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Slide 1 - Model organism genetics and human disease With an emphasis on….. APOYG!
Slide 2 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms
Slide 3 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000
Slide 4 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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
Slide 5 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells”
Slide 6 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells”
Slide 7 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast
Slide 8 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms
Slide 9 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625.
Slide 10 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability
Slide 11 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease
Slide 12 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP)
Slide 13 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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”
Slide 14 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function
Slide 15 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25
Slide 16 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer
Slide 17 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate)
Slide 18 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase
Slide 19 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3
Slide 20 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2%
Slide 21 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer
Slide 22 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN?
Slide 23 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen
Slide 24 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes
Slide 25 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates
Slide 26 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection
Slide 27 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs?
Slide 28 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers
Slide 29 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs
Slide 30 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1
Slide 31 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%)
Slide 32 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers
Slide 33 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers
Slide 34 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers
Slide 35 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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
Slide 36 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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 6000 19,000 14,000 21,000 Four volumes of the Encyclopedia of Life
Slide 37 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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 6000 19,000 14,000 21,000 Four volumes of the Encyclopedia of Life April, 2003 April, 1953 Human genome sequence “completed”
Slide 38 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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 6000 19,000 14,000 21,000 Four volumes of the Encyclopedia of Life April, 2003 April, 1953 Human genome sequence “completed”
Slide 39 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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 6000 19,000 14,000 21,000 Four volumes of the Encyclopedia of Life April, 2003 April, 1953 Human genome sequence “completed” ~10,000 parts ~4,000,000 parts ~20,000 genes ~6,000 genes
Slide 40 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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 6000 19,000 14,000 21,000 Four volumes of the Encyclopedia of Life April, 2003 April, 1953 Human genome sequence “completed” ~10,000 parts ~4,000,000 parts ~20,000 genes ~6,000 genes
Slide 41 - Model organism genetics and human disease With an emphasis on….. APOYG! Model Organisms 6,000 19,000 14,000 Not so many genes! 21,000 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 Saccharomyces cerevisiae Budding yeastThe “E.coli of eukaryotic cells” Yeast vs. Human ~50% of yeast genes have at least one similar human gene ~50% of human genes have at least one similar yeast gene Human vs. Yeast Human disease genes in model organisms Human disease genes in model organisms Heo et al. (1999) Genes to Cells 4, 619-625. APOYG and Disease: Two examples Zelwegers Syndrome Peroxisome biogenesis Colorectal Cancer Genome instability Zellweger Spectrum Zellweger syndrome Neonatal adreno- leukodystrophy Infantile Refsum Disease Zellweger Patient Cells Share a Common Phenotype with Yeast pex Mutants Zellweger patient Control Wild-type pex mutant Human  PTS1) Yeast (PTS1 - GFP) 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” Yeast / Human Connections Human Yeast Identification Function PEX Genes Discovery of Yeast and Human PEX Genes Yeast Human 1990 1996 1992 1994 1998 2000 5 10 0 15 20 25 C. Rieder If you want to understand cancer, you need answers to the many questions about the role genome instability plays. ---Bert Vogelstein, 2002 Cancer Genetic Instability in Human Cancers MIN: Microsatellite instability (increased mutation rate) CIN: Chromosome instability (increased aneuploidy rate) Metaphase Anaphase Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 Spindle Checkpoint APCCdc20 Securin Separase Cohesin Improperly attached kinetochore Bub1, Bub3, Mad1, Mad2, Mad3 hDING hMRE11 hBUB1 hCDC4 11% 4% 4% 2% Yeast as a model CIN biology (gene function) CIN candidate genes- (Cancer CIN genes) Therapeutics Finding an “Achilles heel” of cancer What are all the proteins mutable to CIN? non-essential Chromosome Fragment M SUP11 + Colony Sectoring Assay Chromosome Transmission Fidelity (ctf) Screen Kinetochore proteins Cohesion DNA /RNA metabolism Summary of the 26 Cloned ctf Mutants Yes 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 96 well plate frozen glycerol stock condense 4 plates onto 1 pin 96 strains onto G418 plates The yeast gene knockout collection Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting) Human homologs? 12 yeast CIN genes have top-hit human homologs that are mutated in cancers CIN mutational spectrum in cancer- Why? Cancer biology Tumor classification Identification of new drug targets CIN gene / Synthetic Lethal gene pairs Synthetic Lethality yfg2 Dead Viable Viable yfg1 Yeast Genetic Interactions MRE11 (4%) BUB1 (2%) 12 yeast CIN genes have human homologs that are mutated in cancers 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 6000 19,000 14,000 21,000 Four volumes of the Encyclopedia of Life April, 2003 April, 1953 Human genome sequence “completed” ~10,000 parts ~4,000,000 parts ~20,000 genes ~6,000 genes Power of Model Organism Research Genetics, biochemistry, genomics Basic biology Human health Human disease Therapy Preventative medicine APOYG! APOWG! APOIBE!