Gustavo Maroni
Department of Biology
University of North Carolina
Chapel Hill, North Carolina
 
 
 
 
 
 
 
©2001 by Blackwell Science, Inc.
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Detecting Mendelian Inheritance in Humans
Test-Crosses and Pure Lines versus Pedigrees and Inferred Genotypes
Patterns of Inheritance and Examples
Autosomal Dominant Traits
Autosomal Recessive Traits
X-Linked Recessive Traits
The Use of Pedigrees to Predict the Results of Matings
Probability of Individual Genotypes
Probability of Group Outcomes
Gathering Data to Test the Mode of Inheritance of a Trait
Pooling Data from Many Families
Ascertainment errors in studies of dominant traits
Ascertainment errors in studies of recessive traits
Inheritance of Multiple Traits: Independent Assortment and Linkage
Determination of Linkage from Human Pedigrees
Genetic Recombination and LOD Scores
Informative and Non-informative Matings
Neutral Polymorphisms, Marker Loci, and Genetic Maps
The use of protein products to define marker loci
The use of directly detected DNA differences as marker loci
Conclusion
Box 1.1. Early observations of Mendelian inheritance in humans
Box 1.2. Internet sites
Example 1.1. Linkage of the Huntington's disease gene to an RFLP
 

Single-Gene Traits Lacking a Simple Mendelian Pattern
Variable Expressivity and Incomplete Penetrance
Complementation
Phenocopies and Pleiotropy
Quantitative Traits
Multiple Alleles
Polygenic Inheritance
Major and Minor Genes
Complex Traits
Epidemiological Analysis of Complex Traits
Liability
Family Clustering
Identical Twins
Localization of Genes Responsible for Complex and Quantitative Traits
Linkage Analysis of Complex Traits
Affected Pedigree Member (APM) or Allele-Sharing Methods
Analysis of quantitative trait loci by allele-sharing methods
Allelic Association
Candidate Gene
Conclusion: Nature versus Nurture
Example 2.1. Familial psoriasis
Example 2.2. Familial breast cancer
Example 2.3. Insulin-dependent diabetes mellitus
Example 2.4. Male homosexuality
Example 2.5. Dyslexia
Example 2.6. Nonsyndromal autosomal recessive deafness
Example 2.7. Neuroticism and genes for serotonin metabolism

Unexpressed DNA, Repetitive and Unique Sequences
Clustered, Highly Repetitive Sequences
The main families of highly repetitive sequences
Small-Cluster, Intermediately Repeated DNA
Dispersed, Intermediately Repeated Sequences
Viral retrotransposons
Nonviral retrotransposons: Alu, L1, and processed pseudogenes
Unique Sequence DNA
Expressed DNA, Genes and Gene Families
The Organization of RNA Polymerase II Genes: Introns and Exons
Gene Families
Ribosomal RNA Genes
Conclusion
Box 3.1. Internet sites
Example 3.1. The a family of highly repetitive DNA
Example 3.2. Collagen
Example 3.3. Cystic fibrosis
Example 3.4. Duchenne muscular dystrophy
Example 3.5. The globin gene family
Example 3.6. The retinal visual pigments

Isolation and Characterization of Human Genes
Expression Cloning
Oligonucleotide probes
Libraries in expression vectors
Functional assays
Differential colony or plaque hybridization (+/- hybridization)
Cloning by Homology to Other Species
Reverse Genetics
Positional Cloning
Chromosome walking and jumping
Heterologous hybridization
Chromosomal rearrangements
CpG islands
Open reading frames
Hybridization to mRNA
Exon amplification
Mutant DNA sequence
Candidate gene
The Human Genome Project
The Genetic Map
Physical Maps
Restriction maps
Pulsed-field gel electrophoresis and restriction enzymes with infrequent
restriction sites (rare-cutters)
Contigs
Fluorescence in situ hybridization
Radiation hybrid mapping
Other Tools
The Sequence-Tagged Site (STS) Proposal
Advances in the Human Genome Project
Identification and localization of genes
Genome sequencing
Directed sequencing
Random (shotgun) sequencing
Conclusion: The End in Sight
Box 4.1. Ethical concerns
Box 4.2. You're going to patent my genes?!
Box 4.3. Internet sites
Example 4.1. Isolation and characterization of a cDNA coding for human factor IX
Example 4.2. Isolation of cDNA clones for human von Willebrand factor
Example 4.3. Cloning of a mammalian proton-coupled metal-ion transporter
Example 4.4. Cloning of gene sequences regulated by platelet-derived growth factor
Example 4.5. The cystic fibrosis gene
Example 4.6. Cloning the Huntington's disease gene (HDH)
Example 4.7. Microsatellite DNA
Example 4.8. Contig of chromosome 21q
Example 4.9. Sequence of chromosome 22

Chapter 5 Chromosomes and Karyotypes

The Morphology of Human Chromosomes
Banding Techniques
Chromosomal Abnormalities
Abnormal Chromosome Numbers
Polyploidy
Aneuploidy
Abnormal Chromosome Structure
Deletions and duplications
Inversions
Translocations
Robertsonian translocations
The Use of FISH to Identify Chromosomal Rearrangements
Sex Chromosomes
The Y-Chromosome
The X-Chromosome and Dosage Compensation
The expression of X-linked genes in heterozygotes
Identification of the inactive X
X-inactivation center (XIC)
X-autosome translocations
The Use of Cytogenetics to Localize Genes
Somatic Cell Genetics
Conclusion
Example 5.1. Aneuploidy in a family with a reciprocal translocation
Example 5.2. Discordant monozygotic twins

