Females Are Mosaics: X Inactivation and Sex Differences in Disease (2nd edition)

ISBN : 9780199927531

Barbara Migeon
328 Pages
163 x 238 mm
Pub date
Dec 2013
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Women can be described as genetic mosaics because they have two distinctly different types of cells throughout their bodies. Unlike males, who have one X chromosome, females have two X chromosomes in every cell. Much has been written about the Y chromosome and its role in inducing maleness. This is the only book about the X chromosome as a key to female development and the role of X-related factors in the etiology of sex differences in human disease. This new edition reflects research advances from the six years since the widely praised first edition. New advances include knowledge of species differences in mammalian X inactivation processes and silencing of the inactive X chromosome.


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

About the author: 

Barbara Migeon, MD, has held fellowships in pediatrics, endocrinology and genetics. She is board certified in pediatrics, biochemical genetics and cytogenetics. She was the founding director of the Hopkins PhD Program in Human Genetics. Her research has been focused on the molecular mechanisms of X inactivation in human cell and the clinical consequences of the single active X chromosome.

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