Molecular and Genetic Analysis of Human Traits

Molecular and Genetic Analysis of Human Traits......Page 0
Contents......Page 9
PREFACE......Page 13
DETECTING MENDELIAN INHERITANCE IN HUMANS......Page 15
Box 1.1 Early observations of Mendelian inheritance in humans......Page 16
PATTERNS OF INHERITANCE AND EXAMPLES......Page 17
Autosomal Dominant Traits......Page 18
Autosomal Recessive Traits......Page 21
X-Linked Recessive Traits......Page 22
Probability of Individual Genotypes......Page 23
Probability of Group Outcomes......Page 24
Ascertainment errors in studies of dominant traits......Page 26
Ascertainment errors in studies of recessive traits......Page 27
Determination of Linkage from Human Pedigrees......Page 28
Genetic Recombination and LOD Scores......Page 31
Informative and Noninformative Matings......Page 34
Box 1.2 Internet sites......Page 35
The use of protein products to define marker loci......Page 36
The use of directly detected DNA differences as marker lod......Page 37
EXERCISES......Page 41
REFERENCES......Page 44
EXAMPLE 1.1 Linkage of the Huntington's disease gene to an RFLP......Page 39
CHAPTER 2 Hereditary Traits That Do Not Show a Simple Mendelian Pattern......Page 45
Complementation......Page 46
Phenocopies and Pleiotropy......Page 47
Multiple Alleles......Page 48
Major and Minor Genes......Page 49
Liability......Page 51
Family Clustering......Page 52
Identical Twins......Page 53
LOCALIZATION OF GENES RESPONSIBLE FOR COMPLEX AND QUANTITATIVE TRAITS......Page 54
Linkage Analysis of Complex Traits......Page 55
Example 2.1. Familial psoriasis......Page 56
Analysis of quantitative trait loci by allele-sharing methods......Page 60
Allelic Association......Page 63
Example 2.6. Nonsyndromal autosomal recessive deafness......Page 65
CONCLUSION: NATURE VERSUS NURTURE......Page 67
REFERENCES......Page 68
Example 2.2. Familial breast cancer......Page 57
Example 2.4. Male homosexuality......Page 61
Example 2.5. Dyslexia......Page 64
Example 2.7. Neuroticism and genes for serotonin metabolism......Page 66
CHAPTER 3 Genome Organization I......Page 70
UNEXPRESSED DNA, REPETITIVE AND UNIQUE SEQUENCES......Page 71
The main families of highly repetitive sequences......Page 72
Minisatellite DNA......Page 75
Dispersed, Intermediately Repeated Sequences......Page 79
Nonviral retrotransposons: Alu, L1, and processed pseudogenes......Page 80
Unique Sequence DNA......Page 82
The Organization of RNA Polymerase I1 Genes: Intmns and Exons......Page 83
Example 3.4. Duchenne muscular dystmphy......Page 91
Ribosomal RNA Genes......Page 96
EXERCISES......Page 97
REFERENCES......Page 98
Box 3.1. Internet sites......Page 84
Example 3.1. The a family of highly repetitive DNA......Page 73
Example 3.3. Cystic fibrosis......Page 88
Example 3.5. The globin gene family......Page 92
Example 3.6. The retinal visual pigments......Page 94
Expression Cloning......Page 100
Oligonucleotide probes......Page 101
Functional assays......Page 103
Example 4.2. Isolation of cDNA dones for human von Willebrand factor......Page 104
Reverse Genetics......Page 106
Positional Cloning......Page 107
Chromosome walking and jumping......Page 109
Open reading frames......Page 111
Mutant DNA sequence......Page 112
Candidate gene......Page 113
Example 4.6. Cloning the Huntington's disease gene (HDH)......Page 116
Box 4.1. Ethical concerns......Page 118
Physical Maps......Page 119
Pulsed-field gel electrophoresis and restriction enzymes with infrequent restriction sites (rare-cutters)......Page 120
Fluorescence in situ hybridization......Page 121
Other Tools......Page 123
The Sequence-Tagged Site (STS) Proposal......Page 125
Example 4.7. Microsatellite DNA......Page 126
Identification and localization of genes......Page 127
Box 4.2. You're going to patent my genes71......Page 135
Random (shotgun) sequencing......Page 136
CONCLUSION: THE END IN SIGHT......Page 137
REFERENCES......Page 140
Box 4.3. Internet sites......Page 138
Example 4.1. Isolation and characterization of a [DNA coding for human factor IX......Page 102
Example 4.4. Cloning of gene sequences regulated by platelet derived growth factor......Page 105