Effects of Mutations on the Quality and Quantity of Protein Products
Mutations in the Coding Region
Mutations outside the Coding Region
Loss-of-Function Mutations
Gain-of-Function Mutations
Mutations in Soluble Enzymes
Electrophoretic Variants
Mutations with Complete or Partial Loss of Enzyme Activity
Gain-of-Function Mutations in Enzymes
Mutations in Structural Proteins
Mutations in Transport Proteins
Mutations in Regulatory Proteins
Conclusion
Box 6.1. Internet sites
Example 6.1. Phenylketonuria
Example 6.2. Galactosemia
Example 6.3. Porphyrias
Example 6.4. Familial amyotrophic lateral sclerosis
Example 6.5. Osteogenesis imperfecta
Example 6.6. Muscular dystrophies
Example 6.7. Hemoglobin
Example 6.8. Cystic fibrosis transmembrane conductance regulator (CFTR)

Endogenous (or Spontaneous) DNA Damage
Instability of the DNA molecule
Tautomeric shifts
Deamination
Oxidation and methylation of bases
Loss of bases
Errors in Replication
Strand slippage
Trinucleotide repeat diseases
Errors in Recombination
Insertional Mutagenesis
Exogenous (or Environmental) DNA Damage
Ionizing Radiation
Ultraviolet Radiation
Chemical Agents
Alkylating agents
Cross-linking agents and bulky adducts
Inactive chemicals metabolized to reactive mutagens
DNA Repair Systems
Reversal of Damage
Base Excision Repair
Nucleotide Excision Repair
Mismatch Repair
Other Repair Processes
Mutation Rates
Somatic Mutations and Mosaicism
Conclusion
Example 7.1. Deamination of cytosine and 5-methylcytosine
Example 7.2. Huntington's disease
Example 7.3. Fragile X mental retardation
Example 7.4. Xeroderma pigmentosum and nucleotide excision repair
Example 7.5. Epidermolytic hyperkeratosis and keratins K1 and K10
Example 7.6. Transmission of fragile X mutation
Example 7.7. Germline mosaicism in a case of Duchenne muscular dystrophy

The Cell Cycle under Control
Nuclear Events
The Cytoplasm: Receiving and Transducing Signals
Cancer Cells
Progression from Normal Cells to Cancer
Cells in Culture
Oncogenes
Growth Factors and Their Receptors as Oncogenic Proteins
Ras and the MAP Kinase Cascade
Nuclear Oncogenes
Suppression of Apoptosis
Tumor Suppressor Genes
Retinoblastoma
p53
HNPCC Family of Mismatch Repair Genes
BRCA1 and BRCA2
Gatekeepers and Caretakers
Mutations and Other Changes That Alter the Function of Cancer Genes
Epigenetic Changes-Altered Chromatin Methylation
Point Mutations
Chromosomal Rearrangements
Activation of proto-oncogenes by translocations
Chimaeric proteins
Gene Amplification
Viruses
Small DNA tumor viruses
Retroviruses
Genetic Instability
Invasiveness
Cellular Immortality and Telomeres
Conclusion
Box 8.1. Internet sites

Prenatal, Neonatal, Childhood, and Adult Genetic Testing
Prenatal Genetic Testing
Neonatal and Childhood Genetic Testing
Adult Genetic Testing
Actual Risk and Perceived Risk
Box 9.1. Case 1: Knowing too much
Box 9.2. Case 2: Disagreement between spouses
Box 9.3. Case 3: Sharing information with adult offspring
Box 9.4. Case 4: When ignorance is not bliss
Box 9.5. Case 5: Similar situations, different courses
Example 9.1. Phenylketonuria

Appendix

One factor crosses
Independent assortment in two-factor crosses
Linkage in two-factor crosses
Synthesis and maturation of messenger RNA
Table of codons and the amino acids
Analyzing DNA with restriction enzymes and gel electrophoresis
cDNA libraries
Genomic libraries
The polymerase chain reaction (PCR)

The goal of this book is to present human genetics as a distinct and coherent field of study. Human genetics has become a discipline not just because the subject of analysis is special, but also-and more importantly-because methods have been developed that are either unique or very specially applied to the study of humans. We could define the broad aim of this discipline, at its current stage, as the characterization of the molecular basis of what we are, of our traits. A precondition of this characterization is, naturally, establishing which traits are genetically determined and which are not. This is one of the primary specific objectives of human genetics.
To appreciate the uniqueness of the subject matter it is necessary to get past the elementary aspects of the study of heredity, those that are better illustrated by examples from model organisms. Thus, this book is aimed at undergraduates and graduate students who have had the equivalent of a one-semester introduction to general genetics. It assumes familiarity with meiosis and Mendelian genetics as well as the basic principles of transmission of information from DNA to RNA to proteins. For those topics deemed most likely in need of reviewing, a series of summary diagrams is provided in the appendix.
The foregoing description applies to the first seven chapters of the book. The last two chapters could be considered applications of human genetics to two very diverse situations: the understanding of cancer, and the use of genetic predictions to counsel families at risk of genetic disease.
The selection of examples throughout the text was driven by two principles. The first is that advances in the field are such that we are long past the point where it would be either possible or desirable to present all the "interesting" cases in which genetics plays a role in human affairs. The second guiding principle is that the organization of this book follows the logic of concepts, rather than that of case studies. Examples, therefore, were chosen to illustrate specific methods or principles under discussion, and for this reason certain genes or genetic diseases may appear in various places in the book. No effort was made to tell "the whole story" about any given trait because this was thought to be distracting from the main effort of conveying the idea of human genetics as more than a collection of genetic diseases.
Illustrations are, to a large extent, taken from or based on the original literature. In these cases figures are visual pedagogical devices, and are used to present data that support contentions made in the text. The end-of-chapter questions reinforce this use of figures by asking the reader to extract information that was intentionally left out of the text.