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Medical Genetics at a Glance
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© 2003 by Blackwell Science Ltd
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First published 2003

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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

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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 Genetic s
International Medical University
Kuala Lumpur
Malaysia

BRUCE R . KOR F
MD, PhD
Wayne H. and Sara Crewes Finley Professor o f 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 6 0
28 Gen e mapping 6 2
29 Mutagenesi s and DNA repair 6 4
Part I Developmenta l biology 30 Mutation s 6 6
1 Basi c biology 8 31 Th e molecular biology o f cancer 6 8
2 Th e cell 1 0 32 Familia l cancers 7 0
3 Th e chromosomes 1 2 33 Immunogenetic s 7 2
4 D N A structure 1 4
5 D N A replication 1 6 Part III Clinica l applications of genetics
6 R N A structure 1 8 34 Clinica l applications of genetics: an overview 7 4
7 Productio n o f messenger RNA 2 0 35 Pedigre e drawin g 7 6
8 Protei n synthesis 2 2 36 Ris k assessment 7 8
9 Th e cell cycle 2 4 37 Dysmorpholog y 8 0
10 Gametogenesi s 2 6 38 Chromosom e analysi s 8 2
11 Embryolog y 2 8 39 Biochemica l diagnosis 8 4
12 Sexua l differentiation 3 0 40 Reproductiv e genetic counselling 8 6
41 Prenata l sampling 8 8
Part II Medica l genetic s 42 Linkag e analysis 9 0
13 Th e place of genetics in medicine 3 2 43 DN A sequencing 9 2
14 Chromosoma l aneuploidies 3 4 44 Souther n blotting 9 4
15 Chromosom e structura l abnormalities 3 6 45 Th e polymerase chain reaction 9 6
16 Mendel' s laws 3 8 46 DN A profiling 9 8
17 Autosoma l dominant inheritance 4 0 47 Avoidanc e an d prevention o f disease 10 0
18 Autosoma l recessive inheritance 4 2 48 Th e management o f genetic disease 10 2
19 Intermediat e inheritance 4 4
20 Sex-relate d inheritance 4 6 Glossary 10 4
21 Congenita l abnormalities 4 8 Appendix: Informatio n resources 10 7
22 Multifactoria l threshol d trait s 5 0 Index 10 9
23 Th e common disorder s o f adult life 5 2
24 Twi n studies 5 4
25 Norma l polymorphism 5 6

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 an d its medical applications , bu t it should be of value also to rately a s component s o f severa l courses . Chapter s are , however ,
advanced student s i n th e biosciences , paramedica l scientists , estab - intended to be read in essentially th e order of presentation, a s concept s
lished medica l doctor s an d health professionals wh o need t o extend or and specialized vocabular y 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 s o
Medical genetics is unusual in that, whereas its fundamentals usually succinct. We believe the relative depth of treatment of topics appropri-
form par t o f first-yea r medica l teachin g withi n basi c biology , thos e 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. Clinica l issues usually form a part of later instruction, Dorian Pritchard
extending int o the postgraduate years . This book is therefore presente d Bruce Kor f

6
Acknowledgements

We thank thousands o f students , for th e motivatio n they provide d b y Principles of Medical Genetics, 2n d edn, p.4. Lippincott, Williams an d
their enthusiastic receptio n of the lectures on which these chapters are Wilkins, Philadelphia .
based. We appreciate also the interest an d support o f many colleagues,
but specia l mentio n shoul d b e mad e o f th e constructiv e criticisms of 22 Multifactorial threshold traits
Paul Brennan. DP wishes to pay tribute to the memory of Ian Cross for Figure 2 2 (Th e threshol d mode l applie d t o creatio n o f clef t palate) :
his friendshi p an d professiona l suppor t ove r man y year s an d fo r hi s Fraser FC (1977) Relation of animal studies to the problem i n man. In:
advice on the chapters dealin g with cytogenetics. W e thank the staff of Wilson JG & Clarke-Fraser F (eds) Handbook of Teratology, vol. 1 , pp.
Blackwell Publishin g fo r thei r encouragemen t an d tactfu l 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, Ne w 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 i n rela-
tion to development): Gelehrte r TD, Collins F S & Ginsburg D (1998)

7
1 Basi c biology

Control points for gene expression within the cell

The case for genetics nomics involve s the genetic engineering of pharmaceuticals. Human
Medicine i s currently in a state of transformation, created by the con- genes, suc h a s thos e fo r insulin an d interfero n ar e introduce d int o
vergence o f tw o majo r aspect s o f technological advance . The firs t i s microorganisms, field crops and farm animals and these species used as
the explosio n i n informatio n technology and th e second , th e rapidl y living factories for production of the human proteins. Genomics is also
expanding scienc e o f genetics . Th e likel y outcom e is tha t withi n the leading t o th e elucidatio n o f molecula r pathways of diseas e an d th e
foreseeable future w e will see the introduction of a new kind of medi- ability to design drugs to target specific steps in these pathways.
cine, individualized medicine , tailore d uniquely to the personal needs In research int o human diseases, diseas e analogues can be created
of each patient . in laborator y animal s b y targete d deletio n o f gene s o f interest . Thi s
Clinicians currentl y use family histories and genetic testin g to iden- approach ha s been used to create anima l models fo r a wide variety of
tify patient s fo r further evaluation an d for guidance o n their manage - diseases such as cystic fibrosis and neurofibromatosis.
ment. Recognitio n o f th e precis e (molecular ) natur e o f a disorde r Some of these topics are outside the scope of this book, but the reader
enables correct interpretation o f ambiguous symptoms. Some diseases, should have no doubt that the medicine of the future, the medicine he or
such a s hypertensio n (hig h bloo d pressure) , hav e man y causes , fo r she will practice , wil l rely ver y heavil y o n th e insight s provide d b y
which a variety of treatments may be possible. Identification of precise genetics.
cause would allow clinician s t o give personal guidanc e on the avoid-
ance of adverse stimul i and enable precise targeting of the disease with Overview of Part I
personally appropriat e medications . At the time of writing (2002) more Although genetic s i s essentiall y abou t th e transmissio n o f harmfu l
than 5000 people worldwide hav e received 'gen e therapy', in which versions o f genes fro m on e generation t o the next, i t encompasse s a
attempts hav e bee n mad e t o correc t error s associate d wit h inherite d great dea l more . Par t I cover s th e basi c biolog y necessar y fo r it s
deficiencies by introduction of normal genes into their cells. understanding.
Pharmacogenetics is the study of differential responses t o unusual
biochemicals. For genetic reasons, som e individuals are hypersensitive The cel l (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 dose s whil e discoveries i n othe r area s o f genetic s ar e stimulating the cell. During embryonic development cells in different part s of the
development o f ne w kind s of medication. The fiel d o f pharmacoge - body becom e expose d t o differen t influence s an d acquir e divergen t

8 Developmental biology
properties, a s the y begi n t o expres s differen t combination s o f th e 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. Thi s is meiosis, whic h plays a critical part
a similar basic structure and composition, as described i n Chapter 2. in the creation of the gametes .

Genetic material (Chapter s 3-5) Embryonic development (Chapters 1 1 and 12 )

Most o f th e biochemica l processe s o f ou r bodie s ar e catalyse d b y Fertilization o f a n eg g b y a sper m restore s th e norma l chromosom e
enzymes an d thei r amin o aci d sequence s ar e define d b y th e genes . number i n th e resultant zygote . Thi s proliferate s t o become a hollow
Genes are coded messages written int o a n enormously lon g molecul e ball tha t implants in the maternal uterus. Developmen t proceeds until
called DNA . This is elaborately coile d an d in growing tissue is foun d birth, normally at around 38 weeks, but all the body organs ar e present
alternately extende d o r tightly contracted . in miniature by 6-8 weeks . Thereafter embryogenesi s mainly involve s
The DN A is distributed betwee n 2 3 pairs o f homologous chromo - growth an d differentiation o f cell types. At puberty developmen t o f
somes. In a normal woma n two of these are large X-chromosomes. A the organ s o f reproductio n i s restimulate d an d th e individua l attain s
normal man also has 46 chromosomes, bu t in place of one X is a much physical maturity.
smaller Y , that carries the single gen e responsible fo r triggering mal e
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 ha s inherited . Phenotype i s our wor d for the anatomi -
The means by which the information contained i n the DNA is interpreted cal, physiologica l an d psychologica l comple x w e recogniz e a s a n
is s o centra l t o ou r understanding , that the phrase : 'DNA makes RN A individual.
makes protein'; or , mor e correctly : 'DN A make s heterogeneou s People have diverse phenotypes partly because they inherited differ -
nuclear RNA, which makes messenger RNA, which makes polypep- ent genotypes , but a n equally important facto r is what we can loosely
tide, whic h make s protein' ; ha s becom e accepte d a s th e 'centra l describe a s 'environment' . Thi s include s nutrient s derived fro m th e
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 i s summarized in the
statement: 'Phenotype i s the product o f interaction between genotype,
Cell division and formation of eggs and sper m environment an d time'; or:
(Chapters 9 and 10)
Phenotype = Genotype x Environment x Time
Body growt h involve s individua l cell s replicatin g their components ,
dividing in half, expanding and doing the same again. This sequence is Practically ever y aspec t o f phenotype ha s bot h geneti c an d envi -
called the cell cycl e an d it involves two critical events: replication o f 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
2 Th e cell

A generalized epithelial cell

10 Developmental biology
Overview and self-replicating , each containin g ribosomes an d u p t o 1 0 or mor e
The cell is the basic functional componen t of the body. It s nucleus is copies of a circular stran d o f mitochondrial DNA carryin g th e mito-
both th e repositor y o f th e vas t majorit y o f th e geneti c informatio n of chondrial genes (se e Chapte r 20) . They contain the enzymes of the tri-
that individual an d the centre of activity involvin g its expression. There carboxylic aci d (TCA ) cycl e an d a major fraction o f those involved i n
are many different types of cell (e.g. epithelial, liver, nerve, etc.) and the the oxidation of fatty acids .
several kind s o f organelle s an d multitude s o f solubl e enzyme s con - Peroxisomes ar e partially responsibl e fo r detoxificatio n of foreign
tained withi n thei r cytoplasm s carr y ou t th e numerou s differentiated compounds suc h as ethanol, but their major role is the oxidation of fatty
aspects o f metabolism characteristi c o f each cel l type . acids.

