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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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slide1

Model organism genetics and human disease

With an emphasis on…..

APOYG!

slide2

1,000 Myr

500 Myr

80 Myr

Mammalian

Biology

Human

Biology

Multicellular

Biology

The “Security Council”

Unicellular

Biology

Model Organisms

slide3

6,000

Not so many genes!

14,000

19,000

21,000

slide4

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

slide7

~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

slide9

Heo et al. (1999) Genes to Cells 4, 619-625.

Human disease genes in model organisms

slide10

APOYG and Disease: Two examples

Zelwegers Syndrome

Peroxisome biogenesis

Colorectal Cancer

Genome instability

zellweger spectrum
Zellweger Spectrum

Zellweger

syndrome

Neonatal adreno-

leukodystrophy

Infantile

Refsum Disease

slide12

Zellweger Patient Cells Share a

Common Phenotype with Yeast pex Mutants

Control

Zellweger patient

Human

 PTS1)

Wild-type

pex mutant

Yeast

(PTS1 - GFP)

strategies for mammalian pex gene identification

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
Yeast / Human Connections

Human

Identification

Function

Yeast

slide15

25

20

15

10

5

0

1990

1992

1994

1996

1998

2000

Discovery of Yeast and Human PEX Genes

Yeast

PEX Genes

Human

slide16

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

slide17

Genetic Instability in Human Cancers

MIN: Microsatellite instability

(increased mutation rate)

CIN: Chromosome instability

(increased aneuploidy rate)

slide18

Metaphase

Anaphase

slide19

Spindle

Checkpoint

Improperly attached

kinetochore

Bub1, Bub3,

Mad1, Mad2, Mad3

Cohesin

APCCdc20

Separase

Securin

slide20

~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%

slide21

Yeast as a model

CIN biology (gene function)

CIN candidate genes- (Cancer CIN genes)

Therapeutics

Finding an “Achilles heel” of cancer

slide22

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?

colony sectoring assay

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

+

summary of the 26 cloned ctf mutants

13 genes

93 / 138

Summary of the 26 Cloned ctf Mutants

Kinetochore proteins

Cohesion

DNA /RNA metabolism

Yes

s cerevisiae genome deletion project
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

yeast cin genes 300 non essential genes 85 coverage 100 essential genes and still counting
Yeast CIN genes~300 non-essential genes (85% coverage)~100 essential genes (and still counting)

Human homologs?

slide29

CIN mutational spectrum in cancer- Why?

Cancer biology

Tumor classification

Identification of new drug targets

CIN gene / Synthetic Lethal gene pairs

slide30

Synthetic Lethality

yfg2

yfg1

Normal

Yfg2 = Drug target

Yfg1 = CIN mutant

Tumor

yfg2

Viable

Viable

yfg1

Dead

slide35

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

slide36

6000

14,000

19,000

Four volumes of

the Encyclopedia of Life

21,000

slide37

April, 1953

April, 2003

Human genome sequence “completed”

slide39

~10,000 parts

~4,000,000 parts

~6,000 genes

~20,000 genes

slide41

Power of Model Organism Research

Genetics, biochemistry, genomics

Basic biology

Human health

Human disease

Therapy

Preventative medicine

APOYG!

APOWG!

APOIBE!