Molecular Genetics of Sex Determination (eBook)

Stephen S. Wachtel (Herausgeber)

eBook Download: PDF | EPUB

2014 | 1. Auflage
518 Seiten
Elsevier Science (Verlag)
978-1-4832-9558-9 (ISBN)

Infos

In this era of accelerated discovery and prolific output, Molecular Genetics of Sex Determination keeps readers abreast of this fields fast-moving biology. Its chapters were completed by experts in eacharea only months before publication. The text is organized into two parts. First, it reviews the basic biology of sex determination and summarizes ground-breaking work in mouse, marsupial, and Drosophila systems. Second, it covers current human genetics, clinical studies, and the syndromes of abnormal sex differentiation. With chapters by preeminent reproductive biologists, this is a capital work. Ohno's law is described by Ohno; the Lyon hypothesis, by Lyon; Sinclair tells how he cloned the testis-determining gene; and so on. Molecular Genetics of Sex Determination is authoritative, comprehensive, and current. It is prime reading for geneticists, developmental biologists, graduate students in these and related fields, clinical researchers, physicians, and medical students. - Reviews the genetics of sex determination in 19 up-to-date chapters - Features research on sex chromosomes and sex-determining genes - Includes abnormalities of sex determination and clinical genetics - Written by scientists who pioneered work in this field