The plasma membran e The secretion pathway

The plasma membrane, or plasmalemma, is a barrier to water-soluble The endoplasmi c reticulu m (ER ) i s a majo r sit e o f protei n an d
molecules an d defines the interface between th e interior and exterior of lipid synthesi s an d represent s th e beginnin g o f the secretio n pathwa y
the cell. It is basically a double, side-by-side array of phospholipid mol - for proteins . It is a bulky maz e of membrane-bound channel s continu -
ecules formin g a sheet o f hydrophobic lipi d sandwiche d betwee n tw o ous with the nuclear envelope. Clos e to the nucleus it holds bound ribo-
sheets of hydrophilic phosphate groups. Within the plasmalemma are a somes an d i s know n a s 'roug h ER'. Away fro m th e nucleu s i t lack s
variety of proteins positioned wit h their hydrophobic regions within the ribosomes an d is called 'smoot h ER'. The ER also plays a role in neu-
lipid interior and their hydrophilic region s a t either surface . Microvill i tralizing toxins.
(singular: microvillus) are extensions o f the apica l plasmalemm a tha t Proteins synthesized i n the ER are passed t o the Golgi complex for
provide an increased surfac e fo r molecular exchange . further processing . Thi s i s a series o f stacked, flattene d vesicles. The y
are then collected i n storage vesicles or secretory vesicles for exocy -
The nucleus tosis, i.e . release from the cell, in response to external stimuli.
The genetic informatio n is carried on the chromosomes (see Chapter 3 )
suspended in the nuclear matrix. Thi s is a mesh of proteinaceous mate - Endocytosis
rial densest close to the nuclear envelop e where i t is called the nuclear Endocytosis is the internalizatio n an d subsequen t processin g of con -
cortex. stituents of the surrounding medium. Small particles are taken into vesi-
The nucleolu s i s a morphologicall y distinc t regio n withi n th e cles by receptor-mediated pinocytosis, which involves internalization
nucleus specialized fo r production of ribonucleic acid components of of surfac e boun d materia l throug h formatio n of a coate d pit . Large r
the ribosomes (rRNA). Atypical human nucleus contains a single large particles are bound to membrane receptor s and engulfed as phagocytic
nucleolus, whic h at interphase (se e Chapter 9 ) contains th e nucleolar vacuoles; solute s ar e taken in by fluid-phase pinocytosis. The content
organizer regions of the acrocentric chromosomes (se e Chapters 3 and of bot h pinocyti c and phagocyti c vesicle s i s usuall y delivered t o th e
38). lysosomes fo r breakdow n b y enzyme s called lysozymes . Durin g thi s
The nucleu s is bounded b y a double membran e calle d th e nuclea r transfer the vesicles are sometimes referred to as endosomes.
envelope, perforate d b y nuclear pores .
Cell junctions
The cytoplas m Tight junctions create a seal between th e apical environment o f epithe-
The cytoplasm consists of a gel-like materia l calle d th e cytosol . Thi s lial cells and their basolateral surfaces . Belt desmosomes are elongated
contains deposit s of glycogen , lipi d droplet s an d fre e ribosome s (se e layers o f fibre s tha t assis t i n th e bindin g together o f adjacen t cells ,
Chapter 8) and is permeated b y an array of interconnected filament s an d together wit h spot desmosomes, whic h are localize d point s of adhe -
tubules that form the cytoskeleton. The latter has three major structural sion. Hemidesmosome s lin k epithelia l cell s t o thei r basa l lamina ,
elements: microtubules, microfilaments and intermediate filaments. which i s a specialize d derivativ e o f th e extracellula r matrix . Ga p
Microtubules are straigh t tubes buil t from alternatin g molecules o f junctions are grouped in junctional complexes . Each of these contains
a- an d p-tubulin. They radiate from a structure called the centrosome, a pore-permitting molecular communication between adjacent cells.
which contains a pair of cylindrical structures called centrioles with a
characteristic nine-uni t structure . (Simila r structure s occu r a s basa l Medical issue s
bodies of cilia.) The microtubula r network is important in the mainte- Several inherite d disease s resul t fro m deficiencie s i n specifi c
nance of cell shape, separation o f the chromosomes during cell division lysozymes, includin g Tay-Sachs, Fabry and Gaucher diseases. Familial
and movement of cilia and sperm . hypercholesterolaemia ca n resul t fro m failur e o f internalizatio n of
Microfilaments ar e double-strande d polymers o f th e protein acti n lipoprotein. Peroxisomes ar e absent in Zellweger syndrome. Disorders
distributed mainl y near th e cel l peripher y an d involve d i n cell move - of the mitochondria are described in Chapter 20 .
ment and change of cell shape . Many therapeutic drugs act on receptors locate d in the plasma mem-
Intermediate filament s ar e tubular structure s that lin k the desmo - brane. Microtubule assembly is disrupted by the anticancer agents, vin-
somes. They ar e compose d o f on e o f fiv e o r mor e differen t proteins , cristine an d vinblastine, as well a s colchicine, whic h is use d t o arres t
depending o n cell type. cells a t metaphas e o f mitosi s (se e Chapte r 9 ) fo r examinatio n o f th e
Mitochondria (singular : mitochondrion) ar e the larges t an d mos t chromosomes (se e Chapters 3 , 14, 15, 28 and 38). Clofibrate, use d clin-
abundant o f the cytoplasmic organelles. Their main function is the pro- ically to lower seru m lipoprotei n levels , act s by inducing formation o f
duction of energy through synthesis of ATP. They are semiautonomous extra peroxisomes.

The cell 1 1
3 Th e chromosome s

The basis of chromosome structure

A typical chromosome at metaphas e of mitosis The basis of chromosome banding

Overview The staining properties of the chromosomes are utilized i n diagnosis

The word 'chromosome' means 'coloured body', referring to the capac- for thei r genera l visualization , for thei r individua l identification and
ity of these structures to take up certain histological stains more effec - for th e elucidation o f chromosomal abnormalities . W e can distinguish
tively than other cell structures . Each chromosome i s composed o f an lightly staining regions designated euchromatin, fro m densely staining
extremely long molecule of DNA complexed with proteins and RNA to heterochromatin. Diagnosti c aspects are dealt with in Chapters 14 , 15
form a substance know n a s chromatin. They dispers e throughout th e and 38.
nucleus durin g interphase o f th e cel l cycl e (i.e. when the cel l i s not The genetic information, or genome, is carried in encoded form in the
dividing), bu t becom e compacte d durin g mitosi s an d meiosis (se e sequence of bases in the DNA (see Chapters 4-8). The vast majority of
Chapters 9 an d 10) . DN A i s package d a s chromosome s probabl y this information i s in the nucleus, on chromosomes, but a small portio n
because packaging facilitates segregation of complete sets of genes into is in the form of naked loops of DNA within each mitochondrion in the
daughter cell s a t mitosi s an d packin g int o sper m head s followin g cytoplasm. Nuclei are present in practically every cell o f the body, the
meiosis. exceptions including red blood cells and the cells of the eye lens.
12 Developmental biology
 A typica l huma n nucleu s contain s aroun d 2 m o f DN A divide d Chromosome banding
between 2 3 pairs of chromosomes, givin g an average o f about 4cm pe r Some part s o f the compacted chromosome stai n densely wit h Giemsa
chromosome. But prior to cell division this is reduced to less than 5 um stain t o creat e G-bands . Thes e contai n tightl y packed , smal l loop s
(0.005 mm) by intricate coiling and packing. because the scaffold attachmen t regions there are close together. They
replicate lat e i n S-phase (se e Chapte r 9) and are relatively inactiv e in
Chromatin structure transcription. Band s tha t stai n lightl y wit h Giems a stain , R-bands ,
In eac h chromosom e th e DN A stran d i s woun d twic e aroun d contain more loosely packed loops, are relatively rich in bases G and C
globular aggregate s o f eigh t histon e protein s t o for m nucleosomes , and sho w mos t transcriptiona l activity . Difference s betwee n bandin g
the whol e appearin g a s a beade d strin g structure . Th e protein s patterns of chromosomes allow their identification (se e Chapter 38).
composing th e nucleosom e cor e particl e ar e tw o molecule s
each o f histone s H2A , H2B , H 3 an d H4 . Histone s ar e positivel y The centromere
charged an d s o ca n mak e ioni c bond s wit h negativel y charge d When visibl e in earl y mitosi s each chromosom e i s composed o f tw o
phosphate group s i n th e DNA . Th e amin o aci d sequence s o f identical structure s called siste r chromatid s connecte d a t a primar y
histones sho w clos e t o 100 % identit y acros s species , indicatin g constriction. This consists of a non-duplicated stretch of DNA called
their grea t importanc e i n maintenanc e o f chromati n structur e an d the centromere that duplicates durin g early anaphas e o f mitosis (see
function. Eac h nucleosom e accommodate s abou t 20 0 bas e pair s Chapter 9).
of DN A an d effectivel y reduce s the lengt h of th e DN A stran d to on e An organelle called the kinetochore becomes located on each side of
tenth. each centromer e i n early prophase o f mitosis and facilitates polymer-
The beaded strin g is then further coiled into a solenoid, o r spiral coil, ization o f tubuli n dimer s t o for m th e microtubule s o f th e mitoti c
with five to six nucleosomes per turn, the structure being maintained by spindle.
mediation o f one molecule o f histone HI per nucleosome. Formatio n
of th e solenoi d decrease s th e effectiv e lengt h of th e DN A stran d b y Thetelomeres
another facto r of five, yieldin g a n overall 'packin g ratio' o f about 50. The ter m 'telomere ' refer s t o th e specialize d end o f a chromosome .
This is the probable stat e of euchromatin at interphase in regions wher e Specific telomeri c protein s bin d to this structure to provide a cap (se e
the genes are not being expressed. Chapter 5).
During mitosi s an d meiosi s th e chromosome s ar e condensed , a The telomere s hav e severa l probabl e functions : preventin g th e
further 100-fold , achievin g packin g ratio s o f aroun d 5000 . The chro - abnormal end-to-en d fusio n of chromosomes, ensurin g complete repli -
matin fibre is thought to be folded into a series of loops radiating from a cation of chromosome extremities, assisting with chromosome pairing
central scaffol d o f non-histon e chromosoma l (NHC ) protein s tha t in meiosis (see Chapter 10 ) and helping to establish the internal struc-
bind to specific base sequences scattere d along the DNA strand. Com - ture of the nucleus during interphase by linking the chromosomes t o the
paction o f th e chromosom e probabl y involve s contraction o f thes e nuclear membrane.
NHC proteins.
One of the most important of the scaffold proteins i s topoisomerase Euchromatin and heterochromatin
II, a DNA-nicking-closin g enzym e that permit s the uncoilin g o f th e Euchromatin is compacted during cell division, but relaxes into an open
two strand s of th e DN A doubl e heli x necessar y fo r th e relaxatio n of conformation durin g interphase. In compacted chromosomes it consti-
DNA supercoil s durin g replicatio n o r transcriptio n (se e Chapter s 5 tutes the palely staining R-bands and contains the majority of the struc-
and 7) . Topoisomerase I I binds to scaffol d attachmen t region s that tural genes.
are AT-ric h (i.e . contai n mor e tha n 65 % o f th e base s A an d T ; se e Heterochromatin i s densely compacted at cell division and remains
Chapter 4) . I t i s believe d tha t eac h loo p ma y possibl y ac t a s a n compacted a t interphase. It is largely concentrated aroun d the nuclear
independent functiona l domai n wit h respec t t o DN A replicatio n or periphery an d nucleolu s an d i s relativel y inactiv e i n transcription.
transcription. Constitutive heterochromati n i s commo n t o al l cell s o f th e body ,
The loope d fibre is then further coile d to create the full y condense d while facultative heterochromati n varies, representing regions of the
heterochromatin of a chromosome at cell division. genome that are expressed differentially i n the different cel l types.

