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Using mouse genetics to understand human disease

What we do . Genetics: the study of the inheritance of biological phenotypeMendel recognized discrete units of inheritanceTheories rediscovered and disputed ca. 1900Experiments on mouse coat color proved Mendel correct and generalizable to mammalsWe now recognize this inheritance as being carrie

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Using mouse genetics to understand human disease

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    1. Using mouse genetics to understand human disease

    2. What we do Genetics: the study of the inheritance of biological phenotype Mendel recognized discrete units of inheritance Theories rediscovered and disputed ca. 1900 Experiments on mouse coat color proved Mendel correct and generalizable to mammals We now recognize this inheritance as being carried by variation in DNA

    3. Why mice? Mammals, much better biological model Easy to breed, feed, and house Can acclimatize to human touch Most important: we can experiment in many ways not possible in humans

    4. Mice are close to humans

    6. Mouse sequence reveals great similarity with the human genome

    7. Genomes are rearranged copies of each other

    8. Mouse sequence reveals great similarity with the human genome

    9. What we can do Directed matings Inbred lines and crosses Knockouts Transgenics Mutagenesis Nuclear transfer Control exposure to pathogens, drugs, diet, etc.

    10. Example: diabetes related mice available from The Jackson Labs Type I diabetes (3) Type II diabetes (3) Hyperglycemic (27) Hyperinsulinemic (25) Hypoglycemic (1) Hypoinsulinemic (5) Insulin resistant (30) Impaired insulin processing (7) Impaired wound healing (13)

    11. Inbreeding Repeated brother-sister mating leads to completely homozygous genome – no variation!

    12. Experimental Crosses Breed two distinct inbred lines Offspring (F1) are all identical – they each have one copy of each chromosome from each parent Further crosses involving F1 lead to mice with unique combinations of the two original strains

    13. Experimental Cross

    14. Experimental Cross: backcross F1 bred back to one of the parents Backcross offspring: 50% red-red 50% red-blue

    15. Experimental Cross: F2 intercross One F1 bred to another F1 F2 intercross offspring: 25% red-red 50% red-blue 25% blue-blue

    16. Trait mapping

    17. Trait mapping

    18. How do we distinguish chromosomes from different strains? Polymorphic DNA markers such as Single Nucleotide Polymorphisms (SNPs) can be used to distinguish the parental origin of offspring chromosomes

    19. Example: susceptibility to Tb C3H mice extremely susceptible to Tb B6 mice resistant F1, F2 show intermediate levels of susceptibility

    20. One gene location already known Previous work identified chromosome 1 as carrying a major susceptibility factor Congenic C3H animals carrying a B6 chromosome 1 segment were bred

    21. Congenic and consomic mice Derived strains of mice in which the homozygous genome of one mouse strain has a chromosome or part of a chromosome substituted from another strain

    22. Tb mapping cross

    23. Results: 3 new gene locations identified!

    24. Gene identified on chromosome 12

    27. Mouse History Modern “house mice” emerged from Asia into the fertile crescent as agriculture was born

    28. Mouse history

    29. Recent mouse history

    30. Mouse history

    31. Mouse history Asian musculus and European domesticus mice dominate the world but have evolved separately over ~ 1 Million years Mixing in Abbie Lathrop’s schoolhouse created all our commonly used mice from these two distinct founder groups

    33. Genetic Background of the inbred lab mice

    34. Comparing two inbred strains – frequency of differences in 50 kb segments

    35. Finding the genes responsible for biomedical phenotypes

    36. Using DNA patterns to find genes

    37. Using DNA patterns to find genes

    38. Example: mapping of albinism

    39. First genomic region mapped

    40. Future Genetic Studies

    41. Thanks to

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