Inhalt

Front Cover 1
Molecular Genetics of Sex Determination 4
Copyright Page 5
Table of Contents 6
Contributors 14
Preface 18
Chapter 1. The Search for the 
20 
I. Introduction 21
II. H-Y Antigen 22
III. Bkm Satellite DNA 24
IV. The Zinc Finger Y Gene [ZFY] 27
IV. The Zinc Finger Y Gene 
27 
VI. SRY and the Search for TDF 35
VII. TDF in Normal and Abnormal Sex 
37 
VIII. Summary 38
References 38
Chapter 2. The Cloning of SRY 42
I. Mammalian Sex Determination 43
II. The Human Y Chromosome 43
III. Early Candidates for TDF 44
IV. Searching for TDF on the Human Y Chromosome 44
V. Walking on the Y Chromosome: Identification of ZFY 45
VI. Difficulties in Equating ZFY and TDF: The Role of 
47 
VII. Reevaluation of the Y-Chromosome Deletion Map 47
VIII. Mapping the Sex-Determining Region 48
IX. SRY, A New Candidate for TDF 48
X. Sequence Analysis of SRY 51
XI. Tissue Distribution and Expression of SRY 52
XII. Genetic Evidence Equating SRY and TDF: 
54 
XIII. SRY is the Testis-Determining Gene 57
Acknowledgments 57
References 58
Chapter 
62 
I. Introduction 63
II. Sex Reversed [Sxr] 63
III. The Role of Yq in Spermatogenesis 70
IV. What Can We Learn from the Human Y 
71 
V. The Sry Gene 73
Acknowledgments 81
References 81
Chapter 4. XX Sex Reversal in the Mouse 88
I. Introduction 89
II. Discovery of Sxr 89
III. Male-Specific Antigen 90
IV. Sex Reversal Sex-Reversed 91
V. A Variant Sxr Fragment 92
VI. DNA Fingerprinting of Sxr 93
VII. Location of Tdy on the Mouse Y Chromosome 94
Vili. Recombination with Sxr 95
IX. Spermatogenesis Gene in Sxr 95
X. Zinc Finger Genes in Sxr 97
References 98
Chapter 5. 
102 
I. Introduction 103
II. XY 
104 
III. XYd Sex Reversal 106
IV. Conclusions 118
Acknowledgments 119
References 119
Chapter 6. Conservation of the X-Linkage Group in Toto by All 
126 
I. Introduction 127
II. Beginning of the Realization 127
III. Of Glucose-6-Phosphate Dehydrogenases and Mules, Hinnies, and 
129 
IV. Of Tfm Loci, Androgen Receptors, 
130 
V. Lazarus in Evolution: Resurrection of Trichrome 
133 
VI. Summary 138
References 139
Chapter 7. 
142 
I. Early History of X-Chromosome Inactivation 143
II. Early Ideas on Mechanisms 146
III. Further Developments 148
IV. Initiation and Maintenance of X-lnactivation 150
V. Summary of Current Knowledge of X-lnactivation 151
VI. Recent Developments 152
VII. Conclusion 157
References 157
Chapter 8. 
162 
I. Introduction 163
II. Marsupial Development and theExperimental Potential of Australian Mammals 163
III. Mammalian Sex Differentiation: 
166 
IV. Evolution of the Mammalian Sex Chromosomes 168
V. Marsupials and the Quest for the Testis Determinant 173
VI. Analysis of the Marsupial SRY Gene 178
VII. Discussion 179
Acknowledgments 185
References 185
Chapter 9. The Feminine Mystique: The Initiation of Sex Determination 
190 
I. Introduction 191
II. Regulation of Somatic Sex Determination 192
III. Regulation of Germline Sex Determination 214
IV. Conclusion 217
Acknowledgments 217
References 217
Chapter 10. 
224 
I. Introduction 225
II. Deletion Mapping of theTestis-Determining 
226 
III. Testis-Determining Region of Yp 229
IV. Preferential Breakage Site 
231 
V. Sequences from Yq in an XX Male (No. 102) 232
VI. The Spermatogenesis Locus of Yq 235
VII. X-Y Homologous Genes 238
VIII. Summary 238
References 239
Chapter 
244 
I. Introduction 245
II. The Pseudoautosomal Region 246
III. X-Y Homology in the Differential Region of the Y 
254 
IV. Evolution of Sex Chromosome Homologies 268
V. Conclusion 275
Acknowledgments 276
References 276
Chapter 12. 
286 
I. Introduction 287
II. XX Males 287
III. XX True Hermaphrodites 291
IV. Familial Occurrence of XX Male Syndrome and XX True Hermaphroditism: The Syndromes as Alternative 
295 
V. Molecular Genetics of XX Sex Reversal 297
VI. Conclusions 300
References 301
Chapter 13. 
306 
I. Introduction 307
II. The Syndrome 308
III. Genetic Basis of XY Gonadal Dysgenesis 310
IV. SRY and the The Molecular 
314 
V. Interaction between SRY and Downstream Genes 316
VI. Germ Cell Tumors in XY Gonadal Dysgenesis 317
VII. Related Syndromes 318
VII. Conclusions 325
References 325
Chapter 14. Phenotypic Correlations of 
330 
I. Historical Introduction 331
II. Major Features of Turner Syndrome 331
III. Phenotype–Karyotype 
344 
IV. Evidence from 
345 
V. X-Chromosome Loss and the Y Chromosome 348
VI. Recent Molecular Approaches 
350 
VII. Conclusion 352
References 353
Chapter 15. Molecular Genetics of Androgen 
360 
I. Introduction 361
II. The Androgen-Response Apparatus 361
III. Androgen Insensitivity 363
IV. Structure-Function Organization of the 
367 
V. Genotype-Phenotype Correlation 
373 
VI. Conclusions 379
Acknowledgments 379
References 379
Chapter 16. 
386 
I. Introduction 387
II. Defects of Testosterone Biosynthesis 388
III. Defect of Testosterone 
395 
IV. Testicular Dysgenesis and 
397 
V. MPH in Various Syndromes 398
VI. Recent Developments in Molecular Biology 
399 
VII. Importance for the Clinician and Conclusions 404
References 404
Chapter 
418 
I. Cortisol Biosynthesis: Enzymes and Defects 419
II. Clinical Forms of 21 -Hydroxylase Deficiency 425
III. Genes for Steroid 21 -Hydroxylase 
430 
IV. Mutations and Rearrangements 434
V. Summary 452
References 453
Chapter 18. The Gene for 
458 
I. Introduction 459
II. The AMH Gene Product 459
III. Structure of the AMH Gene 461
IV. Expression of the AMH Gene 463
V. AMH Gene Mutations 467
References 470
Chapter 19. Müllerian-Inhibiting Substance: Critical Roles in Sexual 
476 
I. Introduction 477
II. Biochemistry of MIS 477
III. Ontogeny of MIS 484
IV. Regulation of MIS Expression 487
V. Biological Roles for MIS 497
VI. Antiproliferative Effects of MIS 505
VII. Studies on Human MIS 510
VIII. Summary 512
References 514
Index 522