The chromosomes 1 3
4 DM A structure

A 3'-5' phosphodiester bond betwee n Base pair linkage s

two molecules of 2'-deoxyribose

A molecul e of 2'-deoxyribose

Schematic diagram of a two-base-pair section of DMA

The DMA double helix

Structural classes of human DN A

14 Developmental biology
Overview The centromeres
As we learnt in Chapter 3, the chromosomes are composed essentiall y Centromeric DN A contain s shor t sequence s o f base s repeate d man y
of DNA , whic h contain s code d instruction s fo r synthesi s o f ever y times 'i n tande m array' . The sequence s var y betwee n chromosomes ,
protein i n the body. DNA consists of millions of nucleotides within two but there are substantial regions of homology. The most important com-
interlinked, coile d chains . Eac h nucleotid e contain s on e of four base s ponent i s a 171-b p repeat calle d alpha-satellite DNA. Thi s is AT-rich
and it is the sequence of these bases that contains th e coded instructions. and contain s a binding sit e for a protein containe d withi n the kineto-
Each bas e o n one chai n i s matched b y a complementary partne r on chore. The latter is responsible for assembly o f the microtubules of the
the other , an d eac h sequenc e provide s a templat e fo r synthesi s o f a spindle apparatus.
copy o f th e other . Synthesi s o f ne w DN A i s calle d replicatio n (se e
ChapterS). Thetelomeres
The uni t of lengt h o f DN A i s the base pai r (bp ) wit h lOOOb p i n a In contras t t o th e centromeri c repeats , telomeri c sequence s ar e th e
kilobase (kb) and 1000,000b p in a megabase (Mb). A typical human same in all human chromosomes and similar to those in other species.
body cell contains nearly 7000Mb of DNA. Human telomeric DNA consists of long arrays of tandem repeats o f the
sequence 5'-GGGTTA-3' extending for several hundre d bases on eac h
The structure of DNA chromosome end . Most of this is double stranded, with 3'-CCCAAT-5'
We can imagine the structure of DNA as like an extremely long , flexible on the complementary strand , but the extreme 3 ' end is single stranded
ladder that has been twiste d right-handed (lik e a corkscrew) by coiling and believe d to loop aroun d and invad e the double heli x severa l kilo -
around a telegrap h pole . Eac h 'upright ' o f th e ladde r i s a serie s o f bases away . Th e triple-strande d structur e s o forme d i s stabilize d b y
deoxyribose suga r molecule s linke d togethe r b y phosphat e group s binding telomere-specific protein (see Chapter 5) .
attached to their 3' ('three prime') and 5' ('five prime') carbon atoms. At
the bottom of one uprigh t is a 3' carbon ato m carrying a free hydroxy l Structural classes of human DN A
(—OH) grou p and , a t the top , a 5' carbo n carryin g a fre e phosphat e The huma n haploid genom e contain s probabl y 30-4000 0 nuclea r
group. O n the other upright this orientation i s reversed . genes, i.e . coding sequence s an d their associate d control elements, i n
The 'rungs ' of the ladder are pairs of nitrogenous bases of two types, addition to 37 (including those for mitochondrial tRNA: see Chapter 6)
purines an d pyrimidines. Th e purine s ar e adenine (A ) an d guanine within the mitochondrial genome. However, the nuclear genome repre-
(G) and the pyrimidines ar e cytosine (C) and thymine (T). Th e bases sents no more than 3% of nuclear DNA, the remainder having no coding
are attached to the 1 ' carbon of each sugar. Each unit of purine or pyrim- function. This includes introns that interrupt the coding exons of most
idine bas e togethe r wit h one attache d suga r and on e phosphate grou p genes, plu s th e 75 % o f huma n nuclea r DN A tha t i s extragenic , i.e.
constitute a nucleotide. A section of double-stranded DNA is therefore outside or between th e genes. Of the latter, 60 % is of unique sequence
essentially tw o linked, coile d chain s of nucleotides. Thi s double helix or moderately repetitive , whil e 40% is moderately t o highly repetitive .
has a major groove corresponding to the gap between adjacent sections The highly repetitive fraction include s microsatellite and minisatel -
of th e su-gar-phosphat e chain s and a mino r groov e alon g th e ro w o f lite DNA, which differ i n the length of the repeat. Satellit e DNA is so-
bases. Ther e ar e 1 0 pair s o f nucleotide s pe r complet e tur n o f th e called becaus e its unusual AT: GC ratio gives it a buoyant densit y that
helix. differs fro m th e bul k o f th e DNA . Thi s cause s i t t o separat e ou t a s a
The pairs of bases o f the 'rungs ' are hydrogen-bonded together an d 'satellite band' when mechanically sheared whol e DNA is subjected to
since both A and T have two sites available for bonding whil e C and G density gradient centrifugation.
each have three. A always pairs with Ton the opposite strand and C with
G. This bas e pairin g (know n as Watson-Crick bas e pairing ) is ver y Medical and legal issues
specific an d ensure s that th e strand s ar e normall y precisely comple - Microsatellite DN A i s scattere d throughou t the genom e an d i s usefu l
mentary to one another. Thu s if one strand read s 5'-CGAT-3', the com - for trackin g th e inheritance o f disease alleles of closely linke d genes .
plementary stran d mus t rea d 3'-GCTA-5 ' i n th e sam e direction , or Minisatellite DNA is concentrated near the centromeres an d telomeres,
5'-ATCG-3' if we obey the normal rule of describing the sequence from so is less useful fo r tracking genes, but, since it is highly variable, i t is
5' t o 3' . Th e numbe r of A residues i n a sectio n o f DN A i s therefor e used fo r producin g DN A fingerprints . Thes e pla y a n exceptionall y
always equal t o th e numbe r of T residues; similarly , the numbe r of C important rol e i n paternit y testin g an d forensi c identificatio n (se e
residues always equals the number of G (Chargaff's rule). Chapter 46).

DNA structure 1 5
5 DN A replication

Replication o f human DNA

Structure of a replication fork

Replication o f telomeric DNA

16 Developmental biology
Overview RNA (see Chapter 6), which acts as a primer for DNA synthesis. Repli-
Cells multiply by the process o f mitosis, but so that genetic information cation o f mitochondria l DN A occur s independentl y o f tha t i n th e
is no t lost , th e whol e o f th e nuclea r genome i s firs t duplicated . Thi s nucleus and utilizes a different se t of enzymes, including the mitochon-
occurs durin g S-phase o f the cell cycl e (se e Chapte r 9) . S-phase lasts dria-specific DNA polymerase y.
about 8h . The DN A at the centromeres of the chromosomes i s repli- The genome contains multiple copies of the five histone genes, from
cated i n th e middl e o f mitosis , just befor e chromosom e segregation . which copious quantities of histones are produced, especially durin g S-
Mitochondrial DNA is replicated ou t of phase with nuclear DNA. phase. These bind immediately ont o the newly replicated DNA.
Although the overall sequence of events during replication of nuclear Since each daughte r DN A duple x contains on e ol d stran d from th e
DNA i n highe r organism s (eukaryotes ) i s simila r to tha t i n bacteri a parent molecul e an d on e newl y synthesize d strand , th e replicatio n
(prokaryotes), the details are subtly different . In eukaryotes replicatio n process is described as semiconservative.
takes place while the (nuclear) DNA remains in nucleosome configura-
tion (see Chapter 3). Replication of the telomere s
Synthesis o f DNA a t the end o f the lagging stran d is problematical a s
Replication DNA polymerase a need s to attach beyond the end of the sequence tha t
GC-rich section s of the DNA, recognizable a s euchromatic R-bands in is being replicate d an d work proximally , in the 5'-3' direction. A spe -
condensed chromati n (se e Chapte r 3) , contai n 'housekeepin g genes ' cialized DN A synthetic enzyme calle d telomerase provides a n exten-
that operate i n every cell. These section s replicate i n the early S-phase sion of the lagging strand that enables this to happen.
(see Chapte r 9) . Th e heterochromati c AT-ric h G-band s contai n fe w Telomerase i s a ribonucleoprotei n tha t contain s a n RN A templat e
genes an d replicat e i n lat e S-phas e (se e Chapte r 3) . Gene s i n AT-rich with the sequence 3'-AAUCCCAAU-3'. This is complementary to one-
regions that code for differentiated propertie s an d operate i n some cells and-a-half copie s of the six-base telomeri c DN A repeat, 5'-GGGTTA -
only ar e found in facultative heterochromatin (see Chapte r 3) . This i s 3' (see Chapter 4). The 3'-AAU of the RNA sequence o f the telomerase
replicated early in those cells in which the genes are expressed an d late binds to the termina l -TTA-5' of the template laggin g strand , leaving
in those in which they are not. the res t o f th e RN A sequenc e exposed . Deoxyribonucleotide s the n
The place on the DNA helix which first unwinds to begin replication assemble on this RNA template, extending the DNA repeat sequence by
is called the replication origin . Her e the double strand is split open by one unit . Th e telomeras e the n detache s an d move s alon g t o th e ne w
a helicase enzyme to expose th e base sequences . Replicatio n proceed s DNA termina l -TTA-3', wher e th e proces s i s repeated. Whe n a suffi -
along the single strands at about 40-50 nucleotides per second, simul- ciently long-termina l repeat ha s bee n formed , DN A polymeras e a
taneously i n both directions. I n higher organism s ther e are many repli- attaches t o the single-strand extensio n an d assembles the complemen -
cation origins spaced abou t 50-300 kb apart. The resulting separations tary DNA strand in a proximal 5'-3' direction back to the old end of the
of the DNA strand are called replication bubbles, a t each end of which double strand, to which it becomes linke d by the action of DNA ligase.
is a replication fork.
New DN A i s synthesize d by enzyme s calle d DN A polymerases , Repair system s
from deoxyribonucleotid e triphosphate s (ATP, GTP, etc.) , which in Occasionally a wrong base i s inserted int o a growing stran d but, fortu-
the proces s ar e converte d int o monophosphat e nucleotide s (AMP , nately, health y cell s contai n postreplicatio n repai r enzyme s an d
GMP, etc.) . Th e releas e an d hydrolysi s of pyrophosphat e fro m th e base mismatch proofreading systems that correct suc h errors. Thes e
triphosphates provide s energy for the reaction an d ensures it is virtually remove an d replace the erroneously inserte d bases, using the templat e
irreversible, making DNA a relatively very robust molecule. strand a s a guide . Thes e repai r system s utiliz e tw o additiona l DN A
All DN A polymerases ca n build new DNA only in the 5' to 3' direc- polymerases: (3 and e (see Chapter 29).
tion, which means they must move along their template strands fro m
3' to 5'. Replication can therefore occur continuously from th e origin of Medical issues
replication along onl y one strand, called th e leading strand. The other Several cancer-predisposin g conditions aris e from defect s i n differen t
strand is called the lagging strand and, because of the orientation of the aspects o f th e postreplicatio n repai r an d mismatc h repai r systems .
sugars along this strand, replication takes place only in short stretches . These includ e th e chromosom e breakag e syndrom e calle d Bloo m
The ne w section s o f DN A alon g th e laggin g stran d ar e typicall y syndrome, familia l predisposition to breast cancer caused by mutations
100-200 bases lon g an d are known as Okazaki fragments . Followin g in th e gene s BRCA 1 an d BRCA 2 an d a n autosoma l dominan t for m
their synthesi s they ar e linked together b y actio n of the enzyme DN A of bowe l cance r calle d hereditar y non-polyposi s colo n cance r
ligase. Whil e awaitin g replication the parental single-stran d sequence (HNPCC) (se e Chapter 32) .
of the lagging strand is temporarily protected by single-strand bindin g One theory holds that telomeres are reduced i n length at every round
protein (or helix-destabilizing protein). of mitosis and that the number of repeats the y contain may play a role in
Leading stran d synthesi s require s DN A polymeras e 6 ; laggin g limiting th e numbe r of time s a cell ca n divide . On thi s theory, abnor-
strand synthesi s use s a differen t enzyme , DN A polymeras e a . Th e mally efficient, mutan t telomerases ma y promote the indefinite growth
latter contains a DNA primase subunit that produces a short stretch of of cancer cells by delaying telomere decay.

DNA replication 1 7
6 RN A structure

RNA structure
Schematic diagram of a two-base section of RNA Transfer RN A
2-dlmenslonal cloverlea f structure 3-dimensiona l L shape

A molecul e of ribos e A molecul e of undin e

Production o f mitochondrial RN A
(the bold arrows indicat e the structura l gene s for
species of mitochondrion-specific tRNAs)

The mitochondrial
genome

Production of 5.85,105 and 26S rRNA

The resultant rRNA , tRNA an d mRN A

Overview organisms) RN A occur s a s si x type s o f molecule : messenge r RN A

In Chapter 4 we learnt that DN A is the double-stranded nucleic acid that (mRNA), it s precurso r heterogeneou s nuclea r RN A (hnRNA) ,
carries the genetic information we received from our parents and which transfer RNA (tRNA), ribosomal RN A (rRNA), small nuclear RNA
we pass on to our children. RNA is a similar molecule that facilitates the (snRNA) and mitochondrial RNA (mtRNA). Heterogeneous nuclea r
expression of this genetic information within our own cells. The main RNA i s characteristic of eukaryotes and i s not foun d i n prokaryote s
differences betwee n RN A and DN A are tha t RNA is (usually ) singl e (literally 'before th e nucleus' , e.g . bacteri a an d viruses) . Som e
stranded, ribose replaces deoxyribose and uracil (U) replaces thymine. viruses us e RN A i n place of DNA fo r storag e an d transfe r of genetic
In eukaryote s (literall y organism s wit h a 'tru e nucleus' , i.e . higher information.

