Human genetics: problems and approaches ; with 217 tables
Gespeichert in:
| Hauptverfasser: | , |
|---|---|
| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Berlin [u.a.]
Springer
1986
|
| Ausgabe: | 2., completely rev. ed. |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | Literaturverz. S. [711] - 772 |
| Beschreibung: | XXXIV, 807 S. Ill., graph. Darst. |
| ISBN: | 3540164111 0387164111 3540094598 0387094598 |
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| 245 | 1 | 0 | |a Human genetics |b problems and approaches ; with 217 tables |c F. Vogel ; A. G. Motulsky |
| 250 | |a 2., completely rev. ed. | ||
| 264 | 1 | |a Berlin [u.a.] |b Springer |c 1986 | |
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Datensatz im Suchindex
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| adam_text | IMAGE 1
TABLE OF CONTENTS
INTRODUCTION HUMAN GENETICS AS FUNDAMENTAL AND APPLIED SCIENCE - SCIENCE
OF GE- NETICS - HOW DOES A SCIENCE DEVELOP? - CENTRAL THEORY OF GENETICS
LOOKED AT AS A PARADIGM - HUMAN GENETICS AND THE GENETIC REVOLUTION -
HISTORY OF HUMAN GENETICS: A CONTEST BETWEEN TWO PARADIGMS - PROGRESS IN
HUMAN GENETICS AND PRACTICAL APPLICATION - EFFECTS OF PRACTICAL APPLI-
CATION ON RESEARCH - DANGERS OF WIDESPREAD PRACTICAL APPLICATION FOR
SCIENTIFIC DEVELOPMENT - ADVANTAGES OF PRACTICAL APPLICATION FOR RE-
SEARCH - HUMAN GENETICS AND THE SOCIOLOGY OF SCIENCE - HUMAN GENETICS IN
RELATION TO OTHER FIELDS OF SCIENCE AND MEDICINE - FUTURE OF HUMAN
GENETICS - FIELDS OF HUMAN AND MEDICAL GENETICS - POSSIBLE FUNCTION OF A
TEXTBOOK
1 HISTORY OF HUMAN GENETICS 9
1.1 THE GREEKS 9
1.2 SCIENTISTS BEFORE MENDEL AND GALTON 10
1.3 F.GALTON SWORK: HEREDITARY TALENT AND CHARACTER 11
1.4 WORK OF GREGOR MENDEL 12
1.5 APPLICATION TO MAN: GARRODS S INBORN ERRORS OF METABOLISM . .. 13
1.6 VISIBLE TRANSMITTERS OF GENETIC INFORMATION:
EARLY WORK ON CHROMOSOMES 14
1.7 EARLY ACHIEVEMENTS IN HUMAN GENETICS 15
1.7.1 ABO BLOOD GROUPS 15
1.7.2 HARDY-WEINBERG LAW 15
1.7.3 DEVELOPMENT BETWEEN 1910 AND 1930 15
1.8 HUMAN GENETICS, THE EUGENICS MOVEMENT, AND POLITICS 15
1.8.1 GREAT BRITAIN AND THE UNITED STATES 15
1.8.2 GERMANY 16
1.8.3 THE SOVIET UNION 17
1.8.4 HUMAN BEHAVIOR GENETICS 17
1.9 DEVELOPMENT OF MEDICAL GENETICS (1950 - T HE PRESENT) 17
1.9.1 GENETIC EPIDEMIOLOGY 17
1.9.2 BIOCHEMICAL METHODS 17
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XII TABLE OF CONTENTS
1.9.3 BIOCHEMICAL INDIVIDUALITY 18
1.9.4 CYTOGENETICS, SOMATIC CELL GENETICS, PRENATAL DIAGNOSIS 18
1.9.5 DNA TECHNOLOGY IN MEDICAL GENETICS 19
1.9.6 UNSOLVED PROBLEMS 19
2 HUMAN CHROMOSOMES 20
2.1 HUMAN CYTOGENETICS, A SUCCESSFUL LATE ARRIVAL 20
2.1.1 HISTORY AND DEVELOPMENT OF HUMAN CYTOGENETICS 20
FIRST OBSERVATIONS ON HUMAN MITOTIC CHROMOSOMES - AN OLD ERROR IS
CORRECTED AND A NEW ERA BEGINS - SOLUTION TO AN OLD RIDDLE: DOWN S
SYNDROME (MONGOLISM) IS DUE TO TRISOMY 21 - FIRST REPORTS ON TRISOMIES
AND MONOSOMIES OF SEX CHROMOSOMES - BIRTH OF HUMAN CYTOGENETICS
1956-1959: A SCIENTIFIC REVOLUTION - PARADIGM GROUP IN EARLY HUMAN
CYTOGENETICS - STEPS IN THE DEVELOPMENT OF HUMAN CYTOGENETICS - CLINI-
CAL CYTOGENETICS, THE MOST POPULAR SPECIALITY OF HUMAN GENETICS
2.1.2 NORMAL HUMAN KARYOTYPE IN MITOSIS AND MEIOSIS 24
2.1.2.1 MITOSIS 24
CELL CYCLE - MITOSIS
2.1.2.2 PREPARATION AND STAINING OF MITOTIC METAPHASE CHROMOSOMES . . 25
PREPARATION - STAINING - BANDING METHODS - AVAILABLE METHODS - CHEMI-
CAL DIFFERENCES REVEALED BY THE BANDING METHODS - SILVER STAINING OF NU-
CLEOLUS ORGANIZER REGIONS - CHROMOSOMES FROM HUMAN SPERMATOZOA
2.1.2.3 NORMAL HUMAN KARYOTYPE IN MITOTIC METAPHASE CHROMOSOMES . 27
CONVENTIONAL STAINING - BANDING TECHNIQUES - INDIVIDUAL CHARACTERIZA-
TION OF HUMAN CHROMOSOMES - CHROMATIN - CHROMOSOME MEASURE- MENTS -
CHROMOSOME HETEROMORPHISMS - HIGH-RESOLUTION BANDING -
ELECTRON-MICROSCOPIC PICTURES FROM HUMAN CHROMOSOMES
2.1.2.4 MEIOSIS 35
BIOLOGIC FUNCTION OF MEIOSIS - MEIOTIC DIVISION I - MEIOTIC DIVISION II
MEIOSIS IN THE HUMAN MALE - MEIOSIS IN THE HUMAN FEMALE - SEX DIFFER-
ENCE IN MEIOSIS
2.2 HUMAN CHROMOSOME PATHOLOGY 40
2.2.1 SYNDROMES DUE TO NUMERIC ANOMALIES OF AUTOSOMES 40
MECHANISMS CREATING ANOMALIES IN CHROMOSOME NUMBERS (GENOME MUTATIONS) -
DOWN S SYNDROME - STANDARD KARYOTYPE IN DOWN S SYN- DROME - OTHER
AUTOSOMAL TRISOMIES - TRIPLOIDY - MOSAICS - STATISTICAL PROBLEM IN THE
DETECTION OF MOSAICS
2.2.2 SYNDROMES DUE TO STRUCTURAL ANOMALIES OF AUTOSOMES 49
2.2.2.1 KARYOTYPES AND CLINICAL SYNDROMES 49
FIRST OBSERVATIONS ON DOWN S SYNDROME - FREQUENCY OF TRANSLOCATION
DOWN S SYNDROME - GAPS AND BREAKS - FATE OF BROKEN CHROMOSOMES -
INTRACHROMOSOMAL REARRANGEMENTS (INTRACHANGES) - INTERCHROMOSOMAL
REARRANGEMENTS (INTERCHANGES) - DESCRIPTION OF HUMAN KARYOTYPES -
PROPOSED CHROMOSOME BAND NOMENCLATURE - DELETION SYNDROMES - IN-
TRACHANGES: PARACENTRIC AND PERICENTRIC INVERSIONS - ANEUSOMIE DE RECOM-
BINATION - RING CHROMOSOMES - FRAGMENTS - ISOCHROMOSOMES - INTER-
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TABLE OF CONTENTS XIII
CHANGES: CENTRIC FUSIONS (ROBERTSONIAN TRANSLOCATIONS) - INTERCHANGES:
RECIPROCAL TRANSLOCATIONS - PHENOTYPES IN AUTOSOMAL CHROMOSOME
ABERRATIONS
2.2.2.2 SEGREGATION AND PRENATAL SELECTION OF TRANSLOCATIONS:
METHODOLOGICAL PROBLEMS 66
DATA USED FOR THIS ANALYSIS - SEGREGATION OF TRANSLOCATIONS IN THE FIRST
MEIOTIC DIVISION - EXPECTATIONS FOR UNBALANCED ZYGOTES - SEGREGATION OF
KARYOTYPICALLY NORMAL AND BALANCED ZYGOTES - PHENOTYPIC DEVIATIONS IN
BALANCED TRANSLOCATION CARRIERS
2.2.3 SEX CHROMOSOMES 69
2.2.3.1 FIRST OBSERVATIONS 69
NONDISJUNCTION OF SEX CHROMOSOMES AND SEX DETERMINATION IN DROSO- PHILA
- XO TYPE IN THE MOUSE - FIRST X-CHROMOSOMAL ANEUPLOIDIES IN HUMANS:
XXY, XO, XXX
2.2.3.2 X-CHROMOSOMAL ANEUPLOIDIES IN HUMANS: CURRENT KNOWLEDGE . 72
DIFFERENCE BETWEEN X-CHROMOSOMAL AND AUTOSOMAL ANEUPLOIDIES - CLINICAL
CLASSIFICATION OF X-CHROMOSOMAL ANEUPLOIDIES: MOSAICS - INTER- SEXES - Y
CHROMOSOME AS THE MALE-DETERMINING UNIT
2.2.3.3 DOSAGE COMPENSATION FOR MAMMALIAN X CHROMOSOMES 74 NATURE OF THE
X CHROMATIN - X INACTIVATION AS THE MECHANISM OF GENE DOSAGE
COMPENSATION: LYON HYPOTHESIS - EVIDENCE FROM THE HUMAN G6PD VARIANT -
OTHER EXAMPLES OF X INACTIVATION IN HUMANS - CELLS IN WHICH THE SECOND X
IS NOT INACTIVATED - WHICH IS EARLIER, X INACTIVATION OR X CHROMATIN
FORMATION? - GENETIC DIFFERENCES IN X INACTIVATION PAT- TERNS? - X
INACTIVATION AND ABNORMAL X CHROMOSOMES - X INACTIVATION
IN SPERMATOGENESIS?
2.2.4 CHROMOSOME ABERRATIONS AND SPONTANEOUS MISCARRIAGE 79 INCIDENCE OF
PRENATAL ZYGOTE LOSS IN HUMANS - INCIDENCE OF CHROMO- SOME ABERRATIONS -
TYPES OF CHROMOSOME ABERRATIONS IN ABORTED FE- TUSES - PHENOTYPES OF
ABORTUSES - SOME CONCLUSIONS
2.3 ORGANIZATION OF GENETIC MATERIAL IN HUMAN CHROMOSOMES . . .. 82
2.3.1 CHROMATIN STRUCTURE 82
2.3.1.1 SINGLE-COPY AND REPETITIVE DNA 82
TOO MUCH DNA IN A HUMAN GENOME? - REPETITIVE DNA - HOW ARE SINGLE-COPY
AND REPETITIVE DNA LOCATED RELATIVE TO EACH OTHER? - RE- PETITIVE DNA
SEQUENCES WITH SPECIFIC FUNCTIONS - SATELLITE DNA
2.3.1.2 HETEROCHROMATIN 84
DEFINITIONS AND PROPERTIES - HETEROMORPHISMS: FUNCTION AND RELATION WITH
SATELLITE DNA
2.3.1.3 THE NUCLEOSOME STRUCTURE OF CHROMATIN 85
CHEMICAL COMPOSITION OF CHROMATIN - NUCLEOSOMES
2.3.1.4 INTEGRATION OF THE CHROMATIN THREAD IN CHROMOSOME STRUCTURE . .
86 INTERPHASE - MITOTIC AND MEIOTIC CHROMOSOMES
2.3.1.5 INTEGRATED MODEL OF CHROMOSOME STRUCTURE 87
2.3.2 THE GENETIC CODE 87
2.3.3 FINE STRUCTURE OF HUMAN GENES: NEW GENETICS 87
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XIV TABLE OF CONTENTS
2.3.3.1 ANALYSIS OF A HUMAN GENE 88
THE /?-GLOBIN GENE - STEPS OF THE ANALYSIS
2.3.3.2 RESTRICTION ENDONUCLEASES 89
THE GERMINAL OBSERVATIONS - PRINCIPLES OF DNA RECOMBINATION TECHNOL- OGY
- IDENTIFICATION AND ANALYSIS OF GENES - PROBES AND GENE LIBRARIES
2.3.3.3 NUCLEIC ACID HYBRIDIZATION 92
THE PRINCIPLE - GENE WALKING - IN SITU HYBRIDIZATION
2.3.3.4 SEQUENCING OF DNA 95
NUCLEOTIDE SEQUENCE AND THE GENETIC CODE
2.3.3.5 CHROMOSOME SORTING BY CYTOFLUORIMETRY 96
WHY DO WE NEED CHROMOSOME SORTING AND PREPARATIONS FROM SINGLE
CHROMOSOMES? - THE PHYSICAL PRINCIPLE - SORTING OF X AND Y CHROMO- SOMES
2.3.3.6 ANALYSIS OF THE /2-GLOBIN GENE AND GENERALIZATIONS WITH EXPERI-
ENCE FROM ONE GENE 97
THE PARADIGMATIC ROLE OF THE /^-GLOBIN GENE
2.3.3.7 STRUCTURE OF FACTOR VIII (ANTIHEMOPHILIC FACTOR) GENE 98 THE
ANTIHEMOPHILIC FACTOR (FACTOR VIII) - RESEARCH STRATEGY OF ELUCIDA- TION
OF THE FACTOR VIII GENE - SIGNIFICANCE OF THESE STUDIES - AN EXERCISE IN
SOCIOLOGY OF SCIENCE
2.3.3.8 GENE FAMILIES 101
EXAMPLES FOR GENE FAMILIES - GENES FOR ACTIN AND MYOSIN - A NEW PRIN-
CIPLE OF GENETIC ANALYSIS
2.3.3.9 RESTRICTION SITE POLYMORPHISMS 102
GENETIC VARIABILITY OUTSIDE CODING GENES - WHY IS KNOWLEDGE OF DNA
POLYMORPHISMS USEFUL FOR THE HUMAN GENETICIST?
