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Introduction; Part I Background; Chapter 1 Sex Differences in Disease; 1.1. Males More Vulnerable at Every Age; 1.2. Vulnerability of Males Leads to Sex-Specific Disease; 1.3. Summary and Speculations; Chapter 2 Evolution of the Human Sex Chromosomes and a Portrait of the Human X; 2.1. Chromosomal Basis of Sex Determination; 2.2. The Human Sex Chromosomes Evolved from Reptilian Autosomes; 2.3. Degeneration of the Y Chromosome; 2.4. Ohno’s Law and the Conservation of the Original X; 2.5. Residual Homology and the Pseudoautosomal Regions; 2.6. Genetic Portrait of the Human X; 2.7. Summary and Speculations; Chapter 3 X Chromosome Dosage Compensation: An Overview; 3.1. X Chromosome Dosage Compensation; 3.2. Heterochromatin and Chromosome Silencing; 3.3. Role in Sex Determination; 3.4. Mechanisms of Dosage Compensation in Other Organisms; 3.5. Mechanisms of Dosage Compensation in Mammals; 3.6. Summary and Speculations; Chapter 4 The Discovery of X Chromosome Inactivation; 4.1. The Lyon Hypothesis; 4.2. General Scheme of Mammalian Dosage Compensation; 4.3. Summary and Speculations; Chapter 5 Experimental Models for X Inactivation Studies; 5.1. Spontaneous Human Mutations that Interfere with Inactivation; 5.2. X-Linked Protein Variants Distinguish Parental Origin of X Chromosomes; 5.3. Characterizing the Inactive X in Human Cell Cultures and Clones; 5.4. Mouse-Human Hybrids Separate Inactive from Active X; 5.5. Mouse Embryonic Stem Cells for Manipulating the Early Steps in X Inactivation; 5.6. Transgenic Mice as a Functional Assay; 5.7. Assays for X Inactivation Patterns in Heterozygotes; 5.8. Summary and Speculations; Part II. Themes and Variations of X Inactivation; Chapter 6 Theme 1: The Initial Steps-Creating the Active and Inactive X; 6.1. Characteristics of the Inactive X Chromosome; 6.2. Time of Initiation in the Embryo; 6.3. Cis Inactivation; 6.4. The Master Control Region: XIC and Xist; 6.5. Silencing the Inactive X Chromosome; 6.6. Single Active X Versus X Inactivation; 6.7. Choosing the Active X Chromosome; 6.8. Summary and Speculations; Chapter 7 Theme 2: Subsequent Steps-Spreading and Maintaining Inactivation; 7.1. Spreading Inactivation by Modifying Chromatin; 7.2. Maintaining Inactivation by DNA Methylation of CpG Islands; 7.3. Escape from Inactivation; 7.4. Transient X Inactivation in Germ Cells; 7.5. Induced X Reactivation in Placental Cells; 7.6. Role of DNA Replication in X Inactivation; 7.7. Summary and Speculations; Chapter 8 Variations 1: Evolution of the X Inactivation Center; 8.1. Variations on the Themes of X Inactivation; 8.2. Divergence in the Physical Map; 8.3. The Effect of Map Changes on X Inactivation in Mouse and Man; Chapter 9 Variations 2: Stability of the Inactive X; 9.1. Stability of X Inactivation & DNA Methylation; 9.2 Genes that Escape Inactivation; 9.3. Summary and Speculations; Chapter 10 Variations 3: Choice of Active X; 10.1. Primary Nonrandom X Inactivation; 10.2. Paternal X Inactivation; 10.3. Relationship of Paternal X Inactivation to Genomic Imprinting; 10.4. Does Antisense Transcription Have a Role?; 10.5. Evolution and Tinkering; 10.6. Effect of Inactivation Timing; 10.7. Summary and Speculations; Part III. Medical Consequences of X Inactivation; Chapter 11 The Single Active X; 11.1. Coping with a Monosomy X; 11.2. Dosage Compensation of the Active X; 11.3. Sex Differences in Susceptibility to Disease; 11.4. Viability of Turner Syndrome, Klinefelter Syndrome, and X Chromosome Aneuploidy; 11.5. X Deletions, Ring X Chromosomes, X Duplications, and Functional Disomy; 11.6. X/Autosome Translocations and Spreading of Inactivation; 11.7. Polyploidy and the Choice of Active X; 11.8. Summary and Speculations; Chapter 12 Mosaicism; 12.1. The X-Linked Phenotype Is Dominant at the Cellular Level; 12.2. Females Are Mosaics; 12.3. Interaction between Mosaic Cell Populations; 12.4. Skewing of X Inactivation Patterns; 12.5. Effect of X Inactivation on Clinical Phenotype; 12.6. Manifesting Heterozygotes; 12.7. Summary and Speculations; Chapter 13 Epimutations, Chromatin Disorders and Sex Differences in Phenotype; 13.1 Epimutations Usually Cause Somatic Diseases; 13.2 Epimutations in Imprinting Disorders; 13.3 Epigenetic Regulation of Autosomal Gene Expression by Sex Chromosomes; 13.4 Disorders of the Epigenetic Machinery; 13.5 Sex Differences in Manifestations of Chromatin Disorders; 13.6 Treatment of Chromatin Disorders; 13.7 Summary and Speculations; Chapter 14 Determinants of Female Phenotypes; 14.1. The Dynamic Effect of Interacting Cell Populations on the Health of Females; 14.2. The Effect of X Inactivation on Normal Female Phenotype and Cell Diversity; 14.3. Epilogue; Appendix A Descriptions of Model X-linked and Other Relevant Diseases; Appendix B Sex Chromosome Aneuploidy, Polyploidy, and Parthenogenetic Conceptuses; Appendix C Effect of X Inactivation on Phenotype and Cell Selection in X-linked Disorders; Glossary; References; Index

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