Medical Genetics at a Glance

116 Pages·2009·12.39 MB·English

Medical Genetics at a Glance
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First published 2003
Reprinted 2005, 2006
Library of Congress Cataloging-in-Publication Data
Pritchard. D. J. (Dorian J.)
Medical genetics at a glance / Dorian Pritchard, Bruce R. Korf.
p. ; m.
Includes bibliographical references and index.
ISBN 0-632-06372-6
1. Medical genetics. 2. Genetics. 3. Developmental biology.
[DNLM: 1. Genetics, Medical. 2. Genetics. QZ 50 P961m 2002]
I. Korf, Bruce R. II. Title.
RBI55 .P6965 2002
616'.042—dc21
2002009523
ISBN 13: 978-0-632-06372-7
ISBN 10: 0-632-06372-6
A catalogue record for this title is available from the British Library
Set in 9/11.5 pt Times by SNP Best-set Typesetter Ltd, Hong Kong
Printed and bound by Replika Press Pvt. Ltd, India
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Medical Genetic s
at a Glance
DORIAN J . PRITCHARD
BSc, Dip Gen, PhD, CBiol, MIBiol
Lecturer in Human Genetics (retired)
University of Newcastle-upon-Tyne
UK
Visiting Lecturer in Medical Genetics
International Medical University
Kuala Lumpur
Malaysia
BRUCE R . KORF
MD, PhD
Wayne H. and Sara Crewes Finley Professor of Genetics
Chairman of Department of Genetics
University of Alabama
Birmingham
Alabama
USA
Blackwell
Science
Contents
Preface 6 26 Allel e frequency 5 8
Acknowledgements 7 27 Geneti c linkage and disease association 60
28 Gen e mapping 6 2
29 Mutagenesi s and DNA repair 6 4
Part I Developmenta l biology 30 Mutation s 66
1 Basi c biology 8 31 Th e molecular biology of cancer 6 8
2 Th e cell 10 32 Familia l cancers 7 0
3 Th e chromosomes 1 2 33 Immunogenetic s 7 2
4 D N A structure 14
5 D N A replication 1 6 Part III Clinica l applications of genetics
6 R N A structure 18 34 Clinica l applications of genetics: an overview 7 4
7 Productio n of messenger RNA 20 35 Pedigre e drawing 76
8 Protei n synthesis 22 36 Ris k assessment 7 8
9 Th e cell cycle 24 37 Dysmorpholog y 8 0
10 Gametogenesi s 2 6 38 Chromosom e analysis 82
11 Embryolog y 2 8 39 Biochemica l diagnosis 84
12 Sexua l differentiation 3 0 40 Reproductiv e genetic counselling 8 6
41 Prenata l sampling 8 8
Part II Medica l genetics 42 Linkag e analysis 90
13 Th e place of genetics in medicine 3 2 43 DN A sequencing 9 2
14 Chromosoma l aneuploidies 34 44 Souther n blotting 9 4
15 Chromosom e structural abnormalities 36 45 Th e polymerase chain reaction 9 6
16 Mendel' s laws 38 46 DN A profiling 9 8
17 Autosoma l dominant inheritance 4 0 47 Avoidanc e and prevention of disease 100
18 Autosoma l recessive inheritance 42 48 Th e management of genetic disease 102
19 Intermediat e inheritance 44
20 Sex-relate d inheritance 46 Glossary 10 4
21 Congenita l abnormalities 48 Appendix: Informatio n resources 10 7
22 Multifactoria l threshold traits 5 0 Index 10 9
23 Th e common disorders of adult life 5 2
24 Twi n studies 54
25 Norma l polymorphism 56
5
Preface
This book is written primarily for medical students seeking a summary in three parts, which can be taken together as a single course, or sepa-
of genetics and its medical applications, but it should be of value also to rately a s components o f severa l courses . Chapter s are , however ,
advanced students in the biosciences, paramedica l scientists , estab - intended to be read in essentially the order of presentation, as concepts
lished medical doctors and health professionals who need to extend or and specialized vocabulary are developed progressively.
update their knowledge. It should be of especial value to those prepar- There are many excellent introductory textbooks in our subject, but
ing for examinations. none, so far as we know, is at the same time so comprehensive and so
Medical genetics is unusual in that, whereas its fundamentals usually succinct. We believe the relative depth of treatment of topics appropri-
form part of first-year medical teaching within basic biology, those ately reflects the importance of these matters in current thinking.
aspects that relate to inheritance may be presented as an aspect of repro-
ductive biology. Clinical issues usually form a part of later instruction, Dorian Pritchard
extending into the postgraduate years. This book is therefore presented Bruce Korf
6
Acknowledgements
We thank thousands of students, for the motivation they provided by Principles of Medical Genetics, 2nd edn, p.4. Lippincott, Williams and
their enthusiastic reception of the lectures on which these chapters are Wilkins, Philadelphia.
based. We appreciate also the interest and support of many colleagues,
but special mention should be made of the constructive criticisms of 22 Multifactorial threshold traits
Paul Brennan. DP wishes to pay tribute to the memory of Ian Cross for Figure 22 (The threshold model applied to creation of cleft palate):
his friendship and professional support over many years and for his Fraser FC (1977) Relation of animal studies to the problem in man. In:
advice on the chapters dealing with cytogenetics. We thank the staff of Wilson JG & Clarke-Fraser F (eds) Handbook of Teratology, vol. 1, pp.
Blackwell Publishing fo r their encouragement an d tactful guidanc e 75-96. Plenum Press, New York.
throughout the production of this book.