2.3.4 THE DYNAMIC GENOME 102
MOVABLE ELEMENTS AND TRANSPOSONS - MOVABLE ELEMENTS IN BACTERIA -
TRANSPOSABLE ELEMENTS IN EUKARYOTES - SIGNIFICANCE OF MOVABLE ELEMENTS
IN EVOLUTION? - MOVABLE ELEMENTS IN THE HUMAN GENOME? - GENE CON-
VERSION - DOES THE GENOME FLUCTUATE? - HOW CONSTANT IS THE GENETIC IN-
FORMATION AND ITS TRANSMISSION?
2.3.5 THE GENOME OF MITOCHONDRIA 107
STRUCTURE AND FUNCTION OF MITOCHONDRIA - THE GENOME OF MITOCHONDRIA -
DNA POLYMORPHISM AND THE QUESTION OF HEREDITARY DISEASES DUE TO MI-
TOCHONDRIAL MUTATIONS
2.3.6 NEW GENETICS AND THE GENE CONCEPT 107
MOLECULAR CYTOGENETICS - WHAT IS A GENE? - THE NEW RESULTS ON STRUC-
TURE OF GENES AND FORMAL GENETICS
3 FORMAL GENETICS OF MAN I LL
3.1 MENDEL S MODES OF INHERITANCE AND THEIR APPLICATION TO HUMANS 111
3.1.1 CODOMINANT MODE OF INHERITANCE 112
IMAGE 5
TABLE OF CONTENTS XV
3.1.2 AUTOSOMAL DOMINANT MODE OF INHERITANCE 112
LATE MANIFESTATION, INCOMPLETE PENETRANCE, AND VARIABLE EXPRESSIVITY -
INFLUENCE OF HOMOZYGOSITY ON THE MANIFESTATION OF ABNORMAL DOMINANT
GENES
3.1.3 AUTOSOMAL-RECESSIVE MODE OF INHERITANCE 116
PSEUDODOMINANCE IN AUTOSOMAL RECESSIVE INHERITANCE - COMPOUND HE-
TEROZYGOTES
3.1.4 X-LINKED MODES OF INHERITANCE 119
X-LINKED RECESSIVE MODE OF INHERITANCE - X-LINKED DOMINANT MODE OF
INHERITANCE - X-LINKED DOMINANT INHERITANCE WITH LETHALITY OF THE MALE
HEMIZYGOTES - GENES ON THE Y CHROMOSOME
3.1.5 PEDIGREES NOT FITTING A KNOWN, SIMPLE MODE OF INHERITANCE . . .
123
3.1.6 LETHAL FACTORS 124
ANIMAL MODELS - LETHALS IN HUMANS
3.1.7 MODIFYING GENES 125
MODIFYING GENES IN THE ABO BLOOD GROUP SYSTEM - SEX-LIMITING MODI- FYING
GENES - MODIFICATION BY THE OTHER ALLELE: ANTICIPATION
3.1.8 NUMBER OF CONDITIONS WITH SIMPLE MODES OF INHERITANCE KNOWN SO FAR
IN HUMANS 128
DIFFERENCE IN THE RELATIVE FREQUENCIES OF DOMINANT AND RECESSIVE CONDI-
TIONS IN MAN AND ANIMALS?
3.2 HARDY-WEINBERG LAW AND ITS APPLICATIONS 129
3.2.1 FORMAL BASIS 129
DERIVATION OF THE HARDY-WEINBERG LAW
3.2.2 HARDY-WEINBERG EXPECTATIONS ESTABLISH THE GENETIC BASIS OF ABO
BLOOD GROUP ALLELES 130
MULTIPLE ALLELISMS - GENETICS OF THE ABO BLOOD GROUPS - MEANING OF A
HARDY-WEINBERG EQUILIBRIUM
3.2.3 GENE FREQUENCIES 132
ONE GENE PAIR: ONLY TWO PHENOTYPES KNOWN
3.3 STATISTICAL METHODS IN FORMAL GENETICS:
ANALYSIS OF SEGREGATION RATIOS 132
3.3.1 SEGREGATION RATIOS AS PROBABILITIES 132
3.3.2 SIMPLE PROBABILITY PROBLEMS IN HUMAN GENETICS 133
INDEPENDENT SAMPLING AND PREDICTION IN GENETIC COUNSELING - DIFFEREN-
TIATION BETWEEN DIFFERENT MODES OF INHERITANCE
3.3.3 TESTING FOR SEGREGATION RATIOS WITHOUT ASCERTAINMENT BIAS:
CODOMINANT INHERITANCE 135
DOMINANCE
3.3.4 TESTING FOR SEGREGATION RATIOS: RARE TRAITS 135
PRINCIPAL BIASES - METHODS OF CORRECTION OF BIAS
3.3.5 DISCRIMINATION OF GENETIC ENTITIES: GENETIC HETEROGENEITY 137
GENETIC ANALYSIS OF MUSCULAR DYSTROPHY AS ONE EXAMPLE - MULTIVARIATE
STATISTICS
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XVI TABLE OF CONTENTS
3.3.6 CONDITIONS WITHOUT SIMPLE MODES OF INHERITANCE 138
EMPIRICAL RISK FIGURES - SELECTING AND EXAMINING PROBANDS AND THEIR
FAMILIES - STATISTICAL EVALUATION, AGE CORRECTION - EXAMPLE -
CALCULATION OF RISK FIGURES FOR SCHIZOPHRENIA - THEORETICAL RISK FIGURES
DERIVED FROM HERITABILITY ESTIMATES?
3.4 LINKAGE: LOCALIZATION OF GENES ON CHROMOSOMES 141
3.4.1 CLASSIC APPROACHES IN EXPERIMENTAL GENETICS: BREEDING EXPERIMENTS
AND GIANT CHROMOSOMES 141
LINKAGE AND ASSOCIATION
3.4.2 LINKAGE ANALYSIS IN HUMANS: CLASSIC PEDIGREE METHOD 142 DIRECT
OBSERVATION OF PEDIGREES - STATISTICAL ANALYSIS - LORD SCORES - RE-
COMBINATION PROBABILITIES AND MAP DISTANCES - RESULTS FOR AUTOSOMAL
LINKAGE, SEX DIFFERENCE, AND PARENTAL AGE - INFORMATION FROM CHROMO-
SOME MORPHOLOGY
3.4.3 LINKAGE ANALYSIS IN HUMANS: CELL HYBRIDIZATION AND DNA TECHNIQUES
147
FIRST OBSERVATIONS ON CELL FUSION - FIRST OBSERVATION OF CHROMOSOME LOSS
IN HUMAN-MOUSE CELL HYBRIDS AND FIRST ASSIGNMENT OF A GENE LO- CUS -
INFLUENCE OF BANDING METHODS FOR CHROMOSOME IDENTIFICATION - OTHER
SOURCES OF INFORMATION FOR GENE LOCALIZATION - DNA POLYMOR- PHISMS AND
GENE ASSIGNMENT - PRESENT STATUS OF GENE LOCALIZATION AND ASSIGNMENT TO
AUTOSOMES - LINKAGE OF X-LINKED GENE LOCI - UNEQUAL
DISTRIBUTION OF RECOMBINATIONAL EVENTS OVER THE LENGTH OF CHROMO- SOME
I? - LINKAGE ANALYSIS WITH GENETICALLY ILL-DEFINED, QUANTITATIVE TRAITS?
- DNA VARIANTS IN LINKAGE - PRACTICAL APPLICATION OF RESULTS FROM
LINKAGE STUDIES
3.5 GENE LOCI LOCALIZED CLOSE TO EACH OTHER AND HAVING RELATED FUNCTIONS
153
3.5.1 SOME PHENOMENA OBSERVED IN EXPERIMENTAL GENETICS 153 CLOSELY
LINKED LOCI MAY SHOW A CIS-TRANS EFFECT - EXPLANATION IN TERMS OF
MOLECULAR BIOLOGY - A NUMBER OF GENES MAY BE CLOSELY LINKED
3.5.2 SOME OBSERVATIONS IN THE HUMAN LINKAGE MAP 153
TYPES OF GENE CLUSTERS THAT HAVE BEEN OBSERVED - CLUSTERS NOT OB- SERVED
SO FAR
3.5.3 WHY DO GENE CLUSTERS EXIST? 154
THEY ARE TRACES OF EVOLUTIONARY HISTORY - COLOR VISION GENES ON THE X
CHROMOSOME - DUPLICATION AND CLUSTERING MAY BE USED FOR IMPROVE- MENT OF
FUNCTION
3.5.4 BLOOD GROUPS: RH COMPLEX, LINKAGE DISEQUILIBRIUM 155
HISTORY - FISHER S HYPOTHESIS OF TWO CLOSELY LINKED LOCI - CONFIRMATION
AND TENTATIVE INTERPRETATION OF THE SEQUENTIAL ORDER - LINKAGE
DISEQUILIB- RIUM
3.5.5 MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) 157
HISTORY - SOCIAL PHENOMENON: FORMATION OF A PARADIGM GROUP - MAIN
COMPONENTS OF THE MHC ON CHROMOSOME 6 - MIXED LYMPHOCYTE CUL- TURES:
