Human Molecular Genetics, 2nd Edition

by Tom Strachan (Univ. of Newcastle-upon-Tyne, UK); Andrew P. Read (Univ. of Manchester, UK)

• ISBN13: 9780471330615
• ISBN10: 0471330612
• Edition: 2nd
• Format: Paperback
• Copyright: 1999-01-01
• Publisher: Wiley-Liss

Summary

"The Art of Human Molecular Genetics 3 "CD-ROM contains the complete set of figures from the book for presentation. The figures are available in JPEG and PowerPoint format.

Author Biography

Tom Strachan BSc PhD, FMedSci: Professor of Human Molecular Genetics and Scientific Director, Institute of Human Genetics University of Newcastle, Newcastle-upon-Tyne, UK Andrew P. Read MA PhD FRCPath FMedSci: Professor of Human Genetics University of Manchester, Manchester UK

Table of Contents

Abbreviations	xiii
Preface to the first edition	xv
Preface to the second edition	xvii
Before we start - genetic data and the Internet	xix
All students of human molecular genetics should be using the Internet	xix
The World Wide Web is the primary way of using the Internet	xix
Useful Internet starting points for human molecular genetics	xxi
The World Wide Web gives access to most human genetic data	xxi
Comprehensive DNA and protein sequence databases cover all organisms	xxi
OMIM is the standard database of human mendelian characters	xxi
Medline is the main way to locate published papers on a topic	xxiii
Searching for a web page	xxiii
DNA structure and gene expression	1	(26)
Building blocks and chemical bonds in DNA, RNA and polypeptides	1	(4)
DNA structure and replication	5	(4)
Examples of the importance of hydrogen bonding in nucleic acids and proteins	5	(4)
RNA transcription and gene expression	9	(5)
RNA processing	14	(4)
Translation, post-translational processing and protein structure	18	(9)
Chromosomes in cells	27	(28)
Organization and diversity of cells	27	(3)
Anatomy of animal cells	29	(1)
Development	30	(4)
A brief outline of animal development	31	(1)
The diversity of human cells	32	(2)
Structure and function of chromosomes	34	(4)
Mitosis and meiosis are the two types of cell division	38	(5)
Studying human chromosomes	43	(4)
Chromosome banding	44	(1)
Chromosome nomenclature	45	(2)
Chromosome abnormalities	47	(8)
Nomenclature of chromosome abnormalities	47	(8)
Genes in pedigrees	55	(16)
Mendelian pedigree patterns	55	(5)
Mendelian pedigree patterns	57	(1)
The complementation test to discover whether two recessive characters are determined by allelic genes	58	(2)
Complications to the basic pedigree patterns	60	(4)
Factors affecting gene frequencies	64	(3)
Hardy-Weinberg equilibrium genotype frequencies for allele frequencies p (A1) and q (A2)	65	(1)
The Hardy-Weinberg distribution can be used (with caution) to calculate carrier frequencies and simple risks for counseling	66	(1)
Mutation-selection equilibrium	66	(1)
Selection in favor of heterozygotes for cystic fibrosis	67	(1)
Nonmendelian characters	67	(4)
Cell-based DNA cloning	71	(24)
Fundamentals of DNA technology and the importance of DNA cloning	71	(1)
Principles of cell-based DNA cloning	72	(10)
Restriction endonucleases and modification-restriction systems	75	(7)
Oligonucleotide linkers	82	(1)
Nonsense suppressor mutations	82	(1)
Vector systems for cloning different sizes of DNA fragments	82	(6)
Cloning systems for preparing single-stranded DNA and for studying gene expression	88	(7)
Nucleic acid hybridization assays	95	(24)
Preparation of nucleic acid probes	95	(5)
Principles of autoradiography	100	(1)
Principles of nucleic acid hybridization	100	(6)
Fluorescence labeling and detection systems	102	(4)
Competition hybridization and Cot-1 DNA	106	(1)
Nucleic acid hybridization assays using cloned DNA probes to screen uncloned nucleic acid populations	106	(8)
Standard and reverse nucleic acid hybridization assays	107	(7)
Nucleic acid hybridization assays using cloned target DNA, and microarray hybridization technology	114	(5)
Evolution and applications of DNA microarrays (`DNA chips')	117	(2)
PCR, DNA sequencing and in vitro mutagenesis	119	(20)
Basic features of PCR	119	(4)
Proofreading by DNA polymerase-associated 3' ⇒ 5' exonuclease activity	122	(1)
Applications of PCR	123	(6)
DNA sequencing	129	(6)
In vitro site-specific mutagenesis	135	(4)
Organization of the human genome	139	(30)
General organization of the human genome	139	(5)
The limited autonomy of the mitochondrial genome	141	(3)
Organization and distribution of human genes	144	(7)
Human gene organization	150	(1)
Human multigene families and repetitive coding DNA	151	(8)
Pseudogenes and gene fragments	157	(2)
Extragenic repeated DNA sequences and transposable elements	159	(10)
Classes of mammalian sequence which undergo transposition through an RNA intermediate	165	(4)
Human gene expression	169	(40)
An overview of gene expression in human cells	169	(1)
