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Mouse Genetics

Concepts and Applications

Lee M. Silver


Title Page


Chapter 1
An Introduction to Mice

1.1 Of mice, men, and a woman
1.1.1 The origin of the house mouse
1.1.2 Domestication and the fancy mouse

1.2 The origin of mice in genetic research
1.2.1 The mouse and Mendel
1.2.2 Castle, Little, and the founders of mouse genetics
1.2.3 The mouse as a model prior to the recombinant DNA revolution

1.3 The new biology and the mouse model
1.3.1 All mammals have closely related genomes
1.3.2 The mouse is an ideal model organism
1.3.3 Manipulation of the mouse genome and micro-analysis
1.3.4 High resolution genetics

Chapter 2
Town Mouse, Country Mouse

2.1 What are mice?

2.2 Where do mice come from?
2.2.1 Mice, people, and dinosaurs
2.2.2 From Asia to Europe and from Europe to the New World
2.2.3 Tracing the movement of humankind with mice as markers

2.3 The Mus species group and the house mouse
2.3.1 Commensal, feral and aboriginal animals
2.3.2 Systematics of the house mouse
2.3.3 Hybrid zones and the species debate
2.3.4 Origin of the classical inbred strains
2.3.5 Close relatives of Mus musculus and inter-population hybrids

2.4 Lifestyles and adaptability of wild house mice
2.4.1 Shelter, food and water
2.4.2 Population structures and reproduction
2.4.3 Adaptability and success

Chapter 3
Laboratory Mice

3.1 Sources of laboratory mice

3.2 Mouse crosses and standard strains
3.2.1 Outcrosses, backcrosses, intercrosses, and incrosses
3.2.2 The generation of inbred strains
3.2.3 The classical inbred strains
3.2.4 Segregating inbred strains
3.2.5 Newly derived inbred strains
3.2.6 F1 hybrids
3.2.7 Outbred stocks

3.3 Coisogenics, congenics, and other specialized strains
3.3.1 The need to control genetic background
3.3.2 Coisogenic strains
3.3.3 Congenic and related strains
3.3.4 Recombinant inbred and related strains

3.4 Standardized nomenclature
3.4.1 Introduction
3.4.2 Strain symbols
3.4.3 Locus names and symbols
3.4.4 Alleles
3.4.5 Transgene loci
3.4.6 Further details

3.5 Strategies for record-keeping
3.5.1 General requirements
3.5.2 The mating unit system
3.5.3 The animal/litter system
3.5.4 Comparison of record-keeping systems
3.5.5 A computer software package for mouse colony record-keeping

Chapter 4
Reproduction and Breeding

4.1 Reproductive performance: comparison of inbred strains

4.2 Germ cell differentiation and sexual maturation
4.2.1 Males
4.2.2 Females

4.3 Mating and pregnancy
4.3.1 Puberty
4.3.2 The estrus cycle
4.3.3 Mating
4.3.4 Fertilization
4.3.5 Determination of copulation and pregnancy
4.3.6 The gestational period
4.3.7 Effects of a foreign male on pregnancy and pup survival

4.4 The postnatal period
4.4.1 Postnatal development
4.4.2 Determination of sex
4.4.3 Lactation, culling and supplementing litters
4.4.4 Foster mothers
4.4.5 Age of weaning
4.4.6 Postpartum estrus
4.4.7 Genetically controlled variation in the adult mouse

4.5 Assisted reproduction for the infertile cross
4.5.1 Artificial insemination
4.5.2 Transplantation of ovaries
4.5.3 In vitro fertilization

Chapter 5
The Mouse Genome

5.1 Quantifying the genome
5.1.1 How large is the genome?
5.1.2 How complex is the genome?
5.1.3 What is the size of the mouse linkage map?
5.1.4 What proportion of the genome is functional?
5.1.5 How many genes are there?

5.2 Chromosomes
5.2.1 The standard karyotype
5.2.2 Robertsonian translocations
5.2.3 Reciprocal translocations

5.3 Genome evolution and gene families
5.3.1 Classification of genomic elements
5.3.2 Forces that shape the genome
5.3.3 Gene families and superfamilies
5.3.4 Centromeres and satellite DNA

5.4 Repetitive "non-functional" DNA families
5.4.1 Endogenous retroviral element
5.4.2 The LINE-1 family
5.4.3 The major SINE families: B1 and B2
5.4.4 General comments on SINEs and LINEs
5.4.5 Genomic stutters: microsatellites, minisatellites, and macrosatellites

5.5 Genomic imprinting
5.5.1 Overview
5.5.2 Why is there imprinting?
5.5.3 The molecular basis for imprinting

Chapter 6
Mutagenesis and Transgenesis

6.1 Classical mutagenesis
6.1.1 The specific locus test
6.1.2 Mutagenic agents
6.1.3 Mouse mutant resources

6.2 Embryo manipulation: genetic considerations
6.2.1 Experimental possibilities
6.2.2 Choice of strains for egg production
6.2.3 Optimizing embryo production by superovulation
6.2.4 The fertile stud male
6.2.5 Embryo transfer into foster mothers