TYPING FOR HLA-D ALLELES - COMPLEMENT COMPONENTS - IMMUNE
REGION-ASSOCIATED ANTIGENS - LINKAGE RELATIONSHIPS WITH OTHER MAR-
KERS - SIGNIFICANCE OF HLA IN TRANSPLANTATION - LINKAGE DISEQUILIBRIUM -
THE NORMAL FUNCTION OF THE SYSTEM
IMAGE 7
TABLE OF CONTENTS XVII
3.5.6 GENETIC DETERMINATION OF MIMICRY IN BUTTERFLIES 165
FALSE WARNING COLORATION - BUTTERFLY ESPECIALLY EFFICIENT IN MIMICKING
OTHERS - GENETIC DETERMINATION - SIMILARITIES WITH THE MHC SITUATION
3.5.7 GENES WITH RELATED FUNCTIONS ON THE HUMAN X CHROMOSOME? . . 168
3.5.8 UNEQUAL CROSSING OVER 168
DISCOVERY OF UNEQUAL CROSSING OVER - UNEQUAL CROSSING OVER IN HUMAN
GENETICS - FIRST EVENT - CONSEQUENCES OF UNEQUAL CROSSING OVER - POSSI-
BLE SIGNIFICANCE IN HUMAN GENETICS - INTRACHROMOSOMAL UNEQUAL CROSS- ING
OVER
3.6 CONDITIONS AND LIMITATIONS OF GENETIC ANALYSIS IN HUMANS:
MULTIFACTORIAL INHERITANCE 170
3.6.1 LEVELS OF GENETIC ANALYSIS 170
3.6.1.1 FINDINGS AT THE GENE:DNA LEVEL 171
3.6.1.2 ANALYSIS AT THE GENE PRODUCT: BIOCHEMICAL LEVEL 172
3.6.1.3 ANALYSIS AT THE QUALITATIVE PHENOTYPIC LEVEL: SIMPLE MODES OF
INHERITANCE 172
RARE CONDITIONS QUALITATIVELY DIFFERENT FROM THE NORMAL - FREQUENT VARI-
ANTS: BIMODAL DISTRIBUTION
3.6.1.4 GENETIC ANALYSIS AT THE QUANTITATIVE PHENOTYPIC-BIOMETRIC LEVEL
. 176 ADDITIVE MODEL
3.6.1.5 HERITABILITY CONCEPT 181
PROPERTIES OF H 2
3.6.1.6 ONE EXAMPLE: STATURE 183
3.6.1.7 QUANTITATIVE GENETICS AND THE PARADIGMS OF MENDEL AND GALTON . .
183
3.6.2 MULTIFACTORIAL INHERITANCE IN COMBINATION WITH A THRESHOLD EFFECT
186
3.6.2.1 DESCRIPTION OF THE MODEL: ANIMAL EXPERIMENTS 186
ANIMAL EXPERIMENTS
3.6.2.2 SIMPLE THEORETICAL MODEL 187
3.6.2.3 HOW SHOULD THE MODEL BE USED FOR ANALYSIS OF DATA? 188
QUALITATIVE (OR SEMIQUANTITATIVE) CRITERIA FOR MULTIFACTORIAL
INHERITANCE - QUANTITATIVE CRITERIA
3.6.2.4 IF THE STATISTICAL ANALYSIS GIVES NO CLEAR ANSWER, HOW SHOULD WE
DECIDE? 190
3.6.2.5 RADIATION-INDUCED DOMINANT SKELETON MUTATIONS IN THE MOUSE:
MAJOR GENE MUTATIONS THAT WOULD NOT BE DISCOVERED IN HUMANS 191
3.6.2.6 ISOLATION OF SPECIFIC GENETIC TYPES WITH SIMPLE DIALLELIC MODES
OF INHERITANCE USING ADDITIONAL, PHENOTYPIC CRITERIA 192
3.6.2.7 HOW CAN AN APPARENTLY MULTIFACTORIAL CONDITION BE ANALYZED
FURTHER, WHEN SPECIAL TYPES WITH SIMPLE MODES OF INHERITANCE CANNOT BE
ISOLATED? 193
A COMPLEX FUNCTIONAL DEFECT IS CAUSED BY A COMBINATION OF SMALL ABER-
RATIONS - A MULTIFACTORIAL SYSTEM COMPRISES A GENERAL DISPOSITION THAT
MAY LEAD TO A GROUP OF RELATED DISEASES; SPECIFIC DISPOSITIONS IN-
FLUENCING THE CLINICAL MANIFESTATION PATTERN
IMAGE 8
XVIII TABLE OF CONTENTS
3.7 GENETIC POLYMORPHISM AND DISEASE 195
3.7.1 NEW RESEARCH STRATEGY 195
3.7.2 DISEASE ASSOCIATION OF THE BLOOD GROUPS 195
3.7.2.1 ABO BLOOD GROUPS 195
WRONG HYPOTHESIS LEADS TO AN IMPORTANT DISCOVERY - STATISTICAL STANDARD
METHOD - A FLOOD OF INFESTIGATIONS AND THEIR RESULTS - POSSIBLE BIASES -
FAILURE TO FIND A MECHANISM
3.7.2.2 THE KELL SYSTEM 198
KELL SYSTEM MUTATIONS, ACANTHOCYTOSIS, AND CHRONIC GRANULOMATOUS DIS-
EASE
3.7.3 THE HLA SYSTEM AND DISEASE 199
ARE THERE, INDEED, HLA-LINKED IMMUNE-RESPONSE GENES IN MAN? AND WHAT IS
THEIR MODE OF ACTION? - LINKAGE AND ASSOCIATION
3.7.4 A R ANTITRYPSIN POLYMORPHISM AND DISEASE 203
A,-ANTITRYPSIN (PI) POLYMORPHISM - ASSOCIATION WITH CHRONIC OBSTRUCTIVE
PULMONARY DISEASE (COPD) - SIGNIFICANCE OF THE NEW RESEARCH STRAT- EGY -
DISEASE ASSOCIATIONS OF OTHER POLYMORPHISMS
3.8 NATURE-NUTURE CONCEPT: TWIN METHOD 205
3.8.1 HISTORICAL REMARKS 205
3.8.2 BASIC CONCEPT 206
3.8.3 BIOLOGY OF TWINNING 206
DIZYGOTIC TWINS - MONOZYGOTIC TWINS - FREQUENCY OF TWINNING - FACTORS
INFLUENCING FREQUENCY OF TWIN BIRTHS: MATERNAL AGE AND BIRTH ORDER -
GENETIC FACTORS - DECREASE IN TWIN BIRTHS IN INDUSTRIALIZED COUNTRIES -
FREQUENCIES OF MULTIPLE BIRTHS OF MORE THAN TWO CHILDREN
3.8.4 LIMITATIONS OF THE TWIN METHOD 209
SYSTEMATIC DIFFERENCES BETWEEN TWINS AND NON-TWINS - PECULIARITIES OF
THE TWIN SITUATION IN POSTNATAL LIFE
3.8.5 DIAGNOSIS OF ZYGOSITY 211
3.8.6 APPLICATION OF THE TWIN METHOD TO ALTERNATIVELY DISTRIBUTED
CHARACTERS 211
3.8.7 ONE EXAMPLE: LEPROSY IN INDIA 212
3.8.8 TWIN STUDIES IN OTHER COMMON DISEASES 213
3.8.9 TWIN METHOD IN INVESTIGATING CONTINUOUSLY DISTRIBUTED CHARACTERS
214
HERITABILITY ESTIMATES FROM TWIN DATA
3.8.10 MEANING OF HERITABILITY ESTIMATES: EVIDENCE FROM STATURE 215
INCREASE IN STATURE DURING THE RECENT CENTURY - MORE DETAILED ANALYSIS -
MOST LIKELY EXPLANATION - LESSON TO BE LEARNED FROM THIS EXAMPLE
3.8.11 TWIN-FAMILY METHOD 217
3.8.12 CO-TWIN CONTROL METHOD 217
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TABLE OF CONTENTS XIX
3.8.13 CONTRIBUTION OF HUMAN GENETICS TO A THEORY OF DISEASE 218
DISEASES WITH SIMPLE CAUSES - GENETICS OF DIABETES MELLITUS - DISEASE
CONCEPTS AND DIAGNOSIS - NORMAL VARIANTS AND DISEASE
3.8.14 CURRENT STATUS OF THE GENETICS OF COMMON DISEASES 221
3.8.14.1 BIOLOGIC AND PATHOPHYSIOLOGIC APPROACHES TO THE GENETIC
ETIOLOGY OF COMMON DISEASES 222
HETEROGENEITY ANALYSIS: DIFFERENTIATION OF MONOGENIC SUBTYPES FROM THE
COMMON VARIETIES - CLINICAL POPULATION GENETICS - SEARCH FOR BIOLOGICAL
HETEROGENEITY - POLYMORPHISM AND DISEASE - HETEROZYGOTES FOR RARE DIS-
EASES MAY BE MORE SUSCEPTIBLE TO DEVELOP A FUNCTIONALLY RELATED COM- MON
DISEASE
3.8.14.2 GENETICS OF CORONARY HEART DISEASE 223
RISK FACTORS - HYPERLIPIDEMIAS - FAMILIAL HYPERCHOLESTERINEMIA - ISOAL-
LELES FOR LDL RECEPTOR? - FAMILIAL COMBINED HYPERLIPIDEMIA - FAMILIAL
HYPERTRIGLYCERIDEMIA - BROAD BETA-DISEASE OF TYPE III HYPERLIPOPROTEIN-
EMIA (REMNANT REMOVAL DISEASE) - ASSOCIATIONS OF CORONARY HEART DIS-
EASE WITH GENETIC MARKERS - GENETIC FACTORS OTHER THAN LIPIDS - IMPLICA-
TIONS
4 GENE ACTION 228
4.1 DEVELOPMENT OF MENDEL S PARADIGM 228
GALTON S AND MENDEL S PARADIGM: GENE ACTION IS WELL UNDERSTOOD - AP-
PLICATION TO HUMAN GENETICS
4.2 GENES AND ENZYMES 230
4.2.1 ONE-GENE-ONE-ENZYME HYPOTHESIS 230
EARLY FORERUNNERS - BEADLE S AND TATUM S SIMPLE ORGANISM AND METHOD OF
ATTACK - FIRST ENZYME DEFECTS IN HUMANS - SOME STEPS IN THE KNOWL- EDGE
OF HUMAN ENZYME DEFECTS
4.2.2 GENES AND ENZYMES IN HUMANS: PRESENT STATE OF KNOWLEDGE . . . 233
SCOPE AND LIMITATIONS OF THIS REVIEW
4.2.2.1 DISCOVERY AND ANALYSIS OF ENZYME DEFECTS 233
DIFFERENCE IN RESEARCH STRATEGY BETWEEN HUMANS AND NEUROSPORA - CLIN-
ICAL SYMPTOMS LEADING TO THE DETECTION OF ENZYME DEFECTS - CLINICAL DI-
AGNOSIS OF METABOLIC DEFECTS - METHODS USED FOR ANALYSIS OF ENZYME DE-
FECTS - EXAMINATION OF ENZYME DEFECTS IN HUMAN FIBROBLAST CULTURES -
DIFFICULTIES OF THE METHOD - GROWTH CHARACTERISTICS OF FIBROBLASTS
4.2.2.2 TYPICAL GROUP OF ENZYME DEFECTS: ERYTHROCYTE ENZYMES 236 ENZYME
DEFECTS IN GLYCOLYSIS - NONSPHEROCYTIC HEMOLYTIC ANEMIAS - EN- ZYME
DEFECTS IN THE GLYCOLYTIC PATHWAY - MATERIAL FOR EXAMINATION IS READILY
AVAILABLE - ANALYSIS AT THE ENZYME LEVEL REVEALS GENETIC HETER- OGENEITY
- IN ALMOST ALL ENZYME DEFECTS, A RESIDUAL ACTIVITY IS FOUND AMONG
HOMOZYGOTES - CLINICAL FINDINGS CAUSED BY AN ENZYME DEFECT
DEPEND ON THE NORMAL ACTIVITY OF THIS ENZYME IN A VARIETY OF DIFFERENT
TISSUES - PYRUVATE KINASE (PK) DEFICIENCY - ENZYME ACTIVITIES AND CLINI-
CAL SYMPTOMS IN HETEROZYGOTES - AEROBIC ENERGY PRODUCTION IN THE RED
CELL: HEXOSE MONOPHOSPHATE (HMP) PATHWAY - DEFICIENCY OF G6PD
(GLUCOSE-6-PHOSPHATE DEHYDROGENASE) - DIFFERENCE BETWEEN THE AFRICAN
AND MEDITERRANEAN VARIANTS - MORE DETAILED CHARACTERIZATION OF G6PD
VARIANTS - ENZYME VARIANTS OBSERVED IN HUMAN POPULATIONS - MORE INCI-
SIVE BIOCHEMICAL AND MOLECULAR ANALYSIS - SIGNIFICANCE OF G6PD VARIANTS
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XX TABLE OF CONTENTS
FOR UNDERSTANDING OF HUMAN ENZYME DEFICIENCIES - PHENOCOPY OF A GE-
NETIC ENZYME DEFECT: GLUTATHIONE REDUCTASE DEFICIENCY - DEFICIENCIES IN
NUCLEOTIDE METABOLISM
4.2.2.3 MUCOPOLYSACCHARIDOSES 246
DEFICIENCIES OF LYSOSOMAL ENZYMES - MUCOPOLYSACCHARIDOSES: CLINICAL
PICTURE - LYSOSOME STORAGE AND URINARY EXCRETION - BIOCHEMISTRY OF SUL-
FATED GLYCOSAMINOGLYCANS - ENZYME DEFICIENCIES - CONSEQUENCES FOR
UNDERSTANDING OF GENETIC HETEROGENEITY - DIFFERENTIAL DIAGNOSIS AND
TREATMENT OF MUCOPOLYSACCHARIDOSES - DEFECT OF A RECOGNITION MARKER FOR
LYSOSOMAL HYDROLASES
4.2.2.4 ENZYME DEFECTS INVOLVING MORE THAN ONE ENZYME 253
MAPLE SYRUP URINE DISEASE (BRANCHED-CHAIN KETOACIDURIA) - OTHER MET-
ABOLIC DEFECTS INVOLVING MORE THAN ONE ENZYME - A FRESH VIEW ON THE ONE
GENE-ONE ENZYME (OR ONE GENE-ONE POLYPEPTIDE) HYPOTHESIS
4.2.2.5 INFLUENCE OF COFACTORS ON ENZYME ACTIVITY 255
ENZYME COFACTORS - FOLIC ACID DEPENDENCY: DEFICIENCIES IN TRANSPORT AND
COENZYME FORMATION - PYRIDOXINE (VITAMIN B 6 ) DEPENDENCY
4.2.2.6 X-LINKED HPRT DEFICIENCIES 258
ENZYME DEFECTS AS TOOLS FOR SOME BASIC QUESTIONS ON GENE ACTION AND
MUTATION - LESCH-NYHAN SYNDROME - MOLECULAR HETEROGENEITY - EVI- DENCE
FOR X-INACTIVATION - METABOLIC CO-OPERATION - OTHER PROBLEMS EX- AMINED
WITH HPRT DEFICIENCY - IMMUNE DEFICIENCY DISEASES ASSOCIATED WITH
ADENOSINE DEAMINASE AND NUCLEOSIDE PHOSPHORYLASE DEFECTS
4.2.2.7 PHENYLKETONURIA: PARADIGM FOR SUCCESSFUL TREATMENT OF A
METABOLIC DISEASE 261 METABOLIC OLIGOPHRENIA - ENZYME DEFECT IN PKU -
DIETARY TREATMENT OF PKU - GENETIC HETEROGENEITY OF PKU
4.2.2.8 HETEROZYGOTE DETECTION 264
HETEROZYGOTE DETECTION FOR PKU AND HYPERPHENYLALANINEMIA - HEALTH STATUS
OF HETEROZYGOTES - HETEROZYGOTE DETECTION IN GENERAL - SUSCEPTI- BILITY
TO COMMON DISEASES IN HETEROZYGOTES OF RECESSIVE CONDITIONS -
HETEROZYGOTE TESTING IN HEMOPHILIA A - HETEROZYGOTE DETECTION IN DU-
CHENNE MUSCULAR DYSTROPHY - PROBLEMS WITH HETEROZYGOTE DETECTION
4.2.2.9 TREATMENT OF INHERITED METABOLIC DISEASE 270
GENERAL PRINCIPLES - SUBSTITUTION (PROTEIN OR ENZYME) THERAPY - ENVIRON-
MENTAL MANIPULATION: REMOVAL OF A METABOLITE AHEAD OF THE BLOCK - EN-
VIRONMENTAL MANIPULATION: SUBSTITUTION OF A METABOLITE BEHIND THE EN-
ZYME BLOCK - ELIMINATION OF THE METABOLITE AHEAD OF THE BLOCK AND
SUBSTITUTION OF THE METABOLITE BEHIND THE BLOCK - TREATMENT BY REMOVING
SECONDARY EFFECTS OF THE METABOLIC DEFECT - DIETARY TREATMENT OF META-
BOLIC DISEASES MAY ONLY BE THE EXTREME OF A MORE GENERAL GENETOTRO-
PHIC PRINCIPLE
4.2.2.10 ENZYME DEFECTS THAT HAVE NOT BEEN DISCOVERED 275
HOW MANY ENZYMES ARE THERE AND WHAT ENZYME DEFECTS ARE KNOWN? - WHICH
ENZYME DEFECTS ARE NOT KNOWN? - WHY DO WE KNOW SO LITTLE ABOUT ENZYME
DEFECTS OF CENTRAL BUILDING FUNCTIONS?
