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An Overview of Mouse Genetics

An Overview of Mouse Genetics. Reference Material. Mouse Genetics, Concepts and Applications . 1995. Silver, L.M. Oxford University Press, New York, NY, 1995, pp 1-362.

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An Overview of Mouse Genetics

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  1. An Overview of Mouse Genetics

  2. Reference Material • Mouse Genetics, Concepts and Applications. 1995. Silver, L.M. Oxford University Press, New York, NY, 1995, pp 1-362. • Genetic Variants and Strains of the Laboratory Mouse, 3rd Edition. 1996. Edited by M. F. Lyon, S. Rastan and S.D.M. Brown. Oxford University Press,New York, NY, 2 Volumes, pp. 1-1807.

  3. Reference Material(Out of Print; Often in Libraries) • The Mouse in Biomedical Research. 1981. Edited by H.L. Foster, J.D. Small and J.G. Fox.Academic Press, New York,NY.4 Volumes. • Inbred Strains in Biomedical Research. 1979. Festing, M.F.W. Oxford University Press, New York, NY. • Origins of Inbred Mice. 1978. Morse III,H.C. Academic Press, New York, NY.

  4. Genetics I: From Fancy Mice to Mendel • Brief History of the Laboratory Mouse • Details and Definitions • Genetic Resources • Gene Mapping • Annotating the Mouse Genome

  5. Origin of the House Mouse

  6. Geographical Ranges of Subspecies

  7. Evolutionary Relationships Among Commonly Used Model Organisms

  8. Mouse as a Model System • Small size: 25-40g (2,000-3000 fold lighter than an average human) • Short gestation time: ~10 weeks from being born to giving birth • Breed well: ~5-10 pups/litter and an immediate postpartum estrus • Fathers do not harm young • Vaginal plug: timed pregnancies

  9. Mouse Genome • 3 x 109 base pairs • ~1450 cM • ~2Mb/cM • ~25,000 genes • Organized into 19 autosomes and the X and Y Chromosome • Chromosomes are acrocentric and show a continual decrease in size

  10. Genetic Resources • Outbred Stocks • Inbred Strains and Substrains • F1 Hybrids • Mutant Strains

  11. Outbred Stocks • Genetically undefined • Bred to maintain a maximal level of heterozygosity in all animals • Long life spans, high disease resistance, large and frequent litters, low neonatal mortality, rapid growth, large size, CHEAP • Examples: CD1, Swiss Webster, ICR, NIH • Useful in experiments where genotype does NOT matter (biochemical purification, stud males) • Should NEVER be used in any breeding experiment because of the genetic uncertainty

  12. Inbred Strains • All members of a strain are genetically identical • Bred by strict brother X sister matings for at least 20 generations (Note: ~3-4 generations/year; at least 5 years)

  13. Consequences of Inbreeding up to 20 Generations

  14. Beck J. A. Nat. Genet. 2000;21:23-25

  15. FVB/NJ AKR/J NOD/LtJ BALB/cWt MRL/MpJ

  16. BALB/cWtY- chromosome non- disjuction • AKR/JLymphatic leukemia • FVB/NJMale pronucleus in fertilized egg is large • MRL/MpJLymphoproliferation • NOD/LtJDiabetes

  17. Substrains

  18. Simpson E. M. Nat. Genet. 1997;16:19-27

  19. Distribution of SNPs and Haplotypes on Chromosome 4

  20. F1 Hybrid Mice • Produced by crossing mice of two different inbred strains • Can be repeatedly produced as long as the parental strains exist • Heterozygous at all loci at which the parental strains differ • Genetically and phenotypically uniform • Do not breed true (F2 generation mice undergo recombination)

  21. Desirable Features and Uses of F1 Hybrid Mice • Hybrid vigor: Increased disease resistance, better survival under stress, greater longevity and larger litters than inbred mice • Useful for carrying deleterious mutations, in radiation research, and for bioassays of pathogens, hormones, drugs, etc………. • Accept transplants of tissue (tumors, skin, ovaries) from mice of either parental strain.

  22. Some Common F1 Hybrid Strains

  23. bgJ white nose Aw-J me c2J

  24. “A Mutation” • What is it?: A variation from wild-type at a single locus • Mode of origin: Spontaneous or induced (Chemicals, Radiation, Gene Modification) • Mode of inheritance: dominant, semidominant, recessive (or not heritable) • Penetrance: complete or incomplete • Interaction with other mutations

  25. Some Practical Information about Mutations • Mouse Gene Symbols: always italicized (or underlined), assigned by the International Mouse Genetics Nomenclature Committee, change often • Example: Dom; rec • Serialization: Dom1, Dom2; rec1, rec2 • Alleles of the Same Locus: Dom1a, Dom1b • Special rules for pseudogenes, transgenics, etc..

  26. A Wealth of Information at…. • The Jackson Laboratory Home Page:http://www.jax.org

  27. Mutant Strains • Coisogenic/Isogenic: mutation arose on an inbred strain and is still maintained on the strain of origin (C57BL/6J-M) • Congenic: constructed by transferring a chromosomal segment carrying a locus, phenotypic trait, or mutation of interest from one strain to another by 10 or more successive backcross matings (B6.C-H-2d)

  28. Genomic Homogeneity and Heterogeneity During the Creation of a Congenic Strain

  29. Average Length of the Differential Chromosomal Segment During the Creation of a Congenic Strain

  30. Why Make Congenic Strains? • Evaluate phenotype of a mutation (single gene trait) on one or more well defined genetic backgrounds • Can be very useful in the analysis of complex traits

  31. The Egfr (ko/ko) Example-Phenotype Dependent on Genetic Background • Peri-implantation lethal on a CF-1 background due to degeneration of the inner cell mass • Mid-gestation lethal on a 129/Sv background due to placental defects • Survive up to weaning with abnormalities in many organs on a CD-1 background • Treadgill et al., Science:269, 230-240, 1995.

  32. Markel P. Nat. Genet. 1997;17:280-284

  33. Consomic Strains • Very similar to congenic strains except that selection is for a whole chromosome instead of a chromosomal segment • A set of consomic strains with each A/J chromosome on a C57BL/6J background have been constructed • Particularly useful for the analysis quantitative trait loci (QTL’s) and modifier loci • Singer et al., Science: 304, 445-448, 2004

  34. Recombinant Inbred Strains

  35. Recombinant Congenic (RC) Strains • Similar to RI strains, initial cross is between two distinct inbred strains • Next two generations are made by backcrossing without selection to one of the parental stains • Next 14 generations of brother x sister matings are performed • Mosaic genomes skewed in the direction of the backcross parent (7/8 versus 1/8)

  36. Gene Mapping-Definitions • Locus - a DNA segment that is distinguishable in some way by some form of genetic analysis (gene, anonymous DNA, etc…) • Genetic map - a representation of the distribution of a set of loci within a genome (linkage, chromosomal, and physical)

  37. Why Map Genes • Facilitate moving from disease phenotype to cloning the causative gene(s) (positional cloning) • Can provide function for a recently cloned gene • Can be used to dissect out the heritable and nonheritable components of complex traits • Comparative genetics

  38. Linkage Maps • Also known as recombination (meiotic) maps • Can only be constructed for loci that occur in two or more heritable forms or alleles • Are generated by counting the number of offspring that receive either the parental or recombinant allele combinations at two or more loci

  39. Where Genetic Recombinants Come From

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