Spatial and temporal restriction of gene expression in mammalian cells	170	(1)
Control of gene expression by binding of trans-acting protein factors to cis-acting regulatory sequences in DNA and RNA	170	(13)
Classes of cis-acting sequence elements involved in regulating transcription of polypeptide-encoding genes	174	(9)
Alternative transcription and processing of individual genes	183	(5)
The classical view of a gene is no longer valid	185	(1)
Alternative splicing can alter the functional properties of a protein	186	(2)
Asymmetry as a means of establishing differential gene expression and DNA methylation as means of perpetuating differential expression	188	(6)
CpG islands	190	(4)
Long-range control of gene expression and imprinting	194	(7)
Mechanisms resulting in monoallelic expression from biallelic genes in human (mammalian) cells	196	(1)
The nonequivalence of the maternal and paternal genomes	197	(4)
The unique organization and expression of Ig and TCR genes	201	(8)
Instability of the human genome: mutation and DNA repair	209	(32)
An overview of mutation, polymorphism, and DNA repair	209	(1)
Simple mutations	210	(7)
Mechanisms which affect the population frequency of alleles	212	(1)
Classes of single base substitution in polypeptide-encoding DNA	213	(4)
Genetic mechanisms which result in sequence exchanges between repeats	217	(5)
Pathogenic mutations	222	(5)
How are new mitochondrial mutations fixed (i.e. achieve a frequency of 100% in a population)?	224	(3)
The pathogenic potential of repeated sequences	227	(8)
DNA repair	235	(6)
Physical and transcript mapping	241	(28)
Low resolution physical mapping	241	(7)
Selecting for the chromosome contents of hybrids	242	(5)
Chromosome painting	247	(1)
High resolution physical mapping: chromatin and DNA fiber FISH and restriction mapping	248	(4)
Assembly of clone contigs	252	(8)
The importance of sequence tagged sites (STSs)	259	(1)
Constructing transcript maps and identifying genes in cloned DNA	260	(9)
Commonly used methods for identifying genes in cloned DNA	261	(8)
Genetic mapping of mendelian characters	269	(14)
Recombinants and nonrecombinants	269	(2)
Genetic markers	271	(3)
The development of human genetic markers	273	(1)
Informative and uninformative meioses	274	(1)
Two-point mapping	274	(3)
Calculation of lod scores	276	(1)
Bayesian calculation of linkage threshold	277	(1)
Multipoint mapping is more efficient than two-point mapping	277	(2)
Standard lod score analysis is not without problems	279	(4)
Genetic mapping of complex characters	283	(12)
Parametric linkage analysis and complex diseases	283	(1)
Nonparametric linkage analysis does not require a genetic model	284	(2)
Association is in principle quite distinct from linkage, but where the family and the population merge, linkage and association merge	286	(2)
The transmission disequilibrium test (TDT)	288	(1)
Linkage disequilibrium as a mapping tool	288	(2)
Thresholds of significance are an important consideration in analysis of complex diseases	290	(3)
Sample sizes needed to find a disease susceptibility locus by a whole genome scan using either affected sib pairs (ASP) or the transmission disequilibrium test (TDT)	292	(1)
Strategies for complex disease mapping usually involve a combination of linkage and association techniques	293	(2)
Genome projects	295	(20)
The history, organization, goals and value of the Human Genome Project	295	(2)
Genetic and physical mapping of the human genome	297	(10)
Human gene and DNA segment nomenclature	299	(7)
Cooperation, competition and controversy in the genome projects	306	(1)
Model organism and other genome projects	307	(3)
Model organisms for which genome projects are considered particularly relevant to the Human Genome Project	308	(2)
Life in the post-genome (sequencing) era	310	(5)
Our place in the tree of life	315	(36)
Evolution of the mitochondrial genome and the origin of eukaryotic cells	315	(3)
The three kingdoms of life	317	(1)
Evolution of the eukaryotic nuclear genome: genome duplication and large-scale chromosomal alterations	318	(4)
Paralogy, orthology and homology	320	(2)
Evolution of the human sex chromosomes	322	(7)
Evolution of human DNA sequence families and DNA organization	329	(5)
Evolution of gene structure	334	(3)
Intron groups and intron phases	336	(1)
What makes us human? Comparative mammalian genome organization and the evolution of modern humans	337	(14)
Identifying human disease genes	351	(26)
Principles and strategies in identifying disease genes	351	(1)
Position-independent strategies for identifying disease genes	351	(5)
In positional cloning, disease genes are identified using only knowledge of their approximate chromosomal location	356	(10)
Transcript mapping: how to identify expressed sequences within genomic clones from a candidate region	358	(2)
Pointers to the presence of large-scale mutations	360	(1)