18 Developmental biology
Heterogeneous nuclear and messenger RNA Ribosomal RN A i s transcribed fro m DN A by tw o additiona l RN A
Heterogeneous nuclea r RN A an d it s derivativ e mRNA carr y geneti c polymerases. Polymerase I (Pol I ) transcribes 5.8S , 1 8 S and 28 S, as
information from the nuclear DNA into the cytoplasm. one lon g 45 S transcrip t which i s then cleave d int o thre e sections , s o
There ar e a s man y specie s o f hnRN A as ther e ar e genes , becaus e ensuring they are produced in equal quantities. We each carry about 250
hnRNA i s th e direc t transcrip t o f th e codin g sequence s o f th e copies of the DNA sequence coding fo r the 45S transcript per haploid
genome. The y ar e transcribe d fro m th e DN A b y th e enzym e RN A genome. These ar e in five clusters of tandem repeats o n the short arms
polymerase I I (Po l II) . Messenger RN A result s fro m th e processin g of chromosomes 13 , 14 , 15, 21 and 22. These ar e known as the nucleo -
of hnRNA , whic h include s th e remova l o f non-codin g intron s an d lar organize r regions , a s thei r transcriptio n an d the subsequen t pro -
linking together of the coding exons (see Chapter 7). mRNA therefore cessing o f th e 45 S transcrip t occur s whil e the y ar e hel d withi n th e
carries onl y th e codin g informatio n of th e correspondin g specie s o f nucleolus.
each hnRNA, plus the flanking leader and trailer, and so is considerably There ar e abou t 200 0 copies o f the 5 S rRN A gene i n a t least thre e
shorter. clusters on Chromosome 1 . These are transcribed b y Pol III outsid e the
nucleolus an d importe d fo r ribosome assembly , alon g wit h ribosomal
Transfer RN A proteins.
Each molecul e of transfer RNA consists of about 75 nucleotides linked
together i n a long chai n which , due to internal base pairing, adopt s a Small nuclear RNA
'clover leaf structure , which then twists into an L shape. Transfer RNA The conversion of hnRNA into mRNA by the removal of introns occurs
is unusual i n containing a variety o f rarer bases in addition t o C, G, A in th e nucleu s i n RNA-protein complexe s called spliceosomes. Eac h
and U, and some o f these ar e modified by methylation. The important spliceosome ha s a core of three small nuclea r ribonucleo-proteins o r
feature of tRNAis that each 'charged' molecule carrie s a n amino acid at snRNPs (pronounce d 'snurps') . Eac h snRN P contain s a t leas t on e
its 3' end, while on the middle 'leaf o f the cloverleaf structure are three snRNA an d severa l proteins . Ther e ar e severa l hundre d differen t
characteristic base s known a s the anticodon. The sequenc e o f bases snRNAs, transcribed mainl y by Pol II, which are believed t o be capable
in th e anticodo n i s specificall y relate d t o th e specie s o f amin o aci d of recognizing specific ribonucleic acid sequences by RNA-RNAbase
attached t o the 3' terminus. For example, tRN A with the anticodon 5' - pairing. The most importan t i n hnRNA processing are U l, U2, U4/U 6
CCA-3' carries the amino acid tryptophan and no other. It is this specific andUS.
relationship that forms the basis o f translation of the genetic messag e
carried b y mRNA (see Chapter 8). Mitochondria! RNA
Transfer RNA molecules are transcribed from their coding sequences Mitochondrial DNA i s in the for m of a continuous loop coding fo r 1 3
in DNA by the enzyme RNA polymerase III (Pol III). There ar e over polypeptides, 22 tRNAs and two rRNAs (one 16S , the other 23S). Most
40 different tRN A subfamilies, each with several members. genes are on one strand, the heavy strand , bu t a few are on its comple-
ment, the light strand and both strands ar e transcribed, a s two contin-
Ribosomal RNA uous transcripts, by a mitochondrion-specific RN A polymerase. This
Ribosomal RN A consists of several species usuall y referred to by their enzyme is coded b y a nuclear gene. The long RNA molecules are then
sedimentation coefficient s i n Svedber g unit s (S) , deduce d b y thei r cleaved t o produc e 3 7 separat e RN A specie s an d th e mitochondrial,
speed of centrifugation i n a dense aqueous medium. ribosomal an d transfe r RNAs join force s t o translate the 1 3 mRNAs .
Each ribosom e consist s o f on e larg e an d on e smal l sub - Many additiona l proteins are imported int o the mitochondria from th e
unit. Thes e contai n man y protein s derive d b y translatio n o f cytoplasm, having been transcribed from nuclear genes.
mRNA, plu s RN A tha t remain s untranslated . The ter m 'ribosoma l
RNA refer s t o th e non-translate d material . Th e smal l ribosoma l Medical issues
subunit contain s 18 S rRN A an d th e larg e subuni t 5S , 5.8 S an d 28 S Patients with systemic lupus erythematosus have antibodies directed
rRNA. against their own snRNP proteins.

RNA structure 1 9
7 Productio n of messenger RNA

Key sequences in mRNA production

Transcription by RNA polymerase II Intron excision and exon splicing

20 Developmental biology
Overview Transcription
Most metaboli c processe s ar e catalyse d b y proteinaceou s enzymes . Transcription is signalled by assembly of protein transcription factors at
Proteins ar e als o th e mai n structura l components o f th e bod y an d th e the promoter. A molecule of Pol II binds to this complex an d splits open
amino acid sequences o f all proteins are coded in the DNA. Conversion the double helix . The complex, no w including the enzyme, the n move s
of th e DNA-encode d informatio n int o protei n involve s transcriptio n downstream causing local unwinding and splitting, followed b y re-for-
into an hnRNA copy, processing int o mRNA, translation into polypep- mation o f the double heli x a s it proceeds, creatin g a 17-b p long tran-
tide and elaboration into protein (se e Chapte r 8). scription bubble. When i t reaches the transcription initiation point it
ejects on e transcription factor , acquires anothe r an d begins t o synthe -
The structure of a gene size RNA.
Eukaryotes diffe r fro m prokaryote s i n tha t mos t o f thei r gene s Using the strand orientated in the 3'-5' direction (fro m left to right) as
contain redundan t DN A tha t interrupt s th e codin g sequences . Thes e a template , Pol I I links ribonucleotides on e by one to produce a com -
stretches o f non-codin g DN A ar e calle d introns , whil e th e codin g plementary RN A sequence, orientate d wit h reverse polarity (i.e . 5' to
sequences ar e called exons . I n both groups , outsid e th e coding regio n 3')- In other words, by applying the rules of base pairing to the template
are a leade r an d trailer , plu s a variet y o f transcriptiona l contro l strand it creates a precise RNA copy of the coding strand. The enzyme
sequences. transcribes throug h leader, exons , intron s an d trailer , an d (apparentl y
Genes tha t cod e fo r protei n ar e calle d 'structura l genes ' an d thei r wastefully!) proceed s indefinitel y downstream (see above) .
transcription i s performed b y RNA polymerase Po l II. A sequence jus t
'upstream' (i.e . 5' ) of the codin g sequenc e constitute s th e promoter, RNA processing
which act s a s a bindin g sit e fo r transcriptio n factor s tha t indicat e As hnRNA transcripts are synthesized, they ar e covalently modifie d to
where Pol II should begin its action. distinguish them a s coded messages fo r later translatio n int o polypep -
Among protein s w e ca n distinguis h 'housekeepin g proteins ' tide. The 5' end is first capped b y addition o f 7-methyl GTP in revers e
present i n all cell types and 'luxury proteins' produced fo r specialized orientation. Whe n th e polyadenylatio n sit e appear s i n th e hnRN A
functions. The promoters o f genes that code for luxury proteins include strand, i t i s cleave d ther e an d poly- A polymerase add s o n 100-20 0
a 'TAT A box', wit h a sequenc e tha t i s a varian t of 5'-TATAAA-3 ' at residues of adenylic acid to form the poly-A tail. Both the cap an d tail
about 2 5 bp upstrea m o f the transcription initiation site. Gene s tha t probably protec t th e molecul e fro m degradation , contribut e t o th e
code fo r 'housekeepin g proteins ' instea d usuall y hav e on e o r mor e 'passport' tha t allow s it s expor t t o th e cytoplas m an d late r provid e
'GC boxes' in variable positions , containin g a variant of 5'-GGGCGG- a recognitio n signa l fo r th e ribosome , indicatin g it s availabilit y fo r
3'. Anothe r commo n promote r elemen t i s th e 'CAA T box ' (e.g . 5' - translation.
CCAAT-3') at -80bp and there ar e often als o enhance r and silencer On average, an hnRNA molecule may have about 700 0 nucleotides
sequences som e distanc e awa y tha t bin d controllin g factors , whic h which ar e reduced t o about 120 0 in the mRNA by removal o f as many
interact with the promoter b y looping of the DNA. Some 'luxury ' genes as 50 introns. Histone genes ar e exceptional i n having no introns.
have additional function-specifi c contro l elements. The ribonucleoprotein complexes that remove th e introns ar e called
'Downstream' (i.e. 3') of the transcription initiation site is the leader spliceosomes and they contain several snRN A species (U1-U6) , eac h
sequence, which is not translated. The coding message follows , usually complexed wit h specifi c proteins . U l snRN P (i.e . ribonucleoprotei n
interrupted b y on e o r mor e intron s an d followe d b y th e non-codin g containing U 1 snRNA ) binds to th e upstrea m splic e site , guide d b y a
trailer. A t the end of the trailer i s the polyadenylation site of variable complementary sequenc e i n th e U l snRNA . U 2 snRN P bind s t o th e
sequence, bu t define d b y 5'-AATAA-3 ' (5'-AAUAA-3 ' i n th e RN A branch site, then becomes linke d to the bound U1, causing a loop in the
transcript), 10-3 0 bases upstream . hnRNA. U 2 the n cut s th e hnRN A immediatel y upstrea m o f G U (se e
Introns begin with the sequence GTA(/G)GAGT an d end with a run above) and joins that upstream cut end of the intron to the junction site,
of Cs or Ts preceding AG . The first GT (G U in the hnRNA) and the last creating a lariat shape. The downstrea m en d of the intro n i s then cu t
AG, togethe r wit h a n A residu e situate d withi n a relativel y standard just beyond AG , releasin g th e RNA lariat, and the spliceosome bring s
sequence nea r th e downstrea m end , ar e importan t i n intro n removal . together and joins the two exons.
The 5' site is known as the donor site, the 3' site is the acceptor and the
A residue is the branch site. Medical issues
In prokaryotes transcriptio n stops a t a specifi c poin t indicate d b y Alpha-amanitin fro m th e deat h ca p mushroom , Amanita phalloides,
an inverte d repea t i n the trailer , followed b y a run o f T residues. Th e blocks the action of Pol II. Alternative RNA splicing occurs normally in
adoption of a hairpin loo p b y bas e pairin g i n the mRN A copy bring s some transcripts , notabl y i n the production o f antibodies (se e Chapte r
transcription t o a n end . A n analogou s structur e exist s i n histon e 33). Man y genetic disorders involve errors in RNA splicing. The antibi-
gene trailers, but no general transcription termination signal ha s been otic, rifampicin (rifamycin) block s bacteria l transcription b y binding to
identified in eukaryotes. the prokaryote promoter; actinomycin intercalates between G- C pairs.

