 14,000. 19,000. 21,000.

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Model organism genetics and human disease With an emphasis on….. APOYG!

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  1. Model organism genetics and human disease With an emphasis on….. APOYG!

  2. 1,000 Myr 500 Myr 80 Myr Mammalian Biology Human Biology Multicellular Biology The “Security Council” Unicellular Biology Model Organisms

  3. 6,000 Not so many genes! 14,000 19,000 21,000

  4. Why we love yeast Model organism Eukaryotic intracellular biology Gene function conservation (e.g., human disease genes) Testbed for genomic technologies Experimental approaches Classical genetics (+biochemistry) Recombinant genetics Emerging technologies Community of “yeast people” Open exchange of ideas, reagents, results Collaboration

  5. Saccharomyces cerevisiaeBudding yeastThe “E.coli of eukaryotic cells”

  6. ~50% of human genes have at least one similar yeast gene Humanvs. Yeast Yeastvs.Human ~50% of yeast genes have at least one similar human gene

  7. Human disease genes in model organisms

  8. Heo et al. (1999) Genes to Cells 4, 619-625. Human disease genes in model organisms

  9. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability

  10. Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease

  11. Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Control Zellweger patient Human  PTS1) Wild-type pex mutant Yeast (PTS1 - GFP)

  12. Strategies for Mammalian PEX Gene Identification Functional complementation Mammalian cDNA expression libraries “Homology probing” Identify all yeast peroxins Identify all homologous human proteins Test as “candidate genes”

  13. Yeast / Human Connections Human Identification Function Yeast

  14. 25 20 15 10 5 0 1990 1992 1994 1996 1998 2000 Discovery of Yeast and Human PEX Genes Yeast PEX Genes Human

  15. Cancer C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002

  16. Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate)

  17. Metaphase Anaphase

  18. Spindle Checkpoint Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Cohesin APCCdc20 Separase Securin

  19. ~20% of CIN mutational spectrum in colon cancer 2% hBUB1 Spindle Checkpoint Improperly attached kinetochore 4% Bub1, Bub3, Mad1, Mad2, Mad3 hMRE11 Cohesin APCCdc20 Separase Securin 11% hDING hCDC4 4%

  20. Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer

  21. Spontaneous mutants eg, CTF mutant collection Systematic screening Non-essential D mutants Ts mutants, semi-permissive Karen Yuen Shay Ben-Aroya HieterLab members (20yrs) What are all the proteins mutable to CIN?

  22. Chromosome Transmission Fidelity (ctf) Screen White colony (10-4) wt EMS mutagenesis Sectored colony ctf mutant (10-2) 138 mutants, ~50 genes Colony Sectoring Assay non-essential Chromosome Fragment SUP11 M +

  23. 13 genes 93 / 138 Summary of the 26 Cloned ctf Mutants Kinetochore proteins Cohesion DNA /RNA metabolism Yes

  24. S. cerevisiae Genome Deletion Project • “Complete” set of yeast nonessential deletion mutants • ~4,700 haploid strains • ~4,700 homozygous diploid strains • nonessential genes deleted with kanMX = fifty 96 well plate • ~5,800 heterozygous diploid strains pin 96 strains onto G418 plates condense 4 plates onto 1 96 well plate frozen glycerol stock

  25. The yeast gene knockout collection

  26. Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs?

  27. 12 yeast CIN genes have top-hit human homologs that are mutated in cancers

  28. CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs

  29. Synthetic Lethality yfg2 yfg1 Normal Yfg2 = Drug target Yfg1 = CIN mutant Tumor yfg2 Viable Viable yfg1 Dead

  30. MRE11 (4%) BUB1 (2%) Yeast Genetic Interactions

  31. 12 yeast CIN genes have human homologs that are mutated in cancers

  32. Yeast CIN Genes and Human Cancer CIN “candidate genes” Somatic mutations in colon cancer ~40% spectrum in 11 genes Cancer therapeutics “Achilles heel” candidate genes Validation in mammalian cells

  33. 6000 14,000 19,000 Four volumes of the Encyclopedia of Life 21,000

  34. April, 1953 April, 2003 Human genome sequence “completed”

  35. ~10,000 parts ~4,000,000 parts ~6,000 genes ~20,000 genes

  36. Power of Model Organism Research Genetics, biochemistry, genomics Basic biology Human health Human disease Therapy Preventative medicine APOYG! APOWG! APOIBE!

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