Textauszug

2

The Cloning of SRY

Andrew H. Sinclair,     Centre for Child Growth and Hormone Research, Royal Children’s Hospital, Parkville, Victoria 3052, Australia

Publisher Summary

The critical factor in mammalian sex determination and differentiation is the development of the gonad. It has been shown that the testes produce testosterone and anti-Müllerian hormone (AMH), which are responsible for inducing the male secondary sex characteristics. Sex determination can be reduced to its essence: the choice between forming testis or ovary. Once gonadal sex is determined, the subsequent processes—sex differentiation—commence. In mammals, sex determination is chromosomally based: females have two X chromosomes and males have an X and a Y. These results implied that the Y chromosome carried a gene required for testis development. In humans, this gene was called the “testis determining factor” (TDF) because of the uncertain nature of the genetic material involved. The role of TDF as a “switch” in sex determination is misunderstood. Many genes are required in the pathway leading to testis formation. Some of these genes are autosomal and some, X-linked, but in the absence of TDF, the pathway would not produce testes. In the presence of TDF, the pathway is completed and testes are produced, leading to male sex differentiation.

I Mammalian Sex Determination

II The Human Y Chromosome

III Early Candidates for TDF

IV Searching for TDF on the Human Y Chromosome

V Walking on the Y Chromosome: Identification of ZFY

VI Difficulties in Equating ZFY and TDF: The Role of Marsupials

VII Reevaluation of the Y-Chromosome Deletion Map

VIII Mapping the Sex-Determining Region

IX SRY, A New Candidate for TDF

X Sequence Analysis of SRY

XI Tissue Distribution and Expression of SRY

XII Genetic Evidence Equating SRY and TDF: Analysis of XY Females

XIII SRY is the Testis-Determining Gene

References

I Mammalian Sex Determination

The critical factor in mammalian sex determination and differentiation is the development of the gonad. In a series of classic experiments, Alfred Jost demonstrated the central role of the testis in male development. When male rabbit embryos were castrated in utero, subsequent development was female; when female rabbit embryos were castrated at the same stage, subsequent development was also female. These results (reviewed by Jost et al., 1973) suggested that the basic mammalian body plan is female but presence of testes determines whether the embryo will develop as a male. Further work showed that the testes produce testosterone and anti-Müllerian hormone (AMH), which are responsible for inducing the male secondary sex characteristics. Consequently, sex determination can be reduced to its essence: the choice between forming testis or ovary. Once gonadal sex is determined, the subsequent processes known as sex differentiation commence.

In mammals, sex determination is chromosomally based: females have two X chromosomes and males have an X and a Y. Ford et al. (1959) showed that individuals with Turner syndrome had a single X chromosome and were female. In the same year, Jacobs and Strong (1959) showed that patients with Klinefelter syndrome had two X chromosomes, and a Y, and were male. These results implied that the Y chromosome carried a gene required for testis development. In humans, this gene was later called the testis determining factor (TDF) because of the uncertain nature of the genetic material involved. Mouse geneticists were less coy, however, and called it the testis determining Y gene (Tdy).

The role of TDF as a “switch” in sex determination is often misunderstood. Evidently, many genes are required in the pathway leading to testis formation. Some of these genes are autosomal and some, X-linked, but in the absence of TDF, the pathway will not produce testes. In the presence of TDF the pathway is completed and testes are produced, ultimately leading to male sex differentiation.