Production of messenger RNA 2 1

8 Protei n synthesis

The genetic code Translation

Betting of the reading frame

The peptkfy ! tran&fera&e reaction

22 Developmental biology
Overview As eac h ribosom e vacate s th e messenge r ca p anothe r attache s an d
The mai n structura l components o f the bod y an d mos t o f its catalysts follows it s predecessor , creatin g a polyribosom e o r polysome. Th e
are proteins, each derived from one or more polypeptides . A polypep- mRNA usually survives for a few hours .
tide is a chain o f amino acids, the sequenc e o f which is determined by
that of the bases i n the corresponding mRNA , in accordance wit h 'the Protein structure
genetic code'. Each amin o acid is represented i n mRN A by one or more The amin o acid sequenc e o f a polypeptide define s its primary struc -
groups o f three base s calle d triplet codons , and their interpretation as ture. Th e secondary structure is the three-dimensional for m o f part s
polypeptide is called translation. Messenge r RN A is translated fro m of th e polypeptide : th e a-helix , th e collagen pro-a helix , o r th e fj -
the 5 ' t o th e 3 ' en d withi n cytoplasmi c ribosomes . Th e resultan t pleated sheet .
polypeptides ar e then modified into proteins. The functional propertie s Tertiary structur e is the folded form of the whole polypeptide, com -
of protein s deriv e largel y fro m th e activ e groups the y display in their posed o f different secondary structures .
tertiary and quaternary conformations. Quaternary structur e i s the fina l nativ e conformatio n o f a multi -
meric protein , e.g . haemoglobi n i s compose d o f tw o oc-globi n
The genetic code monomers, tw o (3-globi n monomers , on e molecul e o f hae m an d a n
Translation requires transfe r RN A molecules charged with amino acid s atom o f ferrous iron . Collagen fibres are cables of many tripl e helices,
appropriate t o their anticodon sequence s (se e Chapte r 6) . Some amin o each formed as a rope o f three pro-a helices .
acids are coded b y several codons , onl y tryptophan and methionine by Structure i s frequently maintained b y disulphid e bridges betwee n
one each. Three of the 64 possible three-fol d combination s of A, C, G cysteine residues on adjacent strands , while enzymic properties depen d
and U in the mRNA code for STOP signals: UGA , UAG and UAA (see on the distribution of charged groups .
The geneti c code ' in the figure). AU G codes for methionine an d also
acts a s a STAR T signal , simultaneousl y determinin g th e amino - Post-translational modification
(or N-) terminal en d of the polypeptide and selecting one of the thre e Post-translational modificatio n include s remova l o f th e N-termina l
possible readin g frame s (se e 'Settin g o f th e readin g frame ' i n th e methionine and cleavage. Association occur s between simila r or differ -
figure). The genetic cod e o f mitochondria i s slightly different. ent polypeptides, or with prosthetic groups such as haem.
Polypeptides destine d fo r extracellula r secretio n ar e firs t glycosy -
Translation lated i n the roug h endoplasmic reticulu m an d Golg i apparatus . Thei r
Initiation selection involves a signal peptide near the N terminus tha t binds to a
A smal l ribosoma l subuni t containin g severa l initiatio n factor s an d signal recognitio n peptide free in the cytoplasm. Thi s link s them to a
methionyl tRN A charge d wit h methionin e binds t o th e 5 ' ca p o n th e receptor i n the membrane of the endoplasmic reticulum . As it is synthe-
mRNA an d the n slide s alon g unti l i t find s an d engage s wit h th e firs t sized th e polypeptid e i s transferre d throug h th e membrane ; whe n it s
AUG sequence. Th e initiation factors are then released, a large riboso - carboxyl terminu s emerges, th e signal peptide i s cleaved off . Polypep -
mal subunit binds t o the small one, an d translation begins . tides ar e transported t o the Golgi apparatu s in vesicles tha t bud off the
The large ribosomal subuni t contains two sites , known as the A site endoplasmic reticulum (see Chapter 2).
(for aminoacyl ) and the P site (for peptidyl). At the end of initiation th e Glycosylation i s usuall y N linked , involvin g additio n o f a
P site contain s a charged met-tRN A with it s anticodon engaged i n the common oligosaccharide to the side chain —NH2 group of asparagine,
first AUG codon, whil e the A site is empty. as i n th e productio n o f antibodie s an d lysozymes . O-linke d
oligosaccharides ar e attache d t o the —OH grou p o n the sid e chai n of
Elongation serine, threonine or hydroxylysine, as with secreted AB O blood grou p
The appropriate aminoacyl tRN A now becomes located in the A site, as antigens.
dictated by the adjacent codon i n the mRNA, with the help of a soluble Other modification s includ e hydroxylation o f lysin e an d proline ,
elongation factor called EF1. The peptidyl transferase reaction then important in creation o f the collagen pro- a helix , sulphation of tyro-
creates a peptide bond between the amino (—NH2) group of the amino sine, a s a signa l fo r compartmentalizatio n an d lipidatio n o f cysteine
acid at the A site and the carboxyl (—COOH) group of that at the P site, and glycin e residues , necessar y fo r anchorin g the m t o phospholipi d
while the first tRNA is released. membranes. Acetylation o f lysine in histone H4 modifies its binding to
The translocas e reactio n nex t promote s expulsio n o f th e DNA. Protei n kinases phosphorylate serine an d tyrosine residues and
uncharged tRNA , move s th e ribosom e thre e bases alon g an d translo - can regulat e enzymi c properties, a s i n th e proto-oncogen e signa l
cates th e growing peptide from A to P. This requires elongation factor , transduction cascade (see Chapter 31).
EF2
Mitochondrial mRNA s ar e translate d b y mitochondria-specifi c Medical issues
tRNAs. I-cell disease is due to deficiency in glycosylation of lysozymes. Ricin
from castor bean s blocks EF2; diphtheria toxin blocks translocase .
Termination Many antibiotic s targe t translatio n specificall y i n prokaryotes .
Elongation continue s unti l a STOP codon enter s the ribosome, al l three These include erythromycin whic h disrupts translocase, chlorampheni-
being recognize d b y a singl e multivalen t releas e facto r (RF) . Thi s col, whic h interfere s wit h peptidy l transferase , tetracycline whic h
modifies th e specificit y of peptidy l transferase s o tha t a molecul e of prevents bindin g o f aminoacy l tRNAs , puromycin, whic h mimic s
water is added t o the peptide instead . The ribosome is then released an d an aminoacy l tRN A an d streptomycin, whic h bind s t o th e smal l
dissociates int o its subunits, so freeing the completed polypeptide. ribosomal subunit . Huma n mitochondri a hav e a n evolutionar y
Synthesis o f an average polypeptid e o f 400 amino acids take s abou t affinity wit h bacteri a an d som e antibiotic s interfer e wit h thei r
20 seconds . action.
Protein synthesis 2 3
9 Th e cell cycle

The cell cycle

24 Developmental biology
Overview S-phase
The body grow s by increas e i n cell siz e and cell number, the latte r by The standar d numbe r o f DNA double-helice s per cell , correspondin g
division, calle d mitosis . Cell s proliferat e i n respons e t o extracellular to th e diploi d numbe r of single-stran d chromosomes , i s describe d a s
growth factors , passin g through a repeated sequenc e of events known 2C. The 2 C complement i s retained throughou t Gl an d into S-phase ,
as the cell cycle. This has four major phases: Gl, the n S, G2 and lastly when new chromosomal DN A is synthesized and the cell becomes 4C .
the mitotic or M-phase. Thi s i s followed b y division of the cytoplasm From th e end of S-phase, throug h G 2 an d into M-phase eac h visuall y
and plasma membran e t o produce tw o identical daughte r cells . Gl , S detectable chromosom e contain s tw o DN A molecules , know n a s
and G 2 togethe r constitut e interphase . Th e chromosome s ar e repli - sister chromatids, boun d tightl y together . I n huma n cells , therefore ,
cated during the DNA synthetic o r S-phase (se e Chapter 5). Most body from th e end of S-phase t o the middle of M there are 23 pairs of chro-
cells are not actively dividing and are arrested a t 'GO' within Gl. mosomes (i.e . 46 observable entities) , but 4C (92) nuclear DNA double
Typically th e M-phas e occupie s betwee n a hal f an d on e hou r o f a helices.
cycle time of about 20 hours. Normal (a s distinct from cancer ) human Mitosis involve s sharin g identica l set s o f chromosome s betwee n
cells can undergo a total of about 80 mitoses, depending o n the age of the tw o daughte r cells , s o tha t eac h ha s 2 3 pair s an d i s 2 C i n term s
the donor. of it s DN A molecules . G l an d G O are th e only phases o f th e cell
cycle throughout which 46 chromosomes correspond to 2C DNA
The biochemistry of the cell cycle molecules.
The cel l cycl e i s driven b y alternatin g activatio n and de-activation of The replication of DNA during S-phase is described in Chapter 5.
key enzyme s know n a s cyclin-dependen t protei n kinase s (CDKs) ,
and their cofactors calle d cyclins . Thi s i s performed b y phosphoryla- G2-phase
tion an d de-phosphorylatio n b y othe r phosphokinase s an d phos - A second checkpoint on cell size occurs during G2, the gap between S-
phatases, specifi c cyclin-CDK complexes triggerin g specific phase s of phase an d mitosis . I n additio n th e G 2 checkpoin t allow s th e cel l t o
the cycle. At appropriate stage s th e same classe s o f proteins cause th e check that DNA replication is complete before proceeding to mitosis.
chromosomes to condense, the nuclear envelop e to break down and the
microtubules o f th e cytoskeleto n t o reorganiz e t o for m th e mitoti c Mitosis or M-phase
spindle. 1 Prophase . Th e chromosomes, eac h consisting of two identical chro-
matids, begin t o contract an d become visibl e within th e nucleus . The
G1-phase spindle apparatus of tubulin fibres begins t o assemble aroun d the tw o
Gl i s the gap between M- and S-phases, when the cytoplasm increase s centrosomes at opposite poles of the cell. The nucleoli disperse.
in volume. It includes the Gl checkpoin t whe n damage to the DNA is 2 Pro-metaphase . Th e nuclea r membrane dissociates . Kinetochore s
repaired and the cell check s that it s environment i s favourable befor e develop aroun d th e centromere s o f th e chromosomes . Tubuli n fibres
committing itself to S-phase. If the nuclear DNA is damaged, a protein enter the nucleus and assemble radiating out from th e kinetochores and
called p5 3 increase s i n activity and stimulates transcription of protein linking up with those radiating from the centrosomes.
p21. Th e latter binds to the specific cyclin-CD K complex responsibl e 3 Metaphase . Tensio n in the spindle fibres causes the chromosomes to
for driving the cell into S-phase, s o inactivating it and arresting the cell align midwa y betwee n th e spindl e poles , s o creatin g th e metaphas e
in Gl. This allows sufficient tim e for the DNA repair enzymes to make plate.
good the damage to the DNA. If p53 is defective the unrestrained repli- 4 Anaphase . Th e centromeri c DN A share d b y siste r chromatid s i s
cation that ensues allows that line of cells to accumulate mutations and duplicated, they separate an d are drawn towards the spindle poles.
a cance r ca n develop . Fo r thi s reason, p5 3 i s known affectionately a s 5 Telophase . Th e separate d siste r chromatids (no w considered to be
'the guardian o f the genome'. chromosomes) reach the spindle poles and a nuclear membrane assem-
bles around each group . The condensed chromati n becomes diffuse and
GO-phase nucleoli reform.
Mammalian cell s wil l proliferat e only i f stimulate d by extracellula r 6 Cytokinesis . Th e cel l membran e contract s aroun d th e mid-region
growth factor s secrete d b y othe r cells . Thes e operat e withi n th e between the poles, creating a cleavage furro w whic h eventually sepa-
cell throug h th e proto-oncogen e signa l transductio n cascad e (se e rates the two daughter cells.
Chapter 31) . If deprived of such signals during G1, the cell diverts from
the cycle and enters the so-calle d G O state. Cells can remain in GO for The centrosome cycle
years befor e recommencing division . At Gl th e pair of centrioles associated with each centrosome separate.
The G O block i s impose d b y mitosis-suppresso r proteins suc h a s During S-phase an d G2 a new daughter centriole grows at right angles
the retinoblastoma (Rb) protein encoded b y the normal allel e of the to each old one. The centrosome then splits at the beginning of M-phase
retinoblastoma gene . Thes e bin d t o specifi c regulator y protein s pre - and the two daughter centrosomes mov e to opposite spindle poles.
venting the m fro m stimulatin g the transcriptio n of gene s require d fo r
cell proliferation . Extracellular growth factor s destro y thi s bloc k b y Medical issues
activating Gl-specifi c cyclin-CD K complexes , whic h phosphorylat e For karyotype analysis (see Chapter 38) dividing cells can be arrested at
the R b protein, alterin g it s conformatio n an d causin g i t to release it s metaphase wit h the drug, colchicine.
bound regulatory proteins. The latter are then free t o activate transcrip- The drug taxol prevents spindle disassembly and is used in the treat-
tion of their target genes and cell proliferation ensues. ment of cancer.