6.3 Transgenic mice formed by nuclear injection
6.3.1 Overview
6.3.2 Tracking the transgene and detecting homozygotes

6.4 Targeted mutagenesis and gene replacement
6.4.1 Overview
6.4.2 Creating "gene knockouts"
6.4.3 Creating subtle changes
6.4.4 Potential problems
6.4.5 The "129 mouse"

6.5 Further uses of transgenic technologies
6.5.1 Insertional mutagenesis and gene trapping
6.5.2 A database and a repository of genetically engineered mice
6.5.3 The future

Chapter 7
Mapping in the mouse: An overview

7.1 Genetic maps come in various forms
7.1.1 Definitions
7.1.2 Linkage maps
7.1.3 Chromosome maps
7.1.4 Physical maps
7.1.5 Connections between maps

7.2 Mendel's genetics, linkage, and the mouse
7.2.1 Historical overview
7.2.2 Linkage and recombination
7.2.3 Crossover sites are not randomly distributed
7.2.4 A history of mouse mapping

7.3 General strategies for mapping mouse loci
7.3.1 Novel DNA clones
7.3.2 Transgene insertion sites
7.3.3 Verification of region-specific DNA markers
7.3.4 Loci defined by polypeptide products
7.3.5 Mutant phenotypes

7.4 The final chapter of genetics
7.4.1 From gene to function
7.4.2 From phenotype to gene
7.4.3 The molecular basis of complex traits

Chapter 8
Genetic Markers

8.1 Genotypic and phenotypic variation

8.2 Restriction fragment length polymorphisms (RFLPs)
8.2.1 Molecular basis for RFLPs
8.2.2 Choice of restriction enzymes to use for RFLP detection
8.2.3 Minisatellites: variable number tandem repeat loci
8.2.4 Dispersed multi-locus analysis with cross-hybridizing probes
8.2.5 Restriction landmark genomic scanning

8.3 Polymorphisms detected by PCR
8.3.1 Restriction site polymorphisms
8.3.2 Detection of allelic changes defined by single basepairs
8.3.3 Single strand conformation polymorphism
8.3.4 Random amplification of polymorphic DNA
8.3.5 Interspersed repetitive sequence PCR
8.3.6 Microsatellites: simple sequence length polymorphisms

8.4 Region-specific panels of DNA markers
8.4.1 Chromosome microdissection
8.4.2 Chromosome sorting by FACS
8.4.3 Somatic cell hybrid lines as a source of fractionated material
8.4.4 Miscellaneous approaches

Chapter 9
Classical Linkage Analysis and Mapping Panels

9.1 Demonstration of linkage and statistical analysis
9.1.1 Mapping new DNA loci with established mapping panels
9.1.2 Anchoring centromeres and telomeres onto the map
9.1.3 Statistical treatment of linkage data

9.2 Recombinant inbred strains
9.2.1 Overview
9.2.2 Using RI strains to determine linkage
9.2.3 Using RI strains to determine map order
9.2.4 Using RI strains to determine map distances
9.2.5 Using RI strains to dissect complex genetic traits

9.3 Interspecific mapping panels
9.3.1 Overview
9.3.2 A comparison: RI strains versus the interspecific cross
9.3.3 Access to established interspecific mapping panels
9.3.4 Is the newly mapped gene a candidate for a previously-characterized mutant locus?

9.4 Starting from scratch with a new mapping project
9.4.1 Overview
9.4.2 Choosing strains
9.4.3 Choosing a breeding scheme
9.4.4 The first stage: mapping to a subchromosomal interval
9.4.5 The second stage: high resolution mapping

9.5 Quantitative traits and polygenic analysis
9.5.1 Introduction
9.5.2 A choice of breeding strategy and estimation of locus number
9.5.3 Choices involved in setting up crosses
9.5.4 An optimal strategy for mapping polygenic loci

Chapter 10
Non-breeding Mapping Strategies

10.1 Linkage maps without breeding
10.1.1 Single sperm cell typing
10.1.2 Mitotic linkage maps

10.2 Chromosomal mapping tools
10.2.1 Conservation of synteny
10.2.2 In situ hybridization
10.2.3 Somatic cell hybrid genetics

10.3 Physical maps and positional cloning
10.3.1 Prerequisites to positional cloning
10.3.2 PFGE and long range genomic restriction maps
10.3.3 Large insert genomic libraries
10.3.4 Protocols for gene identification

10.4 The Human Genome Project and the ultimate map

Appendix A. Suppliers of mice

Appendix B. Computational Tools and Electronic Databases

Appendix C. Source materials for further reading

Appendix D. Statistics

D1 Confidence limits and mean estimates of linkage distance
D2 Quantitative differences in expression between two strains

Appendix E. Glossary of Terms







User's Guide

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