Example 4.5. The cystic fibrosis gene......Page 114
Example 4.8. Contig of chromosome 21 q......Page 128
Example 4.9. Sequence of chromosomes 21 and 22......Page 139
THE MORPHOLOGY OF HUMAN CHROMOSOMES......Page 143
Banding Techniques......Page 145
CHROMOSOMAL ABNORMAUTIES......Page 149
Aneuploidy......Page 150
Deletions and duplications......Page 152
Translocations......Page 153
Robertsonian translocations......Page 155
The Y-Chromosome......Page 158
The X-Chromosome and Dosage Compensation......Page 159
X-inactivation center (XIC)......Page 161
THE USE OF MOGENETlCS TO LOCALIZE GENES......Page 163
Somatic Cell Genetics......Page 164
EXERCISES......Page 165
REFERENCES......Page 167
Example 5.1. Aneuploidy in a family with a redprocal translocation......Page 156
Example 5.2. Discordant monozygotic twins......Page 160
EFFECTS OF MUTATIONS ON THE QUAUTV AND QUANTITY OF PROTEIN PRODUCTS......Page 168
BOX 6.1. Internet Sites......Page 169
Mutations outside the Coding Region......Page 170
Loss-of-Function Mutations......Page 171
Electrophoretic Variants......Page 172
Mutations with Complete or Partial Loss of Enzyme Activiv......Page 173
Gain-of-Function Mutations in Enzymes......Page 177
Example 6.4. Familial amyotrophic lateral sclerosis......Page 178
MUTATIONS IN TRANSPORT PROTEINS......Page 182
MUTATIONS IN REGULATORY PROTEINS......Page 188
CONCLUSION......Page 190
REFERENCES......Page 191
Example 6.1. Phenylketonuria......Page 175
Example 6.3. Porphyrias......Page 176
Example 6.5. Osteogenesis imperfeaa......Page 179
Example 6.6. Muscular dystrophies......Page 180
Example 6.7. Hemoglobin......Page 183
Example 6.8. Cystic fibrosis transmembrane conductance regulator (CFTR)......Page 189
CHAPTER 7 Mutations: Damage and Repair of DNA......Page 193
Tautomeric shifts......Page 194
Deamination......Page 195
Oxidation and methylation of bases......Page 197
Errors in Replication......Page 198
Strand slippage......Page 199
Trinucleotide repeat diseases......Page 200
Example 7.2. Huntington's disease......Page 203
Ultraviolet Radiation......Page 208
Inactive chemicals metabolized to reactive mutagens......Page 209
Base Excision Repair......Page 210
Mismatch Repair......Page 212
MUTATION RATES......Page 217
SOMATIC MUTATIONS AND MOSAICISM......Page 219
Example 7.7. Getmline mosaicism in a case of Duchenne muscular dystrophy......Page 222
REFERENCES......Page 224
Example 7.1. Deamination of cytosine and 5-methylcytosine......Page 196
Example 7.3. Fragile X mental retardation......Page 204
Example 7.4. Xeroderma pigmentosum and nudeotide excision repair......Page 214
Example 7.5. Epidermolytic hyprkratosis and keratins K1 and K10......Page 220
Example 7.6. Transmission of a fragile X mutation from an affected male to his normal daughter......Page 221
CHAPTER 8 Cancer: A Genetic Disease......Page 226
Nuclear Events......Page 227
The Cytoplasm: Receiving and Traducing Signals......Page 229
Progression from Normal Cells to Cancer......Page 231
Cells in Culture......Page 233
ONCOGENES......Page 234
Growth Factors and Their Receptors as Oncogenic Proteins......Page 237
RAS and the MAP Kinase Cascade......Page 238
Suppression of Apoptosis......Page 239
Retinoblastoma......Page 240
P53......Page 245
HNPCC Family of Mismatch Repair Genes......Page 248
MUTATIONS AND OTHER CHANGES THAT ALTER THE FUNCTION OF CANCER GENES......Page 249
Chromosomal Rearrangements......Page 250
Activation of proto-oncogenes by translocations......Page 251
Gene Amplification......Page 252
Retroviruses......Page 253
GENETIC INSTABILITY......Page 254
CELLULAR IMMORTAUTY AND TELOMERES......Page 256
CONCLUSION......Page 258
Box 8.1. Internet sites......Page 260
REFERENCES......Page 261
Prenatal Genetic Testing......Page 263
Example 9.1. Phenylketonuria......Page 266
Box 9.4. Case 4: When ignorance is not bliss......Page 269
REFERENCES......Page 271
Box 9.1. Case 1: Knowing too much......Page 264
Box 9.2. Case 2: Disagreement between spouses......Page 267
Box 9.3. Case 3: Sharing information with adult offspring......Page 268
Box 9.5. Case 5: Similar situations, different courses......Page 270
APPENDIX......Page 272
INDEX......Page 285