26 Allele frequency
Figure acknowledgements Figure 26: Bodmer WF & Cavalli-Sforza LL (1976) Genetics, Evolu-
8 Protein synthesis tion and Man. WH Freeman, New York.
Figure 8: Pritchard DJ (1986) Foundations of Developmental Genetics,
p. 157. Taylor & Francis, London.
13 The place of genetics in medicine
Figure 13 (Expression of the major categories of genetic disease in rela-
tion to development): Gelehrter TD, Collins FS & Ginsburg D (1998)
7
1 Basi c biology
Control points for gene expression within the cell
The case for genetics nomics involves the genetic engineering of pharmaceuticals. Human
Medicine is currently in a state of transformation, created by the con- genes, such as those for insulin and interferon are introduced into
vergence of two major aspects of technological advance. The first is microorganisms, field crops and farm animals and these species used as
the explosion in information technology and the second, the rapidly living factories for production of the human proteins. Genomics is also
expanding science of genetics. The likely outcome is that within the leading to the elucidation of molecular pathways of disease and the
foreseeable future we will see the introduction of a new kind of medi- ability to design drugs to target specific steps in these pathways.
cine, individualized medicine, tailored uniquely to the personal needs In research into human diseases, disease analogues can be created
of each patient. in laboratory animals by targeted deletion of genes of interest. This
Clinicians currently use family histories and genetic testing to iden- approach has been used to create animal models for a wide variety of
tify patients for further evaluation and for guidance on their manage- diseases such as cystic fibrosis and neurofibromatosis.
ment. Recognition o f the precise (molecular) natur e of a disorder Some of these topics are outside the scope of this book, but the reader
enables correct interpretation of ambiguous symptoms. Some diseases, should have no doubt that the medicine of the future, the medicine he or
such as hypertension (hig h blood pressure), have many causes, for she will practice, will rely very heavily on the insights provided by
which a variety of treatments may be possible. Identification of precise genetics.
cause would allow clinicians to give personal guidance on the avoid-
ance of adverse stimuli and enable precise targeting of the disease with Overview of Part I
personally appropriate medications. At the time of writing (2002) more Although genetics i s essentially abou t the transmission o f harmful
than 5000 people worldwide have received 'gene therapy', in which versions of genes from one generation to the next, it encompasses a
attempts have been made to correct errors associated with inherited great deal more. Part I covers the basic biology necessary fo r its
deficiencies by introduction of normal genes into their cells. understanding.
Pharmacogenetics is the study of differential responses to unusual
biochemicals. For genetic reasons, some individuals are hypersensitive The cell (Chapter 2)
to standard doses of commonly prescribed drugs, while others respond Typically every cell in our bodies contains a pair of each of our genes
poorly. Genetic insight will guide physicians in the correct prescription and these are controlled and expressed in molecular terms at the level of
of doses while discoveries in other areas of genetics are stimulating the cell. During embryonic development cells in different parts of the
development of new kinds of medication. The field of pharmacoge- body become exposed to different influences and acquire divergent
8 Developmental biology
properties, a s they begin to express differen t combination s of the A modified version of mitosis results in cells with only one, instead
30-40000 gene pairs they each contain. Nevertheless, most cells have of two, sets of chromosomes. This is meiosis, which plays a critical part
a similar basic structure and composition, as described in Chapter 2. in the creation of the gametes.
Genetic material (Chapters 3-5) Embryonic development (Chapters 11 and 12)
Most of the biochemical processe s o f our bodies are catalysed by Fertilization of an egg by a sperm restores the normal chromosome
enzymes and their amino acid sequences ar e defined by the genes. number in the resultant zygote. This proliferates to become a hollow
Genes are coded messages written into an enormously long molecule ball that implants in the maternal uterus. Development proceeds until
called DNA. This is elaborately coiled and in growing tissue is found birth, normally at around 38 weeks, but all the body organs are present
alternately extended or tightly contracted. in miniature by 6-8 weeks. Thereafter embryogenesis mainly involves
The DNA is distributed between 23 pairs of homologous chromo- growth and differentiation o f cell types. At puberty development of
somes. In a normal woman two of these are large X-chromosomes. A the organs of reproduction i s restimulated an d the individual attain s
normal man also has 46 chromosomes, but in place of one X is a much physical maturity.
smaller Y, that carries the single gene responsible for triggering male
development. Genotype and phenotype
Genotype i s th e wor d geneticist s us e fo r th e geneti c endow -
Gene expression (Chapters 6-8) ment a person has inherited. Phenotype i s our word for the anatomi-
The means by which the information contained in the DNA is interpreted cal, physiological an d psychological comple x w e recognize as an
is so central to our understanding, that the phrase: 'DNA makes RNA individual.
makes protein'; or , more correctly : 'DN A makes heterogeneous People have diverse phenotypes partly because they inherited differ-
nuclear RNA, which makes messenger RNA, which makes polypep- ent genotypes, but an equally important factor is what we can loosely
tide, which makes protein'; has become accepted as the 'central describe as 'environment'. This includes nutrients derived from the
dogma' of molecular biology. The production of the protein product of bodies of our mothers, growing space, our postnatal feeding and expe-
any gene can potentially be controlled at many steps (see figure). rience, sunlight, exercise, etc. A valuable concept is summarized in the
statement: 'Phenotype i s the product of interaction between genotype,
Cell division and formation of eggs and sperm environment and time'; or:
(Chapters 9 and 10)
Phenotype = Genotype x Environment x Time
Body growth involves individual cells replicating their components,
dividing in half, expanding and doing the same again. This sequence is Practically every aspect of phenotype has both genetic and envi-
called the cell cycle and it involves two critical events: replication of ronmental components. This is a point well worth remembering when
chromosomal DNA, and segregation of the duplicated chromosomes by we consider the possible causes of any disease, and an issue we address
mitosis. more closely in Part II.
Basic biology 9