4.2.2.11 SOME GENERAL CONCLUSIONS SUGGESTED BY ANALYSIS OF HUMAN ENZYME
DEFECTS 277
DETECTION OF ENZYME DEFECTS - ELUCIDATION OF METABOLIC PATHWAYS BY UTI-
LIZATION OF ENZYME DEFECTS - CHARACTERISTICS OF MUTATIONS LEADING TO EN-
ZYME DEFECTS IN HUMANS - MODE OF INHERITANCE: HETEROZYGOTES
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TABLE OF CONTENTS XXI
4.3 MAN S HEMOGLOBIN 278
4.3.1 HISTORY OF HEMOGLOBIN RESEARCH 278
SICKLE CELL ANEMIA: A MOLECULAR DISEASE - SINGLE AMINO ACID SUBSTITU-
TION
4.3.2 GENETICS OF HEMOGLOBINS 279
HEMOGLOBIN MOLECULES - HEMOGLOBIN GENES - PROMOTERS - DOWNSTREAM
SEQUENCES - DNA POLYMORPHISMS AT THE GLOBIN GENES - HEMOGLOBIN VARIANTS
- CLINICAL EFFECTS OF HEMOGLOBIN VARIANTS - UNSTABLE HEMOGLO- BINS -
METHEMOGLOBINEMIA DUE TO HB M - ERYTHROCYTOSIS DUE TO HEMO- GLOBINS WITH
ABNORMAL OXYGEN AFFINITY - SICKLE CELL DISORDERS
4.3.3 OTHER TYPES OF HEMOGLOBIN MUTATIONS 289
DELETIONS - DUPLICATIONS
4.3.4 THALASSEMIAS AND RELATED CONDITIONS 292
TRANSCRIPTION OR PROMOTER MUTATIONS - A RNA CLEAVAGE MUTATION - TER-
MINATOR (NONSENSE) AND FRAMESHIFT MUTATIONS - RNA PROCESSING MUTA- TIONS
- DELETION MUTATIONS AT THE HB FI GLOBIN GENE CLUSTER AND HEREDI- TARY
PERSISTENCE OF FETAL HEMOGLOBIN - HETEROCELLULAR HEREDITARY PERSIS-
TENCE OF FETAL HEMOGLOBIN - CLINICAL IMPLICATIONS - A-THALASSEMIA:
DELETION A-THALASSEMIA - HB A NONDELETION THALASSEMIA
4.3.5 POPULATION GENETICS OF HEMOGLOBIN GENES 299
4.3.6 PRENATAL DIAGNOSIS OF HEMOGLOBINOPATHIES 300
HEMOGLOBIN AS A MODEL SYSTEM
4.4 GENETICS OF ANTIGEN-RECEPTOR/ ANTIBODY 302
FUNCTION AND FORMATION OF ANTIBODIES - MYELOMA PROTEINS AS RESEARCH
TOOLS - CLASSES OF IMMUNOGLOBULINS - CONSTANT AND VARIABLE PARTS -
COMMON ORIGIN OF THE GENES FOR ALL CHAINS - GENETIC DETERMINATION OF THE
VARIABLE CHAINS - SOMATIC MUTATION OR SELECTIVE ACTIVATION OF GENES?
- V PARTS AND THE SPECIFICITY OF ANTIBODIES
4.5 PHARMACOGENETICS AND ECOGENETICS 307
4.5.1 PHARMACOGENETICS 307
G6PD SYSTEM - PSEUDOCHOLINESTERASE VARIATION - ACETYLTRANSFERASE VARIA-
TION - DISTRIBUTION CURVES AND GENE ACTION - DEBRISOQUINE-SPARTEINE
POLYMORPHISM - MEPHENYTION POLYMORPHISM - OTHER MONOGENIC PHAR-
MACOGENETIC TRAITS - MULTIFACTORIAL PHARMACOGENETICS - PHARMACOGENETIC
VARIATION AT THE LEVEL OF THE TARGET ORGAN
4.5.2 ECOGENETICS 313
CARCINOGENS - ^-ANTITRYPSIN DEFICIENCY - PARAOXONASE - FOOD
4.6 MECHANISMS OF AUTOSOMAL DOMINANCE 316
4.6.1 ABNORMAL SUBUNIT AGGREGATIONS 316
DYSFIBRINOGENEMIAS
4.6.2 DISTURBANCE OF MULTIMERIC PROTEIN FUNCTION BY ABNORMAL SUBUNITS
317
HEMOGLOBIN DISEASES
4.6.3 ABNORMAL FEEDBACK INHIBITION OF ENZYMES AND STRUCTURALLY ABNORMAL
ENZYMES 317
PORPHYRIA - DECREASED ENZYME ACTIVITY - INCREASED ENZYME ACTIVITY IN
GOUT
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XXII TABLE OF CONTENTS
4.6.4 RECEPTOR MUTATIONS 318
RECEPTORS - FAMILIAL HYPERCHOLESTEROLEMIA - DOMINANT HEMOLYTIC ANEMIA
DUE TO INCREASED RED CELL ADENOSINE DEAMINASE - A RECEPTOR DEFECT?
4.6.5 MEMBRANE DEFECTS 320
4.6.6 DEPOSITION OF ABNORMAL FIBRILLAR PROTEINS: HEREDITARY AMYLOIDOSES
320
4.6.7 DOMINANTLY INHERITED TUMOR DISEASES 321
GENERAL REMARKS
4.7 GENETICS OF EMBRYONIC DEVELOPMENT 322
4.7.1 GENE ACTIVITY IN EARLY DEVELOPMENT 322
LARGER CONTRIBUTION OF MATERNAL THAN PATERNAL GENOTYPE TO THE CHILD S
PHENOTYPE? - MOUSE TERATOCARCINOMAS AS RESEARCH TOOLS FOR INVESTIGA-
TION OF EARLY DEVELOPMENT
4.7.2 LATER PHASES OF EMBRYONIC DEVELOPMENT, PHENOCOPIES, MALFORMATIONS
324
INDICATIONS FOR INTERACTION BETWEEN GENETIC AND NONGENETIC FACTORS IN
MALFORMATION PRODUCTION
4.7.3 GENE REGULATION IN BACTERIA AND EUKARYOTES 325
NEGATIVE AND POSITIVE CONTROL - FUNCTION OF REGULATORY MECHANISMS -
BRITTEN-DAVIDSON MODEL
4.7.4 GENOTYPE-PHENOTYPE RELATIONSHIPS IN HUMAN CHROMOSOME ABERRATIONS
327
4.7.4.1 GENE DOSAGE EFFECTS IN TRISOMIES AND GENE MAPPING 327 EARLY
ATTEMPTS AT CHROMOSOME MAPPING BY GENE DOSAGE EFFECTS
4.7.4.2 OTHER BIOCHEMICAL ANOMALIES IN CHROMOSOME ABERRATIONS . . .. 328
FETAL AND EMBRYONIC HEMOGLOBINS IN TRISOMY 13 - TRISOMY 21 AND DNA
REPAIR
A.I A3 CELLULAR STUDIES IN CHROMOSOME ABERRATIONS 329
CELLULAR PHENOTYPES IN HUMAN CHROMOSOME ABERRATIONS - EXAMINATION OF
ABORTUSES - ANEUPLOID MICE AS MODELS FOR DEVELOPMENTAL STUDIES -
ABNORMAL PHENOTYPES DUE TO CHROMOSOME ABERRATION AND GENE REGULA- TION
4.7.5 SEX DIFFERENTIATION AND ITS DISTURBANCES 330
DEVELOPMENT OF SEX CHARACTERISTICS - Y CHROMOSOME AND H-Y ANTIGEN -
DEVELOPMENT OF SECONDARY SEXUAL CHARACTERS - TESTICULAR FEMINIZATION
SYNDROME - GENETIC HETEROGENEITY
5 MUTATION 334
5.1 SPONTANEOUS MUTATION 334
5.1.1 REAPPRAISAL OF GENETIC VARIANTS THAT MAY OCCUR BY NEW MUTATION 334
CELLS IN WHICH MUTATIONS MAY OCCUR - MUTATION RATES
5.1.2 GENOME AND CHROMOSOME MUTATIONS IN HUMANS 335
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TABLE OF CONTENTS XXI11
5.1.2.1 MUTATION RATES 335
METHODS USED - INCIDENCE AND MUTATION RATES: GENOME MUTATIONS - IN-
CIDENCE AND MUTATION RATES: CHROMOSOME MUTATIONS
5.1.2.2 NONDISJUNCTION AND THE AGE OF THE MOTHER 336
STATISTICAL EVIDENCE - IS, INDEED, ONLY THE AGE OF THE MOTHER INVOLVED?
- HIGHER RISK IN CHILDREN OF VERY YOUNG MOTHERS? - AGE-SPECIFIC RATES IN
TRISOMIES - MATERNAL AGE EFFECT IN OTHER TRISOMIES
5.1.2.3 IN WHICH SEX AND AT WHICH MEIOTIC DIVISION DOES NONDISJUNCTION
OCCUR? 339
EVIDENCE FOR THE X CHROMOSOME FROM X-LINKED MARKER STUDIES - DIRECT
EVIDENCE FROM CHROMOSOME VARIANTS - UTILIZATION OF CHROMOSOMAL VARI-
ANTS FOR IDENTIFICATION OF NONDISJUNCTION - INFORMATION FROM BIOCHEMICAL
VARIANTS WILL HELP TO ENHANCE THE NUMBER OF INFORMATIVE FAMILIES
5.1.2.4 NONDISJUNCTION, CHROMOSOME VARIANTS, AND SATELLITE ASSOCIATION .
344 SATELLITE ASSOCIATION - THYROID DISEASE AND ANTITHYROID ANTIBODIES -
DO THYROID AUTOANTIBODIES AND AUTOIMMUNE DISEASE ALSO ENHANCE THE RISK
FOR OTHER ANEUPLOIDIES? - DO ORAL CONTRACEPTIVES ENHANCE THE RISK FOR
DOWN S SYNDROME?
5.1.3 GENE MUTATION: ANALYSIS AT THE PHENOTYPE LEVEL 347
5.1.3.1 METHODS FOR ESTIMATING MUTATION RATES 347
DIRECT METHOD - DANFORTH S FORMULA - HALDANE S INDIRECT METHOD FOR
MUTATION RATE ESTIMATION - PRACTICAL PROBLEMS IN APPLICATION OF THE
INDI- RECT METHOD - MUTATION RATES CANNOT BE ESTIMATED FOR
AUTOSOMAL-RECES- SIVE DISEASES
5.1.3.2 RESULTS ON MUTATION RATES 349
ESTIMATES BASED ON POPULATION SURVEYS - X-LINKED RECESSIVE CONDI- TIONS
- ARE THESE MUTATIONS REPRESENTATIVE OF COMPARABLE MUTATIONS IN THE
HUMAN GENOME? - DO THESE MUTATION RATES COMPRISE THE TOTAL
MUTABILITY OF THE GENE LOCI CONCERNED? - IN WHAT CONTEXT SHOULD HUMAN
MUTATION RATES INVOLVING DOMINANT OR X-LINKED PHENOTYPES BE
INVESTIGATED? - MUTATION RATES FOR RARE ENZYME VARIANTS
5.1.3.3 MUTATION RATE AND AGE OF THE FATHER 355
ONE OF WEINBERG S BRILLIANT IDEAS - WATSON-CRICK MODEL STIMULATED NEW
RESEARCH ON PATERNAL AND MATERNAL AGE INFLUENCES - CELL DIVISIONS DUR-
ING GERM CELL DEVELOPMENT IN THE TWO HUMAN SEXES - EARLY DEVELOP- MENT -
OOGENESIS - SPERMATOGENESIS - INCREASE OF MUTATION RATE WITH PA- TERNAL
AGE - OTHER DOMINANT MUTATIONS FOR WHICH A PATERNAL AGE EFFECT
IS POSSIBLE - MUTATIONS LEADING TO UNSTABLE HEMOGLOBINS OR HEMOGLO- BIN
M AND PATERNAL AGE - SOME DOMINANT MUTATIONS SHOW ONLY A SMALL PATERNAL
AGE EFFECT - ANOTHER X-LINKED DISORDER: LESCH-NYHAN SYN-
DROME
5.1.3.4 POSSIBLE SEX DIFFERENCE OF MUTATION RATES 361
SEX DIFFERENCE IN THE MUTATION RATE FOR HEMOPHILIA A - LIKELY HIGHER
MUTATION RATE IN MALE GERM CELLS IN THE LESCH-NYHAN SYNDROME - THE
MARKER (X) SYNDROME - NO SEX DIFFERENCE IN MUTATION RATES IN THE
DUCHENNE-TYPE OF MUSCULAR DYSTROPHY - INDIRECT EVIDENCE FOR A HIGHER
MUTATION RATE IN MALE GERM CELLS - SEX DIFFERENCE IN MUTATION RATES OF
THE MOUSE - STATISTICAL RESULTS AND MUTATION MECHANISM
5.1.3.5 GERM CELL AND SOMATIC CELL MOSAICS FOR DOMINANT OR X-LINKED
MUTATIONS 365
PEDIGREE OBSERVATIONS - SOMATIC MOSAICISM FOR DOMINANT MUTATIONS -
HALF-CHROMATID MUTATIONS?