In summary, the main event in mammalian sex differentiation is the formation of testes, which is controlled by the Y-linked TDF gene. In this chapter we will briefly review the search for TDF, the identification of SRY, and show that SRY can be equated to TDF.

II The Human Y Chromosome

The human Y chromosome is a bipartite structure with two different functions. At male meiosis the Y chromosome must pair with the X chromosome and it must encode TDF (Ellis, 1991). These functions are mediated by distinct regions on the Y chromosome. Pairing with the X chromosome occurs within a region shared between the short arms of the X and Y chromosomes known as the pseudoautosomal region (PAR) (Burgoyne, 1982). An obligate recombination event within the PAR is necessary to ensure correct meiotic segregation (Ellis, 1991). There is a distinct delineation between the two regions marked by the pseudoautosomal boundary (PAB) (Ellis et al., 1989). The boundary separates the pseudoautosomal region from the Y-specific region which, by definition, does not participate in homologous recombination with the X chromosome and must carry TDF.

III Early Candidates for TDF

For more than 10 years, many believed that the male-specific H-Y antigen was the product of TDF (Wachtel et al., 1975), but the discovery of male mice failing to express H-Y excluded the Hya gene as a possible candidate (McLaren et al., 1984). Another candidate was the Bkm repeat sequence first isolated from a snake called the banded krait (Jones and Singh, 1981). Although Bkm sequences were found on the sex chromosomes of many mammals, their absence from the human Y excluded them as a candidate for TDF (Kiel-Metzger et al., 1985; reviewed in Chapter 1, this volume).

IV Searching for TDF on the Human Y Chromosome

In order to find TDF on the Y chromosome, three types of detailed maps were constructed: a meiotic map of the pseudoautosomal region (Goodfellow et al., 1986; Weissenbach et al., 1987); a deletion map based on the analysis of sex-reversed XX males and XY females (Vergnaud et al., 1986; Guellaen et al., 1984), and a long-range restriction map linking the first two maps (Pritchard et al., 1987). By studying individuals with Y-chromosome deletions it was possible to localize TDF to the short arm (Yp) (Goodfellow et al., 1985). However, a more precise localization was made possible by examining the chromosomes of XX males. These sex-reversed individuals appear to lack the Y chromosome but have a male phenotype with infertile testes. XX males occur mainly because of an abnormal recombination event between the X and Y chromosomes at male meiosis. This aberrant exchange extends beyond the pseudoautosomal region into the Y-specific region and results in transfer of TDF to the X chromosome (Ferguson-Smith, 1966; Guellaen et al., 1984; Petit et al., 1987). Transfer of varying portions of the Y chromosome to the X in different XX males allowed construction of a deletion map. This allowed TDF to be mapped to the most distal part of the Y-specific region, adjacent to the pseudoautosomal boundary. The meiotic map of the pseudoautosomal region indicated that MIC2 was the closest pseudoautosomal gene to TDF (Goodfellow et al., 1986). In order to link the deletion map and the meiotic map (which are based on different principles) a long-range restriction map was constructed (Pritchard et al., 1987). This map began at the 5′ CpG-rich island of the MIC2 gene in the pseudoautosomal region, spanned the boundary, and identified a CpG island in the Y-specific region. As CpG-rich islands are often associated with genes, it was predicted that this Y-specific island might define a new candidate for TDF (Pritchard et al., 1987).

V Walking on the Y Chromosome: Identification of ZFY

On the basis of this information, Goodfellow and colleagues initiated a Y-chromosome walk from MIC2 across the pseudoautosomal boundary into the Y-specific region toward the CpG island identified by Pritchard et al. (1987). This walk finished 5 kb distal (telomeric) to the CpG island that marked a possible candidate for TDF. At the same time Page and...

Produkt-Details

• Erscheint lt. Verlag: 23.7.2014
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber ► Natur / Technik ► Naturführer
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Innere Medizin
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• ISBN-10: 1-4832-9558-3 / 1483295583
• ISBN-13: 978-1-4832-9558-9 / 9781483295589