The cell cycle 2 5

10 Gametogenesi s

Melosis i Meiosis

Spermatogenesis Oogenesis

26 Developmental biology
Overview cytokinesis. Thes e resembl e th e equivalen t phase s o f mitosi s i n tha t
Each body cell contains two sets of chromosomes, one from th e mother pairs o f chromatid s (bivalents ) linke d a t thei r centromere s becom e
and on e fro m th e father . The y ar e describe d a s 2 N o r diploid . Th e aligned at the metaphase plate and are then drawn into separate daugh-
sperm an d ova contain onl y one set of chromosomes and are said to be ter cells following replication o f the centromeric DNA.
1 N, or haploid. Th e process by which the diploid number is reduced to At the end of Meiosis II the cells contain 23 chromosomes (1 N), each
haploid durin g th e formatio n o f th e ger m cell s i s calle d meiosis . consisting of a single chromatid (1C).
In term s o f th e numbe r o f centromeres , thi s involve s a reductional
division followe d by an equational divisio n know n as Meiosis I and Male meiosi s
Meiosis II . In men meiosis occur s by the pattern see n i n most diploid Spermatogenesis include s all the event s by whic h spermatogonia ar e
species, but in women there ar e several differences. transformed int o spermatozoa an d takes abou t 64 days. Cytokinesis i s
Crossing-over betwee n maternall y and paternally derive d chromo - incomplete throughout, so that each generation of cells remains linked
somes ensure s reshufflin g o f th e geneti c informatio n between eac h by cytoplasmic bridges.
generation. At fertilization, fusio n o f the haploi d chromosom e com - A diploid primary spermatocyt e undergoes Meiosis I to form two
plement o f the sper m wit h that of the ovu m restores th e chromosom e haploid secondary spermatocytes. Thes e bot h undergo Meiosis I I to
number to diploid in the zygote. produce fou r haploi d spermatids . The spermatid s becom e elaborate d
into spermatozoa durin g spermiogenesis. This includes: (i) formation
Meiosis I of the acrosome containing enzymes that assist with penetration of the
Meiosis I has similarities wit h mitosis, bu t is much more complex an d egg; (ii) condensation o f the nucleus; (iii) shedding o f most of the cyto-
extended i n time . Primar y spermatocyte s an d primar y oocyte s ente r plasm; and (iv) formation of the neck, midpiece and tail.
meiosis following G2 of mitosis, so they each have a diploid set of chro-
mosomes (2N) , bu t eac h o f these contain s replicate d DN A as sister Female meiosi s
chromatids (i.e. are 4C; see Chapter 9). Prophase I involves reciprocal Oogenesis begins in the fetus at 1 2 weeks, but ceases abruptl y at about
exchange between maternal and paternal chromatids by the process of 20 weeks, th e primar y oocyte s remainin g a t diplotene of prophase I
crossing-over. until ovulation, this suspended state being called dictyotene .
Ovulation begin s a t pubert y an d usuall y onl y on e oocyt e i s she d
Prophase I per month . Under stimulatio n by hormone s a primar y oocyt e swell s
1 Leptotene . Th e chromosome s appea r a s lon g thread s attache d a t accumulating cytoplasmic materials. At completion o f Meiosis I these
each end to the nuclear envelope. are inherite d b y on e daughte r cell, th e secondar y oocyte . Th e othe r
2 Zygotene . The chromosomes contract , pair with and adhere closely nucleus passe s int o th e firs t pola r body , whic h usuall y degenerate s
to (o r 'synaps e with' ) thei r homologues . Thi s normall y involve s without furthe r division . Meiosi s I i s complete d rapidl y then , afte r
precise registration , gen e fo r gen e throughou t the entir e genome . I n a pause , th e secondar y oocyt e i s she d int o th e uterine , o r Fallopian,
primary spermatocyte s X - an d Y-chromosomes synaps e at the tip s of tube.
their short arms only. Meiosis II stops at metaphase until the entry of a sperm. It then com-
3 Pachytene . Siste r chromatids begin to separate, the double chromo- pletes division , producin g a larg e haploi d ovu m pro-nucleus , which
some being known as a bivalent. Th e chromosome pai r represented b y fuses with the sperm pro-nucleus, an d a very small second polar body,
four doubl e helices i s called a tetrad. On e o r both chromatids of each which degenerates.
paternal chromosome crosses ove r with those from th e mother in what The whole process takes from 1 2 to 50 years, depending when fertil-
is known as a synaptonemal complex. Every chromosome pai r under- ization takes place .
goes a t least one cross-over.
4 Diplotene . Th e chromatid s separate excep t a t the regions of cross - The significance of meiosis
over o r chiasmat a (singular : chiasma). Thi s situatio n persists i n all 1 Th e diploi d chromosom e conten t o f somati c cell s i s reduce d t o
primary oocyte s unti l they are shed at ovulation. haploid in the gametes.
5 Diakinesis . th e reorganized chromosomes begin to move apart. Each 2 Paterna l an d materna l chromosome s becom e reasserted , wit h a
bivalent can now be seen to contain four chromatids linked by a common potential for 223 (= 8 388 608) different combinations, excluding recom-
centromere, while non-sister chromatids are linked by chiasmata. bination within chromosomes.
Metaphase I , Anaphase I , Telophase I , Cytokinesis I. These follow 3 Reassortmen t of paternal an d maternal allele s within chromosome s
a similar course to the equivalent stages in mitosis (see Chapter 9), the creates an infinite potential for genetic variation between gametes.
critical differenc e bein g that , instea d o f non-siste r chromatid s being 4 Th e randomness o f reassortmen t o f paterna l an d materna l allele s
segregated, pair s of reciprocally crossed-over siste r chromatids joined during meiosis (and at fertilization) ensures the applicability o f proba-
at their centromeres are distributed to the daughter cells. bility theory to genetic ratios and the general validity of Mendel's laws
At th e en d o f Meiosi s I , secondar y spermatocyte s an d secondar y (see Chapter 16).
oocytes contai n 2 3 chromosome s ( I N ) , eac h consistin g o f tw o 5 Th e frequenc y o f cross-ove r betwee n gene s within chromosome s
chromatids (i.e. 2C). allows the relative positions of genes to be mapped (see Chapters 27,28).
6 Error s sometime s occu r a t chromosome pairin g and crossing-over ,
Meiosis II which ca n produc e translocations , a s wel l a s a t thei r separatio n o r
There i s a transient interphase, during which no chromosome replica- disjunction, whic h can lead to aneuploidy (se e Chapter 14) .
tion occurs, followed by prophase, metaphase, anaphase, telophase and

Gametogenesis 2 7
11 Embryolog y

Fertilization and implantatio n (uterus not to 0cale)

Formation of the embryoni c disc Embryonic disc

F&tterrr of neyreiJ tube

closure {21-20 <feys)

28 Developmental biology
 Time saale of embryogene&m

Overview amniotic cavity . A double-layere d dis c calle d th e embryoni c dis c

Fertilization b y a sperm initiate s embryogenesis. Mitosis ensues and forms fro m th e epiblas t an d hypoblas t a t 7-12 days , from which th e
the pre-embryo implant s i n the uterus. The embryo proper develop s embryo proper develops.
from a few interna l cells , through creation o f three embryoni c germ
layers. Organogenesi s involve s interaction s betwee n thes e an d i s The embryo (weeks 2-8)
completed b y 6-8 weeks . During the subsequent perio d of growth and Gastrulation is the process which creates the embryonic mesoderm
cytodifferentiation the individual is called a fetus . and initiate s activit y o f th e embryo' s ow n genes . Th e primitiv e
streak first appears in the epiblast a t the caudal (tail ) end of the embry -
The pre-embryo (day s 0-14) onic disc , extend s toward s its centre an d then develop s th e primitiv e
The secondary oocyte is shed into the peritoneal cavit y and directed into groove in it s amnioti c (i.e . dorsal ) surface . A t the crania l (head ) end
the adjacen t uterin e (Fallopian ) tube , wher e fertilizatio n mus t tak e of thi s develops a nodule o f cell s called th e primitiv e (o r Hensen's )
place within 24 hours. The sperm performs fou r functions: (i ) stimula- node.
tion o f metaphase I I i n th e secondary oocyte; (ii ) restoration o f th e Epiblast cells migrate acros s th e disc, through th e primitive groov e
diploid number o f chromosomes; (iii ) initiation o f cleavage; an d and int o the space above th e hypoblast. Thes e become the embryonic
(iv) determination o f sex. mesoderm, creating the three germ layers: ectoderm from the epiblast,
The sperm passes through the corona cells on the oocyte surface and mesoderm and endoderm from the hypoblast togethe r with some epi -
adheres t o the zona pellucida . Th e acrosome i n the sper m hea d the n blast cell s tha t merge wit h it . Mesoderm cell s tha t migrat e anteriorly
releases enzymes tha t digest a tunnel through the zona pellucida, allow - and accumulat e i n the midlin e for m th e notochorda l process, which
ing th e sper m t o pas s int o th e perivitellin e spac e an d fus e wit h the later extends caudally.
oocyte membrane . Th e sper m hea d become s engulfe d by th e oocyte , The epiblas t thicken s t o for m th e neura l plat e an d a neural fol d
entry of more sperms being prevented by a rapid cortical reaction . Th e arises o n either side of the central axis . These curv e over, contact an d
oocyte nucleu s completes metaphas e II, expels th e second pola r bod y from 22 days fuse in five separate movement s to create the neural tube,
and maternal and paternal pronuclei fus e t o form the zygote . which late r become s th e spina l cord . Alon g th e dorsa l edge s o f th e
Mitosis o f the pre-embryo is called cleavage , an d the resultant blas- neural fold s ar e the neural cres t cell s tha t migrate ou t to give rise t o
tomeres ar e smalle r afte r eac h division , the 16-cel l morul a passing several cel l types , includin g nerve , bone, supportin g structure s o f th e
down th e uterin e tub e aide d b y peristalsi s an d ciliar y movement. A heart, adrenalin-secretin g and pigmen t cells . As th e primitiv e nod e
space called the blastocoel forms off-centre in the morula to create the moves caudall y down the midline , blocks of mesoderm o n either sid e
blastocyst, whic h swells and bursts from th e zona pellucida. Two dif- rotate to create 42-44 pairs of segmental somites, th e most caudal 5- 1
ferent cel l type s ar e no w recognizable : th e flattene d trophectoder m of which subsequently disappear.
cells o f the oute r trophoblast an d th e eccentricall y placed inne r cel l
mass or embryoblast. The fetus (weeks 8-38)
On da y 6 th e blastocys t implant s i n th e endometriu m linin g th e The ectoder m i s th e origi n o f th e oute r epitheliu m an d CN S and ,
uterus. Som e trophoblas t cell s fus e t o form the invasiv e syncytiotro - with mesoderm, periphera l structures such as limbs; mesoderm form s
phoblast, th e remainder constituting the cytotrophoblast. Th e blasto- muscles, circulator y system, kidneys , se x organ s an d togethe r wit h
cyst no w takes nourishmen t from th e mothe r an d grow s rapidl y a s it endoderm, the internal organs; endoderm gives rise to the gut and diges-
sinks further into the endometrium. tive glands. The rudiment s of all the major organs are formed through
The inne r cel l mas s expose d ventrall y to th e blastocoe l flatten s t o 'inductive' tissue interactions by abou t 6 weeks, when the heart start s
form th e primitiv e endoderm , o r hypoblast , whil e th e remainde r beating. Thereafte r developmen t mainl y involve s increas e i n th e
forms the primitive ectoderm, or epiblast, within which develops the number and types of cells. Birth normally occurs at 38 weeks .

Embryology 2 9
12 Sexua l differentiation

Sexual differentiation of gonadf and 0enital ducts

Sexual differentiation of external genitalla

30 Developmental biology
Overview inhibiting substance (MIS), which causes the paramesonephric duct s
Sexual differentiation is initiated at fertilization, depending on whether to degenerate .
the sper m carrie s an X or a Y chromosome. A t the blastocyst stage in Testosterone bind s t o a n intracellula r recepto r protei n an d th e
XX embryo s on e X chromosom e i n ever y cel l i s permanently inacti- hormone-receptor comple x the n bind s t o specifi c control site s i n th e
vated, otherwise development of the sexes is similar until the SRY gene DNA an d regulate s transcriptio n o f tissue-specifi c genes . I n mal e
on th e Y chromosom e come s int o operatio n an d certai n structures, embryos testosteron e convert s th e mesonephri c duct s int o th e va s
including the brain, become progressivel y more masculinized. deferens an d epididymis.