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XXIV TABLE OF CONTENTS
5.1.4 GENE MUTATION: ANALYSIS AT THE MOLECULAR LEVEL 366
5.1.4.1 CODON MUTATION RATES 366
FIRST EXAMINATION OF THIS PROBLEM - ESTIMATE WITH MORE DIRECT DATA - HOW
DO THESE CODON MUTATION RATES COMPARE WITH ESTIMATES AT THE PHENOTYPIC
LEVEL? - RELATIVE MUTATION RATES FOR THE DIFFERENT MOLECULAR TYPES OF
MUTATIONS IN THE HEMOGLOBIN GENES
5.1.4.2 PROBLEM OF THE TOTAL MUTATION RATE PER GENOME AND PER GENERATION
369
REQUIREMENTS FOR AN ESTIMATE - ARE THE KNOWN HEMOGLOBIN MUTANTS DIS-
TRIBUTED AT RANDOM OVER THE LENGTH OF THE HB A AND /? GENES? - THERE MAY
BE MANY NEW MUTATIONS PER GENOME AND GENERATION, BUT A RELI- ABLE
ESTIMATE IS NOT YET POSSIBLE
5.1.4.3 MUTATIONS IN HEMOGLOBIN GENES AND THE GENETIC CODE 370 AMINO
ACID REPLACEMENTS INDICATE CORRESPONDING BASE SUBSTITUTIONS IN THE DNA -
TRANSITIONS ARE MORE FREQUENT THAN EXPECTED IF BASE SUBSTI- TUTIONS
OCCURRED AT RANDOM
5.1.4.4 MUTATIONS IN MICROORGANISMS: THEIR CONTRIBUTION TO UNDERSTANDING
OF HUMAN MUTATION 371 MUTATIONS AS ERRORS OF DNA REPLICATION - MUTATOR
GENES - MUTATION- LIKE EVENTS DUE TO EXTRANUCLEAR ENTITIES SUCH AS
VIRUSES AND TRANS-
POSONS?
5.1.5 EXAMINATION OF GENE MUTATIONS IN SINGLE CELLS 373
ATTEMPT AT EXAMINATION OF MUTATIONS OCCURRING IN VIVO - EXAMINATION OF
MUTANT CELLS IN VITRO
5.1.6 SOMATIC MUTATIONS 374
5.1.6.1 FORMATION OF MOSAICS FOR GENOME MUTATIONS 375
MECHANISM OF MOSAIC FORMATION IN EARLY CLEAVAGE
5.1.6.2 HEREDITARY SYNDROMES WITH INCREASED CHROMOSOME INSTABILITY .
.376 FANCONI S ANEMIA - BLOOM S SYNDROME - ATAXIA-TELANGIECTASIA - CHRO-
MOSOME INSTABILITY AND CANCER
5.1.6.3 MOLECULAR MECHANISMS OF CHROMOSOMAL INSTABILITY AND TUMOR
FORMATION DUE TO SOMATIC MUTATION 378
XERODERMA PIGMENTOSUM - MECHANISMS OF DNA REPAIR - ENZYME DE- FECTS IN
XERODERMA PIGMENTOSUM-LIKE DISEASES - GENETIC HETEROGENEITY - MALIGNANT
NEOPLASIAS IN PATIENTS WITH XP - INCREASED CANCER RISK IN HETEROZYGOTES
- MOLECULAR MECHANISMS IN SYNDROMES WITH ENHANCED
CHROMOSOME INSTABILITY - CHAIN OF EVENTS IN THE FORMATION OF MALIGNANT
NEOPLASIAS BY SOMATIC MUTATION
5.1.6.4 OTHER OBSERVATIONS POINTING TO SOMATIC MUTATION AS A MECHANISM
IN CARCINOGENESIS 384
HISTORY OF THE SOMATIC MUTATION HYPOTHESIS OF CANCER - VIRUS ETIOLOGY
VERSUS SOMATIC MUTATION? - NEOPLASIAS WITH CONSTANT CHROMOSOMAL
ABERRATIONS - RETINOBLASTOMA - TWO MUTATIONAL STEPS IN THE INHERITED
TYPE - GENETIC SYNDROMES ASSOCIATED WITH TUMORS
5.1.6.5 ONCOGENES 389
BASIC PRINCIPLES - CELLULAR TRANSFORMATION - ONCOGENES INVOLVED IN CAR-
CINOGENESIS DUE TO CHROMOSOMAL REARRANGEMENTS
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TABLE OF CONTENTS XXV
5.1.6.6 A GENETIC VIEW OF H U M AN CANCER 391
5.1.6.7 SOMATIC MUTATION AND AGING 393
AGING AND DEATH - STUDIES ON BIOLOGICAL MECHANISMS OF AGING IN SINGLE
CELLS - MOLECULAR AND CHROMOSOMAL MECHANISMS
5.2 MUTATION INDUCTION BY IRRADIATION AND CHEMICAL MUTAGENS . . .. 394
PUBLIC INTEREST IN INDUCED MUTATION
5.2.1 RADIATION-INDUCED MUTATION 395
5.2.1.1 BASIC FACTS AND THE PROBLEMS POSED BY THEM 395
CAPACITY OF ENERGY-RICH RADIATION TO INDUCE MUTATION - SOME TECHNICAL
REMARKS ON RADIATION - RESULTS AND CONCEPTS OF CLASSIC RADIATION GE-
NETICS - CONFIRMATION AND EXTENSION OF THESE RESULTS - INFLUENCE OF THE
CHEMICAL ENVIRONMENT, ESPECIALLY THE O 2 CONTENT OF IRRADIATED TISSUE -
MOLECULAR EFFECTS OF RADIATION - BASIC FACTS OF RADIATION GENETICS RE-
CONFIRMED IN HUMAN LYMPHOCYTE CHROMOSOMES
5.2.1.2 PROBLEM OF ESTIMATING THE GENETIC RISK DUE TO RADIATION AND
OTHER ENVIRONMENTAL MUTAGENS 399
PRINCIPLES OF MUTAGENICITY TESTING - IN VIVO TEST SYSTEMS FOR MUTAGENIC
AGENTS IN GERM CELLS OF THE MOUSE - MULTIPLE RECESSIVE MUTATION METH- OD
- TEST SYSTEMS FOR SOMATIC MUTATIONS
5.2.1.3 RESULTS OF RADIATION MUTAGENICITY TESTING IN MAMMALS 403
GENERAL EFFECTS OF RADIATION ON MAMMALIAN GERM CELLS - CHROMOSOME
MUTATIONS IN MALE AND FEMALE GERM CELLS OF MICE - DIRECT EVIDENCE OF THE
OUTCOME OF INDUCED CHROMOSOME ABERRATIONS - RADIATION-INDUCED GENOME AND
CHROMOSOME MUTATIONS: SENSITIVITY OF CERTAIN CELL STAGES -
RADIATION-INDUCED GENE MUTATION IN THE MALE GERM LINE - DOSE-RATE EFFECT
- DOUBLING DOSE - POPULATION EXPERIMENTS WITH MICE AND OTHER MAMMALS -
CONCLUSIONS FROM MOUSE RADIATION GENETICS FOR GENETIC HAZARDS TO HUMANS
- IMPACT OF PRENATAL OR POSTNATAL MUTATIONAL DAMAGE ON MAN
5.2.1.4 H U M AN POPULATION EXPOSURE TO IONIZING RADIATION 408
NATURAL BACKGROUND RADIATION - ADDITIONAL IRRADIATION DUE TO MODERN
CIVILIZATION
5.2.1.5 HOW MUCH OF AN INCREASE IN THE SPONTANEOUS MUTATION RATE MUST BE
ANTICIPATED? 409
HOW MANY ADDITIONAL MUTATIONS PER DOSE WILL BE INDUCED? - PHENOTYP- IC
CHARACTERISTICS IN IRRADIATED HUMAN POPULATIONS - SURVIVORS OF ATOMIC
BOMBS IN HIROSHIMA AND NAGASAKI - SHIFT IN SEX RATIO DUE TO X-LINKED
LETHALS? - SUPPORT FOR THE SEX RATIO SHIFT BY STUDIES AFTER EXPOSURE TO
X- RAYS - SECOND STUDY IN HIROSHIMA AND NAGASAKI: NO SEX RATIO SHIFT - A
REASSESSMENT USING ADDITIONAL DATA AND METHODS - IRRADIATION OF PAR-
ENTS FOR MEDICAL REASONS AND TRISOMY 21 IN CHILDREN - HIGHER INCIDENCE
OF STRUCTURAL CHROMOSOME ANOMALIES AND DOWN S SYNDROME IN HUMAN
POPULATIONS EXPOSED TO HIGH BACKGROUND RADIATION? - EVIDENCE IN SO-
MATIC CHROMOSOME MUTATIONS AFTER EXPOSURE TO RADIATION: MEDICAL THERAPY
- PROFESSIONAL EXPOSURE - ATOMIC BOMB SURVIVORS - NEOPLASTIC
DISEASE IN ATOMIC BOMB SURVIVORS - PROJECTED ADDITIONAL MUTATIONS PER
DOSE - GENOME MUTATIONS - STRUCTURAL CHROMOSOME ABBERATIONS - POINT
MUTATIONS - HOW MANY OF NATURALLY OCCURRING, SPONTANEOUS MUTA- TIONS
ARE CAUSED BY NATURAL BACKGROUND RADIATION? - HOW MANY MUTA- TIONS WOULD
OCCUR SPONTANEOUSLY, I.E., WITHOUT ADDITIONAL IRRADIATION
DUE TO MODERN CIVILIZATION? - AMOUNT OF GENETIC DISEASE IN THE POPULA-
TION IS NOT KNOWN - EVALUATION OF AD HOC STUDIES MIGHT GIVE AN IDEA OF
THE PREVALENCE OF DOMINANT AND X-LINKED CONDITIONS - FREQUENCY OF
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XXVI TABLE OF CONTENTS
NEW MUTATIONS IN AUTOSOMAL DOMINANT DISEASE AND BIOLOGIC FITNESS -
EDUCATED GUESSES AS TO INCOMPLETE PENETRANCE AND MULTIFACTORIAL DIS-
EASES
5.2.2 CHEMICALLY INDUCED MUTATIONS 421
5.2.2.1 EXTENT OF THE PROBLEM 421
HISTORY - MUTAGENIC COMPOUNDS IN THE HUMAN ENVIRONMENT - MOLECULAR
MECHANISMS OF CHEMICAL MUTAGENESIS - DIFFICULTIES IN SETTING UP RE-
SEARCH STRATEGIES FOR DISCOVERING GENETIC THREATS DUE TO CHEMICAL MUTAG-
ENS - EXTRAPOLATION FROM OTHER MAMMALIAN SPECIES TO HUMANS AND FROM ONE
HUMAN BEING TO ANOTHER - DIFFERENCES BETWEEN CHEMICAL MUTAGENS AND
IONIZING RADIATION AND BETWEEN DIFFERENT CLASSES OF CHEMICAL MU- TAGENS
IN THE INDUCTION OF GENOME AND CHROMOSOME MUTATIONS
5.2.2.2 RESEARCH STRATEGIES FOR ASSESSMENT OF GENETIC RISKS DUE TO
CHEMICAL MUTAGENS 425
WHAT QUESTIONS SHOULD WE TRY TO ANSWER?
