Institute of Laboratory Animal Science University of Zurich

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Transgenic Mouse ModelsBio 426 / HS 2007
Kurt Bürki, Institute of Laboratory Animal
Science, University of Zurich
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Artefacts with Transgenic Models

• Fraud
• Irreproducible Results
• Technical Artefacts (Gene Construct / Analysis)
• Genetic Complexity
• Biological Complexity
• Mouse-Man Differences

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Artefacts with Transgenic Models

• Fraud
• Irreproducible Results
• Technical Artefacts (Gene Construct / Analysis)
• Genetic Complexity
• Biological Complexity
• Mouse-Man Differences

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Kawabata et al. (1991)
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Paper to Read

• Lavitrano M. et al. Sperm Cells as Vectors for
  Introducing Foreign DNA into Eggs Genetic
  Transformation of Mice. Cell 57, 717-723 (1989).

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Sperm Mediated Gene Transfer - Claims

• About 30 transgenic founders by Southern
  blotting
• Transmission to offspring
• Mammalian-specific methylation pattern
• CAT gene expression (tail/muscle)

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Artefacts with Transgenic Models

• Fraud
• Irreproducible Results
• Technical Artefacts (Gene Construct / Analysis)
• Genetic Complexity
• Biological Complexity
• Mouse-Man Differences

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Genetic Background

• Unsuitable background
• Unidentified modificators
• Drifting background

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Example Cftr knock-out mice(Cystic Fibrosis,
Intestinal Obstruction)

• DBA/2
• C57/BL6
• BALB/c

• Survive lt 10 days
• Survive gt 20 days
• Many survive for prolonged period

Cfm1 Modificator gene identified in mice and
humans
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Modifiers may cause

• More extreme (enhanced) phenotypes
• Less extreme (reduced) phenotypes
• Novel (synthetic) phenotypes
• Wild-type phenotypes

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Modifier Genes
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Genetic Drift
100 80 60 40 20 0
A brother x sister mating B
random mating 5 breeding pairs C random
mating 80 breeding pairs
Inbreeding coefficient
0 5 10
15 20
Generations
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Artefacts with Transgenic Models

• Fraud
• Irreproducible Results
• Technical Artefacts (Gene Construct / Analysis)
• Genetic Complexity
• Biological Complexity (Unexpected Phenotypes)
• Mouse-Man Differences

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Transgenic Models Genotype to Phenotype

• Prediction based on
• Gene expression pattern
• In vitro observation
• Different species

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Unexpected Phenotypes

• Phenotype more severe than expected
• Early lethal
• Lack of inductive signals
• Phenotype less severe than expected
• Incomplete gene disruption
• Genetic redundancy
• Functional redundancy (compensation)

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Mouse Man Differences

• Difference in metabolic pathways Example
  Lesch-Nyhan Disease (HPRT Deficiency) Difference
  in Purine metabolism
• Differences in tissue architecture
• Absolute time versus relative time

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Paper to Read

• Gu H. et al. Deletion of a DNA Polymerase beta
  segment in T Cells Using Cell Type-Specific Gene
  Targeting. Science 265, 103-106 (1994).