X chromosome inactivatio n External genitali a

At the late blastocyst stag e cells inactivate al l but one of their X chro- The external genitalia are derived from a complex of mesodermal tissue
mosomes. Th e nucle i o f norma l X X femal e cell s therefor e com e t o located aroun d the urogenital sinus. At the end of the 6th week in both
contain one inactive X, which can be seen at interphase as a Barr body sexes thi s consist s o f th e genita l tubercl e anteriorly , th e paire d
in addition to their active X (see Chapter 20). Presence o r absence of a urogenital fold s o n eithe r sid e an d latera l t o thes e th e labioscrota l
Barr body is the basis of the original Olympic sex test. The choice of swellings.
whether i t i s th e paternal , o r materna l X whic h become s inactiv e i s In females oestrogen stimulates sligh t elongation of the genital tuber -
random in each somatic cell, but in descendent cells it remains the same. cle to form the clitoris, while the urogenital folds remain separate a s the
Every woman therefore develops as a mosaic with respect to expression labia minora. Th e urogenital sinus remains open a s the vestibule an d
of her two X chromosomes. In the extra-embryonic trophoblast cells the the labioscrotal swelling s become th e labia majora .
paternal X i s preferentially inactivated. In oogoni a th e inactiv e chro- The tissue s aroun d th e urogenita l sinu s synthesiz e 5-alpha -
mosome i s reactivated. reductase which in males converts testosterone secreted b y the Leydig
Genes i n the pairin g (pseudo-autosomal) regio n and severa l othe r cells t o dihydrotestosterone . Unde r th e actio n o f thi s hormon e th e
sites on the X are not subject to inactivation, accountin g fo r the sexua l genital tubercl e elongate s int o the penis , pullin g the urethra l fold s
abnormalities of XXY and XO individuals (see Chapter 14). forward t o form the lateral walls of the urethral groove. A t the end of
the 3r d month th e tops o f the walls fuse t o create th e penile urethra ,
Early developmen t while the urogenital sinus becomes th e prostate .
At the beginning of week 5, up to 2000 primordial ger m cells migrate
from th e endoderm cell s of the yolk sac and infiltrate the primitive se x Descent of the testis
cords withi n the mesodermal genita l ridges , whic h are developments Usually i n th e 7t h mont h th e teste s descen d fro m th e peritonea l
of the coelomic epithelium. The paired indifferent gona d is identical in cavity betwee n th e peritonea l epitheliu m an d pubi c bone s an d int o
males and females. the scrotum . Thi s i s mediate d finall y b y th e gubernaculu m con -
tracting unde r th e influenc e o f testosterone , bu t descen t ma y no t
The ovary be completed until birth.
In th e earl y ovar y th e primitiv e se x cord s brea k down , bu t th e
surface epitheliu m proliferate s an d give s ris e t o th e cortica l cords , Puberty
which split into clusters, each surrounding one or more germ cells. The Puberty i s triggere d b y hormone s secrete d b y th e pituitar y glan d
latter, no w calle d oogonia , proliferat e the n ente r rneiosis a s primar y acting o n ovaries, teste s an d adrena l glands . In girls, usually between
oocytes. ages 1 0 an d 14 , th e ovarie s respon d b y secretin g oestroge n tha t
stimulates breast growth . About a year later menstruation commences,
The testis accompanied b y maturatio n o f th e uteru s an d vagin a an d broadenin g
The SRY gene carried only on the Y chromosome i s expressed i n week of th e pelvis . Testosteron e synthesi s i s stimulate d i n th e adrena l
7 i n the cells o f the primitiv e se x cords. It s produc t i s a zinc finger glands and i s responsible fo r growth of pubic and axillary (underarm)
protein ( a gen e switchin g protein) that bind s to DN A i n thos e sam e hair in girls.
cells, leading to a new pattern of specifi c gen e expression. These cells In boys, starting at about 11-1 2 years, the testes enlarge and synthe-
proliferate into the testis cords . sis o f androgen s i s reactivated . Th e testi s cord s acquir e a lumen ,
Leydig cell s derived fro m th e original mesenchyme of the gonadal so forming th e seminiferous tubules , whic h link u p wit h the urethra.
ridge mov e i n around th e 8t h week an d until weeks 17-1 8 synthesiz e The androgen s enhanc e growt h o f th e peni s an d laryn x an d initiat e
male sex hormones, or androgens, includin g testosterone, whic h initi- spermatogenesis.
ate sexual differentiation o f the genital ducts and external genitalia. By
the 4th month the male gonads als o contain Sertoli cell s derive d fro m Medical issue s
the surface epithelium of the gonad. The mos t common cause s o f ambiguous genitalia are adrenal hyper -
plasia i n girl s an d androge n insufficienc y i n boys . Patient s wit h
Genital duct s testicular feminizatio n syndrom e inheri t a Y chromosome , bu t
Initially bot h sexe s hav e tw o pair s o f genita l ducts : mesonephri c develop a convincin g female externa l phenotyp e becaus e the y lac k
(or Wolffian ) an d paramesonephric (o r Mullerian). I n female s th e testosterone receptors . Failur e o f testicula r descen t i s calle d
mesonephric duct s regres s unde r th e actio n o f oestrogen s produce d cryptorchidism.
by th e materna l system , placent a an d feta l ovaries , bu t th e para - Tumours arising from primordia l germ cells are known as teratomas.
mesonephric ducts remain and become the uterine tube s and uterus. They ca n contai n severa l well-differentiate d tissues (e.g . hair , bone ,
In males the Sertoli cell s produce a growth factor called Mulleria n sebaceous gland, thyroid tissue) and are usually benign (see Chapter 31) .

Sexual differentiation 31
13 Th e place of genetics in medicin e

Geneticdisorders in children as causes of Expression of the major cate0ories of genetic

death In PHtain and among those a^tnitted disease in relation to development
to hospital rn North Americ a

Introduction ible wit h survival . Abnormal o r unequa l exchange o f chromosoma l

The true scale of genetic disease has only recently become appreciated. material create s a variety o f abnormalities, of varying severity . Thes e
One survey of over a million consecutive births showed that at least one are describe d i n Chapter s 1 4 and 15 . I t i s interestin g to not e that th e
in 20 people under the age of 25 develop a serious disease with a major three chromosomes associated with live birth of chromosomal triomies
genetic component . This , however , i s probably a n underestimate as it (13,18 and 21) are the ones with the lowest gene density or the smallest
depends on how disease is defined an d how strong the genetic compo- size
nent needs to be for it to be included.
Studies o f th e cause s o f deat h o f mor e tha n 120 0 Britis h children Single gene defects (Chapters 16-19)
suggest that about 40% die d a s a result of a genetic condition . Other The foundation of the science of genetics is a set of principles of hered-
studies i n North America indicat e that genetic factors are important in ity discovered i n the mid-19th century by an Augustinian monk called
50% o f th e admission s t o paediatri c (children's ) hospitals . Through Gregor Mendel and described in Chapter 16. These give rise to charac-
variation in immun e responsiveness, geneti c factor s eve n play a rol e teristic pattern s o f inheritance , dependin g o n whethe r th e diseas e i s
in infectiou s diseases, althoug h these migh t be though t to b e wholly dominant o r recessive. Recognitio n o f the patter n o f inheritanc e of a
environmental. disease is central to prediction of the risk of producing an affected child,
Traditionally geneti c disease s ar e classifie d int o thre e majo r cat - as described in Chapters 1 7 and 18 . Chapter 1 8 also explains the risks
egories: chromosomal, singl e gene and multifactorial. Chromosomal associated wit h consanguineous mating. Chapter 1 9 deals with single-
defects can create major physiological disruptio n and most are incom- gene conditions that are less easily classified .
patible with even prenatal survival. These ar e responsible for the vast
majority of deaths in the first trimester of pregnancy and about 2.5% of Sex-related inheritance (Chapter 20)
childhood deaths . Mos t single-gen e defects revea l thei r presence after There are many reasons why the sexes may express diseases differently .
birth and are responsible fo r 6-9% o f early morbidity (sickness ) and Of thes e th e mos t importan t relate s t o th e possessio n b y male s o f
mortality. The multifactorial disorders account for about 30% of child- only a singl e X-chromosome . Mos t sex-relate d inherite d diseas e
hood illnes s an d i n middle-to-late adul t lif e pla y a major rol e i n th e involves expression in males of recessive alleles carried on the X. The
common illnesses from which most of us will die. most commo n condition s i n thi s categor y ar e defectiv e colou r vi -
sion an d neurodevelopmenta l dela y (menta l retardation ) i n males .
Overview of Part II Mitochondrial disorders are uniquely transmitted by mothers to all their
Chromosomal defects (Chapters 1 4 and 15) children.
If chromosome segregatio n i s incomplete or unequal at meiosis, chro-
mosomally abnorma l embryos ca n result . Sinc e a n averag e chromo - Congenital and complex traits (Chapter s 21-24)
some carrie s abou t 200 0 genes , to o man y o r to o fe w chromosome s Some conditions, includin g man y congenital abnormalities , ar e due to
cause gross abnormalities of phenotype, most of which are incompat- the combined action of several genes, or the adverse effects o f environ-
32 Medical genetics
mental factors . Thes e fal l int o th e categor y o f multifactoria l in - Mutation and its consequences (Chapters 29-32)
heritance. Geneti c counsellin g i n relatio n t o thi s grou p i s generall y Mutation of DNAcan involve chemical modification of bases, destruc-
problematic a s pattern s o f inheritanc e ar e usuall y no t discernible . tion, deletio n o r relocation o f critica l sequences . Repai r mechanisms
Multifactorial traits are of immense importance as they include most of usually correc t muc h o f th e damage , bu t ne w allele s ar e sometime s
the common disorders o f adult life. Muc h current research i s concen- created that can be passed on to offspring. I t is generally accepted that
trated in this area. most mutationa l changes ar e eithe r neutra l i n effec t o r deleterious ,
although very , ver y occasionall y a new , apparently beneficia l allel e
Polymorphism (Chapters 25 and 26) does appear . Geneticist s therefor e generall y conside r tha t conditions
'Polymorphism' refers t o variation betwee n normall y health y individ - which increase the rate of mutation ar e best avoided.
uals. This concept is especially important in pharmacogenetics, bloo d Damage that occurs to the DNA of somatic cells can result in cancer,
transfusion an d orga n transplantation . Th e frequenc y o f polymor - when a cell start s t o proliferate ou t of control. Thi s can give ris e t o a
phisms within populations is dealt with in Chapter 26. tumour which may break up and its component cells migrate and estab-
lish secondar y tumours . The molecula r details o f carcinogenesis ar e
Genetic linkage and association (Chapters 27 and 28) outlined in Chapter 31 and families with a tendency toward cancer are
If genes reside side-by-sid e on the same chromosome they are 'geneti- described in Chapter 32.
cally linked' . I f on e i s a diseas e gene , bu t canno t easily be detecte d
whereas it s neighbou r can, the n allele s o f th e latte r ca n b e use d a s Immunogenetics (Chapter 33)
markers for the disease allele. This allows prenatal assessment, inform- A healthy immune system may eliminate many thousands o f potentia l
ing decisions about pregnancy termination, selection of embryos ferti- cancer cells every day, in addition to disposing of infectious organisms.
lized i n vitro, presymptomatic diagnosi s an d diagnosis o f problemati c Molecular biologist s believe that the genetic event s tha t tak e plac e in
conditions. the immun e system ar e uniqu e to tha t system. These event s involve
'Genetic association ' refer s t o th e coinciden t presenc e o f certai n cutting, splicing and reassembly of alternative DNA sequences to create
alleles with certain diseases although the basis of the relationship may billions o f ne w gene s withi n individual B- an d T-lymphocytes . A n
be obscure. outline of these events is given in Chapter 33.