5.2.2.3 IN WHAT WAY DO CHEMICAL MUTAGENS AFFECT THE GENETIC MATERIAL?
426 PLANNING OF TEST PROGRAMS - DETERMINE PRECISELY WHAT YOU WANT TO
KNOW - AMES TEST AS A SCREENING TEST FOR CARCINOGENS? - METABOLISM -
TISSUE DIFFERENCES IN MUTATION? - EXTRAPOLATION FROM HIGH TO LOW
DOSES - THRESHOLDS IN ENVIRONMENTAL MUTAGENESIS? - PLAN YOUR TEST PRO-
GRAM TO ANSWER SPECIFIC QUESTIONS
5.2.2.4 HOW WIDELY IS THE HUMAN POPULATION EXPOSED TO THE AGENT? . . .
428 AN IMPORTANT, BUT SOMETIMES NEGLECTED QUESTION - POPULATION EXPOSURE
TO A FREQUENTLY USED DRUG - POPULATION EXPOSURE TO HIGHLY MUTAGENIC
DRUGS - SIMILAR STUDIES ARE NEEDED FOR OTHER CHEMICALS
5.2.2.5 HOW HIGH AN INCREASE IN THE SPONTANEOUS MUTATION RATE MUST BE
ANTICIPATED DUE TO CHEMICAL MUTAGENS? 429
CHEMICALLY INDUCED AS COMPARED TO RADIATION-INDUCED MUTATIONS -
MONITORING OF HUMAN POPULATIONS FOR INCREASED MUTATION RATES - PRESENT
ATTITUDES OF SOCIETIES TOWARD MUTAGENICITY TESTING - MEDICAL AND SOCIAL
SIGNIFICANCE OF DIFFERENT TYPES OF MUTATIONS
6 POPULATION GENETICS 433
6.1 POPULATION DESCRIPTION 434
6.1.1 HARDY-WEINBERG LAW: EXTENDED CONSIDERATION - GENE FREQUENCIES 434
HARDY-WEINBERG LAW FOR AUTOSOMAL GENES - HARDY-WEINBERG LAW FOR X-
LINKED GENES - GENE FREQUENCIES
6.1.2 GENETIC POLYMORPHISMS 435
DEFINITION AND HISTORY - PRESENT SITUATION - BIOCHEMICAL INDIVIDUALITY
FOR POLYMORPHISMS - WHAT IS THE PROPORTION OF POLYMORPHIC HUMAN GENE
LOCI? - RARE VARIANTS - MUTATION RATE MAY BE LOW - DISTRIBUTION OF VARI-
ANTS ACCORDING TO THEIR FREQUENCIES - GENETIC POLYMORPHISMS FOR OTHER
(EG., STRUCTURAL) PROTEINS - DNA POLYMORPHISMS - TYPES OF DNA POLY-
MORPHISMS - APPLICATIONS OF DNA MARKER STUDIES - MITOCHONDRIAL DNA
POLYMORPHISMS
6.1.3 HEREDITARY DISEASES 443
DOMINANT AND X-LINKED RECESSIVE DISEASES - AUTOSOMAL RECESSIVE DIS-
EASES - PHENYLKETONURIA AND HYPERPHENYLALANINEMIA - OTHER CONDI- TIONS -
HIGH FREQUENCIES OF RECESSIVE DISEASES IN SPECIAL POPULATIONS
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TABLE OF CONTENTS XXVII
6.2 SYSTEMATIC CHANGES IN GENE FREQUENCIES: MUTATION AND SELECTION 445
6.2.1 NATURAL SELECTION 445
6.2.1.1 MATHEMATICAL SELECTION MODELS: DARWINIAN FITNESS 445 SCOPE OF
MATHEMATICAL MODELS IN SELECTION THEORY AND THEIR LIMITA- TIONS -
DETERMINISTIC AND STOCHASTIC MODELS: USE OF COMPUTERS - HOW SHOULD
MODELS BE USED IN PRACTICE? - CONCEPT OF DARWINIAN FITNESS
6.2.1.2 SELECTION LEADING TO CHANGES OF GENE FREQUENCIES IN ONE
DIRECTION 447
SYMBOLS USED - ELIMINATION OF HETEROZYGOUS DOMINANT PHENOTYPES -
PARTIAL ELIMINATION OF AUTOSOMAL DOMINANTS - SELECTION RELAXATION - SE-
LECTION RELAXATION IN RETINOBLASTOMA - SELECTION BY COMPLETE ELIMINATION
OF HOMOZYGOTES - PARTIAL ELIMINATION OF HOMOZYGOTES - A BIT OF CALCULUS
- GAMETIC SELECTION
6.2.1.3 SELECTION LEADING TO A GENETIC EQUILIBRIUM 451
SELECTION IN FAVOR OF HETEROZYGOTES WITH SELECTIVE DISADVANTAGE OF BOTH
HOMOZYGOTES - HETEROZYGOTE ADVANTAGE: FORMAL CONSEQUENCES
6.2.1.4 SELECTION LEADING TO AN UNSTABLE EQUILIBRIUM 451
SELECTION AGAINST HETEROZYGOTES - PERICENTRIC INVERSIONS - SELECTION
AGAINST RH HETEROZYGOTES - ABO BLOOD GROUP SYSTEM
6.2.1.5 OTHER MODES OF SELECTION 454
FREQUENCY-DEPENDENT SELECTION - FREQUENCY-DEPENDENT SELECTION IN
COMBINATION WITH LINKAGE DISEQUILIBRIUM - DENSITY-DEPENDENT SELEC- TION
- KIN SELECTION - SELECTION IN CONTINUOUSLY DISTRIBUTED, MULTIFACTORI-
ALLY DETERMINED CHARACTERS
6.2.1.6 SELECTION DUE TO INFECTIOUS DISEASES 458
SELECTION DUE TO INFECTIOUS DISEASES IN HISTORICAL POPULATIONS - HISTORY
OF SOME INFECTIOUS DISEASES - DISTRIBUTION OF SICKLE CELL GENE AND OTHER
ABNORMAL HEMOGLOBIN GENES IN THE WORLD POPULATION - DIFFERENTIAL MU-
TATION RATES TO HBS? - MALARIA HYPOTHESIS - EVIDENCE FOR THE MALARIA HY-
POTHESIS - SOME OTHER ASPECTS OF THE MALARIA HYPOTHESIS - WHAT WILL
HAPPEN IF THE ADVANTAGE OF HETEROZYGOTES DISAPPEARS? - POPULATION GE-
NETICS OF G6PD VARIANTS AND FALCIPARUM MALARIA - IN VITRO STUDIES OF MA-
TERIAL GROWTH IN RED CELLS - ASCERTAINING AND MEASURING OF SELECTION IN
HUMANS
6.2.1.7 NATURAL SELECTION AND POPULATION HISTORY: HBE AND /^-THALASSEMIA
466
INTERACTION OF TWO ABNORMAL HEMOGLOBIN GENES IN A POPULATION - DISTRI-
BUTION OF HBE AND THALASSEMIA - HBE AND MALARIA - FITNESS OF THE GENO-
TYPES INVOLVING HBE AND THALASSEMIA: PROBLEM OF A GENETIC EQUILIBRIUM -
POPULATION DYNAMICS OF HB/JE AND HB/TT - SELECTION RELAXATION - IM-
PLICATIONS OF THESE RESULTS FOR THE POPULATION HISTORY OF SOUTHEASTERN
ASIA - COMPARISON WITH HB/?S IN WESTERN AFRICA - HEMOGLOBIN /JE IN THE
AUSTROASIATIC (MON-KHMER) LANGUAGE GROUP - PREDICTION CONFIRMED - SOME
GENERAL CONCLUSIONS FROM THE STUDIES ON HBE AND THALASSEMIA - SIMILAR
STUDIES ON SICKLE CELL POLYMORPHISM IN AFRICA: A STOCHASTIC MODEL
FOR REPLACEMENT OF ONE ALLELE BY ANOTHER
6.2.1.8 SELECTION IN THE ABO BLOOD GROUP SYSTEMS AND IN OTHER
POLYMORPHISMS 472
ABO BLOOD GROUPS AND DISEASES - ABO BLOOD GROUPS AND INFECTIONS DISEASE
- DISTRIBUTION OF ABO ALLELES IN THE WORLD POPULATION - SYPHILIS AND
BLOOD GROUP O - CHOLERA AND BLOOD GROUP O - PLAGUE AND BLOOD
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XXVIII TABLE OF CONTENTS
GROUP O - DOES A COMMON BLOOD GROUP ANTIGEN OF THE MICROORGANISM
IMPAIRTHE IMMUNE REACTION OF THE HOST? E.COLI AND INFECTIOUS DIARRHEAS.
- ABO BLOOD GROUPS AND SMALLPOX - ASSOCIATION STUDIES ON SMALLPOX
PATIENTS GAVE CONTRADICTORY RESULTS - BLOOD GROUP A AND SMALLPOX IN THE
WORLD POPULATION - DISTRIBUTION OF ABO BLOOD GROUP GENES IN THE
WORLD POPULATION AND SELECTION BY INFECTIOUS DISEASES - LESSON OF
STUDIES ON ABO BLOOD-GROUP SELECTION FOR RESEARCH ON NATURAL SELECTION
IN HUMAN POPULATIONS - GENETIC SUSCEPTIBILITIES AND INFECTIOUS DISEASE -
NATURAL SELECTION BY INFECTIOUS AGENTS IS LIKELY FOR THE MHC POLYMOR-
PHISM - DOES GENETIC LIABILITY TO ATOPIC DISEASES LEAD TO AN INCREASED
RESISTANCE TO HELMINTH INFESTATION?
6.3 DEVIATIONS FROM RANDOM MATING 481
6.3.1 CONSANGUINEOUS MATINGS 482
6.3.1.1 INBREEDING COEFFICIENT 482
ALL HUMAN BEINGS ARE RELATIVES - DEGREES OF RELATIONSHIP NORMALLY
CONSIDERED - TWO USEFUL MEASURES: COEFFICIENT OF KINSHIP AND INBREED-
ING COEFFICIENT - COEFFICIENT OF INBREEDING AND THE HARDY-WEINBERG LAW -
CALCULATION OF THE INBREEDING COEFFICIENT/ - EXAMPLES - INBREED-
ING COEFFICIENT OF A POPULATION
6.3.1.2 INBREEDING, ISOLATE SIZE, AND INHERITED DISEASE 485
FREQUENCY OF CHILDREN WITH RECESSIVE AND MULTIFACTORIAL DISEASES IN CON-
SANGUINEOUS MATINGS COMPARED WITH NONCONSANGUINEOUS MATINGS -
CALCULATION OF ISOLATE SIZE FROM THE FREQUENCY OF CONSANGUINEOUS MAR-
RIAGES - INBREEDING COEFFICIENT FIN VARIOUS POPULATION GROUPS - DECLINE
OF CONSANGUINITY IN INDUSTRIAL COUNTRIES - SOCIAL AND PSYCHOLOGICAL
INFLU- ENCES ON THE FREQUENCY OF CONSANGUINEOUS MARRIAGES - INFLUENCE OF
THE DECLINE OF CONSANGUINITY ON THE INCIDENCE OF RECESSIVE DISEASES
6.3.2 CONCEPT OF GENETIC LOAD 491
6.3.2.1 THEORY 491
ESTIMATION OF THE OVERALL NUMBER OF RECESSIVE GENES IN THE HUMAN POP-
ULATION - INTUITIVE BACKGROUND: OUR LOAD OF MUTATIONS - EFFECT OF VARIA-
TION ON FITNESS - DEFINITION OF THE GENETIC LOAD - AN EXAMPLE - ESTIMATE
OF THE EXPRESSED GENETIC DAMAGE - ESTIMATE OF THE OVERALL MUTATION RATE
OF DETRIMENTAL MUTATIONS - IMPACT OF THE GENETIC LOAD CONCEPT ON HU- MAN
POPULATION GENETICS - DISCUSSIONS AND CONTROVERSIES CONCERNING THE LOAD
CONCEPT
6.3.2.2 PRACTICAL APPLICATIONS OF THE THEORY 494
ATTEMPTS TO ASSESS THE GENETIC LOAD BY CONSANGUINITY STUDIES - RECES-
SIVE DISEASES AND CONGENITAL MALFORMATIONS IN THE OFFSPRING OF CONSAN-
GUINEOUS MARRIAGES - OTHER PARAMETERS SHOWING AN INBREEDING EFFECT:
COGNITIVE ABILITIES - OVERALL ESTIMATE OF ZYGOTE LOSS DUE TO PARENTAL
CONSANGUINITY
6.3.2.3 CRITICAL EVALUATION 498
THEORETICAL INTERPRETATION - MEDICAL EVIDENCE
6.3.2.4 MORE DIRECT APPROACHES FOR ESTIMATING THE NUMBER OF RECESSIVE
GENES PER INDIVIDUAL 499
STUDIES ON CHILDREN FROM INCESTUOUS MATINGS - CONSANGUINITY IN PARENTS
OF SEVERELY MENTALLY RETARDED CHILDREN - ALTERNATIVE APPROACH FOR ESTI-
MATING THE AVERAGE NUMBER OF RECESSIVE GENES IN HUMANS - CONSAN- GUINITY
EFFECTS AND THE LEVEL OF GENETIC ANALYSIS - EFFECT OF LONG-STAND- ING
INBREEDING
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TABLE OF CONTENTS XXIX
6.3.3 DIFFERENTIATION BETWEEN POPULATION SUBGROUPS: GENETIC DISTANCE 502
REAL MATING STRUCTURE OF HUMAN POPULATIONS - POPULATION HISTORY OR SE-
LECTION? - METHODS FOR DETERMINING GENETIC DISTANCES
6.3.4 GENE FLOW 502
EFFECTS ON MIGRATION ON GENE FREQUENCIES - MIGRATION AND SELECTION -
MEASURING THE ADMIXTURE OF GENES TO A POPULATION SUBGROUP - RATIONALE
FOR MEASURING THE ADMIXTURE OF GENES TO A POPULATION SUBGROUP - ESTI-
MATES FOR ADMIXTURE OF GENES FROM WHITES TO AMERICAN BLACK POPULA- TIONS
- EVIDENCE FOR SELECTION
6.4 CHANCE FLUCTUATIONS OF GENE FREQUENCIES 504
6.4.1 GENETIC DRIFT 504
DETERMINISTIC AND STOCHASTIC MODELS - ISLAND MODEL - A MORE GENERAL CASE
- DECAY OF VARIABILITY
6.4.2 GENETIC DRIFT IN CO-OPERATION WITH MUTATION AND SELECTION . . ..
506
MUTATION - FATE OF A NEW MUTATION - SELECTION - MUTATION AND SELECTION
TOGETHER - RARE INHERITED DISEASES IN HUMAN ISOLATES - EXAMPLE: MAI DE
MELEDA - RARE FLORA IN RARE SOIL : HEREDITARY DISEASES IN FINLAND -
POPULATION HISTORY OF FINLAND - RECESSIVE DISORDERS IN FINLAND - CONCLU-
SIONS FROM THE EXPERIENCE IN FINLAND FOR RESEARCH IN POPULATION GENETICS
OF RARE DISORDERS
7 HUMAN EVOLUTION 512
7.1 PALEOANTHROPOLOGIC EVIDENCE 512
POPULATION GENETICS HELPS TO UNDERSTAND EVOLUTION - EVIDENCE FROM
PALEOANTHROPOLOGY
7.2 GENETIC MECHANISMS OF EVOLUTION OF THE H U M AN SPECIES 513
7.2.1 CHROMOSOME EVOLUTION AND SPECIATION 514
CHROMOSOME NUMBER OF HUMANS AND CLOSELY RELATED NONHUMAN PRI- MATES -
COMPARISON OF CHROMOSOME STRUCTURE WITH BANDING METHODS - EXAMPLE -
COMPARISON OF OVERALL KARYOTYPES OF THE FIVE SPECIES - INCON-
SISTENCIES AND THEIR POSSIBLE EXPLANATION BY AN UNORTHODOX PRINCIPLE -
PRESENCE AND ABSENCE OF CERTAIN SEGMENTS - CHROMOSOME REARRANGE- MENTS
IN EVOLUTION AND IN THE CURRENT POPULATION - SELECTIVE ADVANTAGE OF HIGH
RATE OF SPONTANEOUS MISCARRIAGE IN HUMANS? - HOMOLOGIES OF CHROMOSOMES
AND CHROMOSOMAL SEGMENTS BETWEEN HUMANS AND OTHER,
MORE REMOTELY RELATED SPECIES - HOW CAN A CHROMOSOME REARRANGE- MENT BE
FIXED IN A POPULATION?
7.2.2 COMPARISON OF SATELLITE D NA IN HIGHER PRIMATES 519
HUMAN SATELLITE DNA - COMPARISON WITH CHROMOSOME EVOLUTION
7.2.3 PROTEIN EVOLUTION 521
PROTEIN SEQUENCES - PHYLOGENETIC TREE FOR HEMOGLOBIN GENES - RATES OF
EVOLUTION FOR DIFFERENT PROTEINS - GENE DUPLICATIONS - EVOLUTION OF GEN-
ES FOR PROTEIN DOMAINS - ADVANTAGEOUS OR NEUTRAL MUTATIONS? - ARGU-
MENTS AGAINST GENERAL APPLICABILITY OF THE NEUTRAL HYPOTHESIS - GENETIC
SUFFICIENCY - LIMITATIONS OF PRESENT KNOWLEDGE OF NATURAL SELECTION
AND NEUTRAL SUBSTITUTIONS IN THE EVOLUTION OF PROTEINS - EVOLUTIONARY
CLOCK AND MUTATION - EVOLUTION BY RESHUFFLING OF EXONS - COMPARISON OF
THE PROTEIN DATA WITH DATA FROM CHROMOSOME EVOLUTION AND SATELLITE DNA
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XXX TABLE OF CONTENTS
7.2.4 RESTRICTION FRAGMENT LENGTH POLYMORPHISMS (RFLPS) AND EVOLUTION
528
ORIGIN OF VARIOUS CODING GENES IDENTICAL IN REPETITIVE OLIGOMER SE-
QUENCES?
7.2.5 BEHAVIOR 528
MAN THE TOOLMAKER - SOCIAL STRUCTURE OF EARLY PREHUMAN AND HUMAN GROUPS
- PRECURSORS OF LANGUAGE AND CULTURAL TRADITION IN APES AND MONKEYS -
BEHAVIORAL CHARACTERISTICS OF HUMANS IN COMMON WITH OTHER SPECIES -
HUMAN SOCIOBIOLOGY
7.2.6 INVESTIGATION OF CURRENT PRIMITIVE POPULATIONS 531
PROBLEMS FOR WHICH PRIMITIVE POPULATIONS COULD PROVIDE EVIDENCE - POP-
ULATIONS IN WHICH THESE PROBLEMS HAVE BEEN INVESTIGATED - SIZE OF POPU-
LATION GROUPS AND ISOLATION - POPULATION CONTROL - NATURAL SELECTION DUE
TO DIFFERENTIAL FERTILITY - BALANCE BY DISEASE - CAN THESE OBSERVATIONS
ON A FEW INDIAN TRIBES BE GENERALIZED? - RELAXATION OF SELECTION
7.3 GENETICS OF G R O UP DIFFERENCES WITHIN THE H U M AN SPECIES 534
7.3.1 RACES 534
RACE CLASSIFICATION - GENETIC DIFFERENCES BETWEEN RACES - HOW DID THE
GENETIC RACE DIFFERENCES EVOLVE? - GENETIC DIFFERENCES THAT CAN BE EX-
PLAINED BY SPECIFIC SELECTIVE MECHANISMS: SKIN PIGMENTATION AND ULTRA-
VIOLET LIGHT - FREQUENCY OF THE FY ALLELE IN BLACKS - LACTOSE
ABSORPTION
AND MALABSORPTION - LACTOSE MALABSORPTION - WHAT IS NORMAL? WHAT IS
ABNORMAL? - ENZYME INDUCTION OR GENETIC VARIABILITY? - MULTIPLE ALLEL-
ISM? - GENETIC MECHANISM - NATURAL SELECTION - VITAMIN D AND GC SE- RUM
GROUPS - POSSIBLE SELECTIVE MECHANISMS FOR OTHER RACIAL CHARACTER-
ISTICS
7.3.2 FUTURE OF H U M AN RACES: RACE-CROSSING 540
WILL RACES DISAPPEAR? - INTERRACIAL CROSSES IN HAWAII - SCOPE OF THE
STUDY AND MATERIAL - RESULTS AND INTERPRETATION - QUESTIONS NOT ANSWER-
ED BY THE HAWAII STUDY
8 GENETICS AND HUMAN BEHAVIOR 543
SCOPE AND CONCEPTUAL DIFFICULTIES OF HUMAN BEHAVIOR GENETICS - PRACTI-
CAL DIFFICULTIES - IMPORTANCE OF THE FIELD - PARADIGMS OF MENDEL AND
GAL- TON IN BEHAVIOR GENETICS
8.1 ANIMAL MODELS 544
8.1.1 RESEARCH IN INSECTS 544
DIALECTS IN THE LANGUAGE OF BEES - AMERICAN FOUL BROOD: A PROBLEM OF
HIVE HYGIENE - GENETIC DISSECTION OF BEHAVIOR IN DROSOPHILA - MOUSE
MUTANTS AFFECTING EMBRYONIC DEVELOPMENT OF THE BRAIN - WHAT CAN WE LEARN
FROM DROSOPHILA AND MOUSE EXPERIMENTS FOR GENETIC ANALYSIS OF
HUMAN BEHAVIOR?