Position effects - a pitfall in disease gene identification	360	(6)
Positional candidate strategies identify candidate genes by a combination of their map position and expression, function or homology	366	(6)
Mapping mouse genes	369	(3)
Confirming a candidate gene	372	(5)
Molecular pathology	377	(24)
Introduction	377	(1)
The main classes of mutation	377	(1)
There are rules for the nomenclature of mutations and databases of mutations	377	(1)
A nomenclature for describing the effect of an allele	378	(1)
Nomenclature for describing mutations	378	(1)
A first classification of mutations is into loss of function vs gain of function mutations	378	(2)
Loss of function mutations	380	(5)
Guidelines for deciding whether a DNA sequence change is pathogenic	380	(2)
Hemoglobinopathies	382	(1)
Molecular pathology of Prader-Willi and Angelman syndromes	383	(2)
Gain of function mutations	385	(4)
Unstable expanding repeats - a novel cause of disease	386	(2)
Laboratory diagnosis of fragile X	388	(1)
Molecular pathology: from gene to disease	389	(4)
Molecular pathology: from disease to gene	393	(2)
Molecular pathology of chromosomal disorders	395	(6)
Genetic testing in individuals and populations	401	(26)
Direct testing is like any other path lab investigation: a sample from the patient is tested to see if it is normal or abnormal	401	(14)
Gene tracking	415	(3)
Gene tracking: four stages in the investigation of a late-onset autosomal dominant disease where direct mutation detection is not possible	416	(2)
Use of Bayes' theorem for combining probabilities	418	(1)
Population screening	418	(4)
DNA profiling can be used for identifying individuals and determining relationships	422	(5)
Cancer genetics	427	(18)
Cancer is the natural end-state of multicellular organisms	427	(1)
Mutations in cancer cells typically affect a limited number of pathways	427	(1)
Two ways of making a series of successive mutations more likely	427	(1)
Oncogenes	428	(2)
Activation of proto-oncogenes	430	(4)
Tumor suppressor genes	434	(4)
Two-hit mechanisms may explain patchy mendelian phenotypes	436	(2)
Control of the cell cycle	438	(2)
Control of the integrity of the genome	440	(2)
The multistep evolution of cancer	442	(3)
Complex diseases: theory and results	445	(20)
Deciding whether a nonmendelian character is genetic: the role of family, twin and adoption studies	445	(2)
Genetic differences between identical twins	446	(1)
Polygenic theory of quantitative traits	447	(3)
Two common misconceptions about regression to the mean	448	(2)
Partitioning of variance	450	(1)
Polygenic theory of discontinuous characters	450	(2)
Segregation analysis allows analysis of characters that are anywhere on the spectrum between purely mendelian and purely polygenic	452	(3)
Correcting the segregation ratio	453	(2)
Seven examples illustrate the varying success of genetic dissection of complex diseases	455	(6)
Applications of genetic insights into complex diseases	461	(4)
Studying human gene structure, expression and function using cultured cells and cell extracts	465	(26)
Gene structure and transcript mapping studies	465	(6)
Obtaining gene clones for studying human gene structure, expression and function	466	(5)
Studying gene expression using cultured cells or cell extracts	471	(9)
Obtaining antibodies	478	(2)
Confocal fluorescence microscopy	480	(1)
Identifying regulatory sequences through the use of reporter genes and DNA-protein interactions	480	(5)
Methods for transferring genes into cultured animal cells	481	(4)
Investigating gene function by identifying interactions between a protein and other macromolecules	485	(6)
Genetic manipulation of animals	491	(24)
An overview of genetic manipulation of animals	491	(1)
The creation and applications of transgenic animals	492	(5)
Isolation and manipulation of mammalian embryonic stem cells	495	(2)
Use of mouse embryonic stem cells in gene targeting and gene trapping	497	(5)
Creating animal models of disease using transgenic technology and gene targeting	502	(6)
The potential of animals for modeling human disease	505	(3)
Manipulating animals by somatic cell nuclear transfer	508	(7)
Gene therapy and other molecular genetic-based therapeutic approaches	515	(30)
Principles of molecular genetic-based therapies and treatment with recombinant proteins or genetically engineered vaccines	515	(5)
General gene therapy strategies	516	(2)
Treatment using conventional animal or human products can be hazardous	518	(2)
The technology of classical gene therapy	520	(6)
Cell therapy	521	(5)
Therapeutics based on targeted inhibition of gene expression and mutation correction in vivo	526	(4)
Gene therapy for inherited disorders	530	(5)
Gene therapy for neoplastic disorders and infectious disease	535	(4)
The ethics of human gene therapy	539	(6)
Glossary	545	(12)
Indexes	557