8.1.2 BEHAVIORAL GENETIC EXPERIMENTS IN THE MOUSE 548
ONE EXAMPLE FOR A SINGLE-GENE ABNORMALITY: THE OBESE MOUSE. INFER- ENCES
TO HUMAN OBESITY - GENETIC DIFFERENCES IN ALCOHOL UPTAKE - EMO-
TIONALITY IN RATS AND ALCOHOL - LEARNING ABILITY - 1. SIMPLE MODE OF
INHERITANCE FOR CONDITIONED AVOIDANCE LEARNING - 2. HEREDITY AND ENVI-
RONMENT IN MAZE LEARNING - 3. PSYCHOSEXUAL BEHAVIOR ALSO HAS TO BE
LEARNED - ATTEMPTS AT ELUCIDATING THE BIOLOGIC MECHANISMS OF BEHAVIOR
DIFFERENCES - POSSIBLE SIGNIFICANCE OF EXPERIMENTS WITH MICE AND OTHER
MAMMALS FOR BEHAVIORAL GENETIC ANALYSIS IN HUMANS
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TABLE OF CONTENTS XXXI
8.2 BEHAVIORAL GENETICS IN HUMANS 552
NORMAL AND ABNORMAL BEHAVIOR - OBSERVATION AND MEASUREMENT OF HU- MAN
BEHAVIOR
8.2.1 INVESTIGATIONS WITH CLASSIC PHENOMENOLOGIC METHODS 553
8.2.1.1 REAPPRAISAL OF CLASSIC METHODS 553
FAMILY INVESTIGATIONS - TWIN METHOD - MZ TWINS REARED APART: STUDIES ON
ADOPTED AND FOSTER CHILDREN
8.2.1.2 MENTAL RETARDATION AND DEFICIENCY 554
DEFINITION - INCIDENCE OF MENTAL SUBNORMALITY - TWO BIOLOGIC GROUPS -
X-LINKED MENTAL RETARDATION - EMPIRICAL RISK FIGURES - TWIN STUDIES
8.2.1.3 INTELLIGENCE AND PERFORMANCE IN THE NORMAL AND SUPERIOR RANGES .
559
SUPERIOR ACHIEVEMENT - VARIABILITY IN THE NORMAL RANGE: NATURE OF INTEL-
LIGENCE - INTELLIGENCE AND INTELLIGENCE TESTING - GROWING UNEASINESS
OVER INTELLIGENCE TESTING AMONG PSYCHOLOGISTS - NEW APPROACHES FOR A
BETTER UNDERSTANDING OF HUMAN INTELLIGENCE - FAMILY AND TWIN STUDIES FOR
AS-
SESSING THE GENETIC CONTRIBUTION TO NORMAL VARIABILITY OF INTELLIGENCE -
SUCCESS IN SCHOOLS - INTELLIGENCE TESTS IN FAMILIES AND TWINS -
HERITABILITY ESTIMATES - TWIN STUDY ON SWEDISH CONSCRIPTS - TWIN
PERFORMANCE ON I.Q. TESTS IS LOWER THAN THAT OF SINGLETONS - MZ TWINS
REARED APART - OVERALL RESULTS OF STUDIES ON MZ PAIRS REARED APART -
STUDIES ON ADOPT-
ED AND FOSTER CHILDREN - WHAT DOES THE AVAILABLE EVIDENCE PROVE RE-
GARDING GENETIC VARIABILITY OF INTELLIGENCE IN THE NORMAL RANGE? - PARA-
DIGM CLASH ALSO IN PSYCHOLOGY - RESEARCH ON I. Q. AND POLITICS
8.2.1.4 SPECIAL COGNITIVE ABILITIES AND PERSONALITY 568
SPECIAL COGNITIVE ABILITIES - INTELLIGENCE IS NOT EVERYTHING - TWIN DATA
FOR TEMPERAMENT, SENSORY AND MOTOR FUNCTIONS, AND PERSONALITY - LONGI-
TUDINAL STUDY OF TWINS - POSSIBLE CONSEQUENCES FOR EDUCATIONAL POLICY -
GENETICS OF SCENT DIFFERENCES ( OLFACTOGENETICS ) - SENSORY HUMAN GE-
NETICS AND BEHAVIOR
8.2.1.5 ABNORMAL AND SOCIALLY DEVIANT BEHAVIOR 571
CRIMINALITY - HOMOSEXUALITY - NEUROSES - THE GENAIN QUADRUPLETS
8.2.2 CHROMOSOME ABERRATIONS AND PSYCHOLOGICAL ABNORMALITIES . . .. 575
HUMAN CHROMOSOME ABERRATIONS AND BEHAVIOR: POSSIBILITIES AND LIMITA-
TIONS
8.2.2.1 AUTOSOMAL ABERRATIONS 576
DOWN S SYNDROME - SOCIAL PROBLEMS
8.2.2.2 ABERRATIONS OF THE X CHROMOSOME 576
KLINEFELTER S SYNDROME - KLINEFELTER VARIANTS - THERAPY AND PREVENTION -
TURNER S SYNDROME - INTELLIGENCE DEFECT IN TURNER S SYNDROME - TRIPLE-X
SYNDROME - EEG ABNORMALITIES
8.2.2.3 X Y Y S Y N D R O ME 579
SOMATIC SYMPTOMS - HIGHER PREVALENCE AMONG CRIMINALS - INTELLECTUAL
DYSFUNCTION OR SIMPLY STATURE? - STUDIES ON UNBIASED SAMPLES - RESULTS
OF THE STUDY - SOCIAL AND THERAPEUTIC CONSEQUENCES - WHAT CAN WE LEARN
FROM THE X YY STORY ABOUT THE ATTITUDE OF SCIENTISTS IN THE FACE OF A
PROBLEM OF GREAT PUBLIC CONCERN? - CHROMOSOME ABERRATIONS AND BE-
HAVIOR: SOME GENERAL CONCLUSIONS - BRAIN MORPHOLOGY IN CHROMOSOMAL
ABERRATIONS
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XXXII TABLE OF CONTENTS
8.2.3 SUGGESTED NEW APPROACHES TO H U M AN BEHAVIOR GENETICS 584
8.2.3.1 GENETIC VARIABILITY THAT COULD INFLUENCE H U M AN BEHAVIOR . .
.. 584
GENERAL METABOLISM - VARIABILITY OF HORMONES - GENETIC VARIABILITY
WITHIN THE BRAIN
8.2.3.2 GENETIC VARIABILITY OUTSIDE THE BRAIN THAT INFLUENCES H U M AN
BEHAVIOR 587
ENZYME DEFECTS LEADING TO MENTAL DEFICIENCY - SELF MUTILATING BEHAVIOR
IN THE LESCH-NYHAN SYNDROME: URIC ACID - HETEROZYGOTES OF RECESSIVE
DISORDERS
8.2.3.3 HORMONE ACTION 589
HOW DO HORMONES ACT? - TOMBOYISM IN GIRLS PRENATALLY EXPOSED TO
MASCULINIZING COMPOUNDS - TESTICULAR FEMINIZATION - HOMOSEXUALITY AND
HORMONES
8.2.3.4 BRAIN PHYSIOLOGY: GENETICS OF THE E EG 590
HUMAN EEG - TWIN STUDIES - FAMILY STUDIES - SEX DIFFERENCE IN EEG
PATTERNS - HOW IS THE EEG PRODUCED IN THE BRAIN? - INFLUENCES OF
INHERIT- ED EEG VARIATIONS ON PERSONALITY - ASSOCIATION BETWEEN A WAVES
AND SPATIAL ABILITY - AVERAGED EVOKED EEG POTENTIALS
8.2.3.5 GENETIC ASPECTS OF ALCOHOLISM 592
ANIMAL MODELS - STUDIES WITH CLASSIC METHODS: TWIN AND ADOPTION STUDIES
- STUDIES WITH CLASSIC METHODS: FAMILY, TWIN, AND ADOPTION STUDIES -
GENETIC VARIABILITY OF ALCOHOL METABOLISM - REACTION OF THE BRAIN TO
ALCOHOL AS MEASURED BY THE EEG - CAN OUR KNOWLEDGE ON NEU-
ROPHYSIOLOGIC MECHANISMS OF THE EEG EXPLAIN THE DIFFERENTIAL REACTION TO
ALCOHOL?
8.2.3.6 BRAIN PHYSIOLOGY: GENETIC VARIABILITY OF NEUROTRANSMITTERS . .
.. 597
ANALYSIS AT THE BIOCHEMICAL LEVEL IS NEEDED: THE SYNAPSIS - CHEMICAL
TYPES OF NEUROTRANSMITTERS - CATECHOLAMINES - ANIMAL EXPERIMENTS ON
GENETIC VARIABILITY ON CATECHOLAMINE METABOLISM - PSYCHOTROPIC DRUGS
8.2.3.7 AFFECTIVE DISORDERS AND SCHIZOPHRENIA 600
GENETIC INVESTIGATIONS IN AFFECTIVE DISORDERS AND SCHIZOPHRENIA - TWIN
AND FAMILY STUDIES IN AFFECTIVE DISORDERS - BIPOLAR AND UNIPOLAR TYPES:
EMPIRICAL RISK FIGURES - SIMPLE MODES OF INHERITANCE? - TWIN AND FAMI-
LY STUDIES IN SCHIZOPHRENIA - EMPIRICAL RISK FIGURES - ADOPTION STUDIES
IN SCHIZOPHRENIA - BIOLOGIC HYPOTHESES IN SCHIZOPHRENIA - SCHIZOPHRE-
NIA IN THE LIGHT OF HUMAN GENETICS - RESEARCH STRATEGIES FOR FURTHER
ELU- CIDATION OF THE GENETIC BASIS OF SCHIZOPHRENIA - NEUROTRANSMITTER
EN- ZYMES AND GENETIC VARIABILITY OF NORMAL BEHAVIOR - OTHER POSSIBLE
PARAMETERS OF BRAIN BIOCHEMISTRY THAT COULD INFLUENCE BRAIN FUNCTION AND
BEHAVIOR - CRITICAL ASSESSMENT OF THE ATTEMPTS TO RELATE BEHAVIORAL
VARIABILITY TO BIOCHEMICAL DIFFERENCES IN BRAIN FUNCTION
8.2.4 DIFFERENCES IN I. Q. AND ACHIEVEMENT BETWEEN ETHNIC GROUPS . . .
608
GROUP DIFFERENCES IN BEHAVIORAL TRAITS? - INTELLIGENCE AND ACHIEVEMENT
OF ASHKENAZI JEWS - DIFFERENCE IN MEAN I. Q. BETWEEN ETHNIC GROUPS IN
THE UNITED STATES, ESPECIALLY BETWEEN BLACKS AND WHITES - EXPLANATION:
GENETIC OR SOCIOECONOMIC? - IS ALL RESEARCH THAT HAS BEEN DONE IN THIS
FIELD SCIENTIFICALLY AND SOCIALLY WORTHLESS? - IF GENETIC GROUP DIFFER-
ENCES DID, INDEED, EXIST, WOULD THEY SUGGEST ANY CONSEQUENCES IN SO-
CIAL POLICY? - INTERMARRIAGE
IMAGE 23
TABLE OF CONTENTS XXXIII
9 PRACTICAL APPLICATIONS OF HUMAN GENETICS AND THE BIOLOGICAL FUTURE OF
MANKIND 614
9.1 APPLICATIONS OF HUMAN GENETICS 614
9.1.1 GENETIC COUNSELING 614
DIAGNOSIS - RECURRENCE RISKS - COMMUNICATION - CONSANGUINITY - HETER-
OZYGOTE DETECTION - REPRODUCTIVE OPTIONS AND ALTERNATIVES - DETECTION OF
GENETIC DISEASES IN RELATIVES - DIRECTIVE VS NONDIRECTIVE GENETIC COUN-
SELING - ASSESSMENT OF GENETIC COUNSELING AND PSYCHOSOCIAL ASPECTS -
PRENATAL DIAGNOSIS - AMNIOCENTESIS - CHORIONIC VILLUS SAMPLING - ULTRA-
SONOGRAPHY - FETOSCOPY - FETAL BLOOD SAMPLING - MATERNAL BLOOD SAM-
PLING - INDICATIONS FOR PRENATAL DIAGNOSIS
9.1.2 GENETIC SCREENING 626
PHENYLKETONURIA SCREENING: PREVENTION OF MENTAL RATARDATION - SCREENING
MOTHERS-AT-RISK FOR CHROMOSOMAL MALFORMATIONS - SCREENING FOR AUTO-
SOMAL RECESSIVE TRAITS - SCREENING FOR NEURAL TUBE DEFECTS - EXTENSIVE
SCREENING OF ALL NEWBORNS FOR MANY POLYMORPHISMS IN FUTURE TIMES?
9.2 GENETIC MANIPULATION 629
CONSERVATIVE APPROACH: GERMINAL CHOICE - DO WE HAVE TO FACE
LARGE-SCALE ATTEMPTS AT BREEDING HUMAN BEINGS BY SUCH METHODS? -
MOLECULAR BIOLOGY AND SPECULATIONS ON GENETIC MANIPULATION - INDUC- TION
OF SPECIFIC MUTATIONS - GENE TRANSFER AND EXPRESSION IN EUKARYO- TES -
ARTIFICIAL GENES - PROSPECTS OF HUMAN GENE THERAPY - DELIVERY AND
EXPRESSION - SAFETY - GENE TRANSFER INTO OOCYTES OR EARLY ZYGOTES -
THER- APY OF FERTILIZED EGGS IN HUMANS? - PUBLIC REACTION TO NEW
ACHIEVE- MENTS AND PROSPECTS OF MOLECULAR BIOLOGY - FURTHER SPECULATIONS
ON GENE MANIPULATION - THE NEED FOR A DIALOGUE ON ETHICAL TISSUES
9.3 BIOLOGIC FUTURE OF MANKIND 636
HUMAN EVOLUTION IS NOT FINISHED - MAIN FORCES DETERMINING EVOLU- TION -
GENETIC DRIFT - MUTATION - TRENDS IN SPONTANEOUS MUTATIONS RATES:
CHROMOSOME MUTATIONS - GENE MUTATIONS - IONIZING RADIATION AND CHEMICAL
MUTAGENS - SELECTION: DOMINANT AND X-LINKED DISEASES - NAT-
URAL SELECTION: RECESSIVE DISEASES - GRADUAL LOSS OF FUNCTIONS THAT ARE
NOW BEING MAINTAINED BY MULTIFACTORIAL GENETIC SYSTEMS - INCREASE IN THE
NUMBER OF INTELLECTUALLY SUBNORMALS? - A FAVORABLE SELECTIVE TREND:
ABANDONING OF GENETIC ADAPTATIONS WITH OTHERWISE UNFAVORABLE EF-
FECTS - THE HUMAN SPECIES IN THE FUTURE
APPENDIX 1. METHODS FOR THE ESTIMATION OF GENE FREQUENCIES 642
APPENDIX2. TESTING FOR SEGREGATION RATIOS: FREQUENT TRAITS, NO
ASCERTAINMENT BIAS, DOMINANCE 645
APPENDIX 3. FORMULAS AND TABLES FOR THE CORRECTION OF ASCERTAINMENT
BIASES, TESTING AND ESTIMATING OF SEGREGATION RATIOS, OTHER STATISTICAL
PROBLEMS AND A CALCULATED EXAMPLE 648
APPENDIX 4. MULTIFACTORIAL INTERITANCE AND MAJOR GENES 659
APPENDIX 5. DIAGNOSIS OF ZYGOSITY 669
APPENDIX 6. HERITABILITY ESTIMATES FROM TWIN DATA 677
APPENDIX 7. METHOD OF PATH COEFFICIENTS 682
IMAGE 24
XXXIV TABLE OF CONTENTS
APPENDIX 8. GENETIC COUNSELING: USE OF CONDITIONAL PROBABILITIES 685
APPENDIX 9. EXAMPLES FOR LINKAGE CALCULATIONS 692
REFERENCES 711
SUBJECT INDEX 773
|
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| author | Vogel, Friedrich 1925-2006 Motulsky, Arno G. |
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| building | Verbundindex |
| bvnumber | BV001061630 |
| callnumber-first | Q - Science |
| callnumber-label | QH431 |
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| callnumber-sort | QH 3431 |
| callnumber-subject | QH - Natural History and Biology |
| classification_rvk | WG 7000 |
| classification_tum | BIO 950f BIO 750f |
| ctrlnum | (OCoLC)299625961 (DE-599)BVBBV001061630 |
| discipline | Biologie |
| edition | 2., completely rev. ed. |
| format | Book |
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| illustrated | Illustrated |
| indexdate | 2024-07-09T15:23:15Z |
| institution | BVB |
| isbn | 3540164111 0387164111 3540094598 0387094598 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-000642394 |
| oclc_num | 299625961 |
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| physical | XXXIV, 807 S. Ill., graph. Darst. |
| publishDate | 1986 |
| publishDateSearch | 1986 |
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| publisher | Springer |
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| spelling | Vogel, Friedrich 1925-2006 Verfasser (DE-588)120928892 aut Human genetics problems and approaches ; with 217 tables F. Vogel ; A. G. Motulsky 2., completely rev. ed. Berlin [u.a.] Springer 1986 XXXIV, 807 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Literaturverz. S. [711] - 772 Erbkrankheit Humangenetik Humangenetik (DE-588)4072653-8 gnd rswk-swf Erbkrankheit (DE-588)4015106-2 gnd rswk-swf Humangenetik (DE-588)4072653-8 s DE-604 Erbkrankheit (DE-588)4015106-2 s 1\p DE-604 Motulsky, Arno G. Verfasser aut SWB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=000642394&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis 1\p cgwrk 20201028 DE-101 https://d-nb.info/provenance/plan#cgwrk |
| spellingShingle | Vogel, Friedrich 1925-2006 Motulsky, Arno G. Human genetics problems and approaches ; with 217 tables Erbkrankheit Humangenetik Humangenetik (DE-588)4072653-8 gnd Erbkrankheit (DE-588)4015106-2 gnd |
| subject_GND | (DE-588)4072653-8 (DE-588)4015106-2 |
| title | Human genetics problems and approaches ; with 217 tables |
| title_auth | Human genetics problems and approaches ; with 217 tables |
| title_exact_search | Human genetics problems and approaches ; with 217 tables |
| title_full | Human genetics problems and approaches ; with 217 tables F. Vogel ; A. G. Motulsky |
| title_fullStr | Human genetics problems and approaches ; with 217 tables F. Vogel ; A. G. Motulsky |
| title_full_unstemmed | Human genetics problems and approaches ; with 217 tables F. Vogel ; A. G. Motulsky |
| title_short | Human genetics |
| title_sort | human genetics problems and approaches with 217 tables |
| title_sub | problems and approaches ; with 217 tables |
| topic | Erbkrankheit Humangenetik Humangenetik (DE-588)4072653-8 gnd Erbkrankheit (DE-588)4015106-2 gnd |
| topic_facet | Erbkrankheit Humangenetik |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=000642394&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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