The place o f genetics i n medicine 3 3

14 Chromosoma l aneuploidie s

Down syndrome Turner syndrom e

Edward syndrome Patau syndrome

Klinefelter syndrome

Frequency of T21 in relation to maternal age,

diagnosis by amniocentesis and at birth

Causation of chromosomal aneuploidfe s

Frequency of chromosomal abnormalities in

fetuses in relation to stage of gestation

34 Medical genetics
Overview 3 Features . Microcephal y (smal l head ) wit h slopin g forehead ; holo -
Chromosomal disorder s involv e both abnorma l number s o f chromo - prosencephaly (failur e o f formatio n o f paire d cerebra l hemispheres) ;
somes an d aberration s i n thei r structur e (se e Chapte r 15) . Euploid y 'rocker-bottom' feet , microphthalmia , anophthalmia , cyclopi a o r
means tha t the chromosome numbe r per body cel l i s an integral multi- hypotelorism (i.e . small o r absent eyes , a single centra l ey e or closely
ple of the haploid number , N - 23 , aneuploidy that it is other tha n an spaced eyes) ; cryptorchidism (undescende d testicles) ; simia n crease ;
integral multiple . Diploid y describe s th e norma l situation , a typical heart defects ; clef t li p an d palate ; micrognathi a an d postaxia l poly -
body cell in humans havin g 2N = 46 chromosomes. Women hav e 2 3 dactyly (sixt h finger present).
similar pairs , includin g a pai r o f X chromosomes , thei r karyotyp e 4 Surviva l rate . Simila r to Edward syndrome, with rather more (50% )
formula bein g 46,XX . In norma l me n ther e i s a n X an d a Y chromo- dying within the first month.
some, thei r karyotype bein g 46,XY . Polyploid y refer s t o multiples of
the haploid numbe r (e.g. triploidy, 3N= 69). Klinefelter syndrome
Trisomy (2 N + 1 ) refers t o the presence o f three copies o f one chro- 1 Karyotype . 47,XX Y (o r 48,XXXY; 49,XXXXY , etc) .
mosome. Possessio n o f only a single copy of an autosome (2 N - 1 ) is 2 Incidence . About 1/50 0 male births.
called monosomy. 3 Features . Phenotyp e i s basicall y male , bu t wit h gynaecomasti a
Mosaic individuals contain two different cell lines derived fro m one (breasts) an d feminin e bod y hai r distributio n (bu t masculin e facia l
zygote. Achimaera also contains two different cell lines, but is derive d hair); small genitalia and infertility. They are tall, with elongated lower
by fusion of two zygotes (e.g. a 46,XX/46,XY hermaphrodite) . legs and forearms. There ma y be learnin g difficulties, scoliosi s (spinal
Possibly as many as 25% of conceptions involve a chromosomal dis- curvature), emphysem a (gaseou s distensio n o f lun g tissues) , osteo -
order, but this is reduced to 0.6% a t birth by natural loss, mainly during porosis (skeleta l breakdown ) an d varicose veins ; 8 % hav e diabete s
the first trimester . mellitus.
The non-sex chromosome s ar e called autosomes . Trisomies 2 1 , 1 8
and 1 3 are th e onl y autosoma l trisomie s compatibl e wit h surviva l t o Turner syndrome
birth and only Trisomy 2 1 with life beyond infancy . 1 Karyotype . 45,X .
2 Incidence . 1/500 0 femal e births . (The fetu s aborts i n ove r 95 % o f
Down syndrome, Trisomy 21 cases.)
1 Karyotype . Trisom y 2 1 (47,XX,+2 1 or 47,XY,+21 ) account s fo r 3 Features . Phenotype i s basically female, bu t patients fai l t o mature
about 96 % o f case s o f Dow n syndrome . Th e remainin g 4 % hav e sexually. There is often als o lymphoedema (excess fluid) in the hands
translocations between 2 1 an d anothe r chromosome (se e Chapter s 1 5 and fee t o f newborns ; exces s ski n formin g a we b betwee n nec k an d
and 29). Some patients ar e mosaics. shoulders an d lo w posterio r hairline ; heart-shape d fac e wit h microg -
2 Incidence . Abou t 1/700 live births. nathia, epicantha l fold s an d strabismu s (squint) ; short stature ; shor t
3 Features . Typicall y there are epicanthal folds an d a flat, broad face . fourth metacarpals ; man y naev i (moles) , shield-shape d ches t wit h
Other feature s includ e a larg e ga p betwee n firs t an d secon d toes , widely space d nipples ; increase d 'carryin g angle ' a t elbo w (cubitu s
webbing o f toe s 2 an d 3 , genera l hypotoni a (poo r muscl e tone) , fla t valgus). Intelligenc e i s normal . Ther e i s congenita l hear t diseas e i n
occiput (back of skull), short stature, Brushfield spots in irides, single 20%, unexplaine d hypertension (high blood pressure) in 30%, kidney
transverse crease in the palm, single fold o n and clinodactyly o f fifth malformations an d thyroiditis. The y ma y develop X-linked recessive
digit (se e figure) , ope n mout h wit h protrudin g tongu e tha t lack s a disease as in males. Some Turner syndrome patients are mosaics (45,X ;
central fissure , hearin g defici t (60-80%), increase d ris k o f infection, 46,XY).
leukaemia (80%) , congenita l hear t defect s (40-50% ) an d epileps y
(5-10%). I Q i s 25-75 , wit h typicall y a happ y temperament , bu t XYY syndrome
Alzheimer-like dementi a ma y occur i n up to 50% in mid-life and ther e 1 Karyotype . 47,XYY .
is often early-onse t atheromatous (i.e. with fatty deposits) degenera - 2 Incidence . 1/100 0 male births.
tion of the cardiovascular system, Hirschprung disease and hypothy- 3 Features . Ver y tall stature , large teeth , learnin g disabilities, some -
roidism( 15-20%). times problems in motor coordination. Early claims of predisposition t o
4 Lif e expectancy. Du e to heart defects, for some it is less than 50 years. aggressive behaviour are not generally upheld. Fertility is normal.

Edward syndrome, Trisomy 18 Triple X syndrome

1 Karyotype . 47,XX, +18 or 47,XY, + 18. 1 Karyotype . 47,XXX .
2 Incidence . About 1/300 0 liv e births. 2 Incidence . 1/100 0 female births
3 Features . Clenched fists with index and fifth fingers overlapping th e 3 Features . Generally tal l with some learnin g problems an d difficult y
rest; 'rocke r bottom ' fee t wit h prominent heels ; low-set , malforme d in interpersona l relationships . Claim s o f reduce d fertilit y ar e no w
ears; micrognathi a (smal l lowe r jaw) ; singl e palma r crease ; growt h sometimes ascribe d t o 45,X oocyte s i n 45,X/47,XXX mosaics .
deficiency; cardia c an d rena l abnormalities ; prominen t occipu t an d
general hypotonia. Causation
4 Mea n survival time . About 2 months; 30% die within a month; only Aneuploidy i s usually ascribed t o failure o f conjugation of chromo -
10% survive beyond a year. somes i n meiosi s I ; o r non-disjunction , prematur e disjunctio n or
anaphase la g (delaye d separation ) i n meiosi s II . Th e frequenc y o f
Patau syndrome, Trisomy 13 chromosomal error s i n oocyte s increase s dramaticall y wit h maternal
1 Karyotype . 47,XX,+13 or 47,XY,+13. age (see figure). Mosaics can be caused by chromosomal non-disjunc-
2 Incidence . Abou t 1/500 0 live births. tion during mitosis.

Chromosomal aneuploidies 3 5
15 Chromosom e structural abnormalities

Structural abnormalities of chromosome ©

36 Medical genetics
Overview Ring chromosome s
Structural aberration s includ e translocations , deletions , rin g chro - If two breaks occur in the same chromosome the broken ends can fus e
mosomes, duplications , inversions , isochromosome s an d centri c as a ring. Acentric rings are lost, but if the ring contains a centromere it
fragments. Mos t o f thes e resul t fro m unequa l exchang e betwee n can surviv e subsequen t cel l division . Clinically a ring represents two
homologous repeate d sequence s o n th e sam e o r differen t chromo - deletions. The y ca n doubl e b y siste r chromatid exchange , leadin g t o
somes, o r whe n tw o chromosom e break s occu r clos e togethe r an d effective trisomy , or be lost, resulting in monosomy.
enzymic repair mechanisms link the wrong ends.
Duplications
Translocations Duplication i s the presence of two adjacent copie s of a chromosoma l
A translocatio n involve s exchang e o f chromosoma l materia l be - segment an d ca n b e eithe r 'direct' , o r 'inverted' . Duplication s ma y
tween chromosomes . Thre e type s ar e recognized : centri c fusio n o r originate by unequal crossing-over in a previous meiosis, or as a conse-
'Robertsonian', reciprocal an d insertional. quence o f translocation , inversion or presence o f a n iso-chromosom e
(see below ) i n a parent. Duplication s ar e more common , bu t generall y
Centric fusion or 'Robertsonian' translocations less harmful tha n deletions.
Centric fusio n arise s fro m break s a t o r nea r th e centromere s o f tw o
chromosomes, followe d b y thei r fusion . Th e lon g arm s o f chromo - Inversions
somes 13,14,15,2 1 and 22 are most commonly involved, especially 13 Inversions arise from two chromosomal breaks with end-to-end switch-
with 14 , and 1 4 with 21. These ar e all acrocentric chromosome s wit h ing of the intervening segment. If this includes the centromere it is peri-
very smal l shor t arm s (se e Chapte r 38) , th e latte r carryin g multipl e centric; i f not, the inversion is paracentric. Th e medica l significance
copies of the ribosomal RNA genes (see Chapter 6). of inversions lies in their capacity to lead to chromosomally unbalanced
Although centri c fusio n involve s loss o f rRN A genes , sufficien t gametes following crossing-over.
intact copies remain for no serious consequence to result. The carrier of
a pai r o f centricall y fuse d chromosome s may therefor e hav e onl y 4 5 Isochromosomes
chromosomes, bu t be quite healthy as the overall los s i s insignificant. An isochromosome has a deletion of one chromosome arm, with dupli-
This is a balanced translocation. cation of the other. In live births the commonest involves the long arm
When centrically fused chromosomes pair during meiosis a trivalent of th e X , resultin g i n Turner syndrom e due t o shor t ar m monosom y
structure i s forme d allowin g contac t betwee n homologou s chromo - (despite lon g arm trisomy). Most isochromosome s caus e spontaneou s
some segments . At anaphas e si x possible gameti c combination s ca n abortion.
then be formed: one normal, one abnormal but balanced and four unbal-
anced (se e figure) . However , selection o f gametes and pregnancy loss Examples of deletion s
Prader-Willi and Angelman syndromes
result in a lower than expected frequency of unbalanced offspring.
The combined incidenc e of Prader-Willi and Angelman syndromes
is 1/2500 0 live births. Around 70% o f patients have a deletion i n the
Reciprocal translocations
long arm of chromosome 15 ; in Prader-Willi thi s is in the paternal copy,
Reciprocal translocatio n involve s interchromosoma l exchange .
in Angelman the maternal (se e Chapte r 19) .
Either ar m o f an y chromosom e ca n b e involve d an d th e carrier s ar e
usually healthy. The medical significance is therefore usually for future
Cri-du-chat syndrome
generations, a s carrier s ca n produc e chromosomall y unbalance d
Cri-du-chat syndrom e is so called because the malformed larynxes of
fetuses.
these babies caus e them to cry with a sound like a cat. They hav e pro-
found learning disability, hypertelorism (widely spaced eyes) , epican -
Insertional translocations thal folds , strabismus , low-se t ears , lo w birt h weigh t an d failur e to
Insertional translocation involves insertion of a deleted segmen t inter- thrive. The cause i s terminal deletion of the short arm of Chromosom e
stitial^ at another location . I t is extremely rar e and balanced carrier s 5 and it occurs in about 1/50000 births.
are usually healthy, but ma y produce chromosomall y unbalance d off-
spring with either a duplication or a deletion. Wolf-Hirschhorn syndrome
Wolf-Hirschhorn syndrome als o occurs in about 1/50000 births, also
Deletions with profoun d cognitive impairment, hypertelorism, epicanthal fold s
Deletion o f part of a chromosome can be interstitial or terminal. Dele- and low-se t ears . Patients typicall y have a broad an d prominent nose ,
tions can arise from tw o breaks, followed by faulty repair, from unequal cleft li p an d palate, microcephaly , hear t defects , convulsion s an d
crossing-over in a previous meiosis, or as a consequence of a transloca- hypospadias (non-closure of the penile urethra). It is caused by termi-
tion in a parent. nal deletion of the short arm of Chromosome 4.
The smallest deletion s detectabl e by high-resolution banding (se e
Chapter 43) are of abou t 3000K b (i.e . 3 millio n base pairs) and are Examples o f translocation s
generally characterize d b y menta l handica p an d multipl e congenital Down syndrome
malformations. About 4% of cases of Down syndrome are due to Robertsonian translo-
Several syndrome s ar e ascribe d t o microscopicall y invisibl e cation between th e lon g arms of Chromosome 2 1 an d any other acro -
microdeletions (se e Chapte r 35) . Whe n severa l gene s ar e delete d centric, usually 14 . In some case s one parent has a balanced versio n of
together th e term contiguous gene syndrome is applied. the same translocation (see figure).

Chromosome structural abnormalities 3 7

16 Mendel' s laws

Matings between different Nomazygote s Makings between F1 heterozygotes

woman. All their children wil l have one copy of each allele , i.e. are Ff ,
Overview and i t is found tha t al l such childre n hav e fre e earlobe s because F i s
Gregor Mendel's law s of inheritanc e were derive d fro m experiment s dominant tof. Th e children constitut e th e first filial generation or Fl
with plants, but they form the cornerstone of the whole science of genet- generation (irrespective o f the symbo l fo r the gene unde r considera-
ics. Previously heredity was considered in terms of the transmission and tion). Individual s wit h identica l allele s ar e homozygotes; thos e wit h
mixing o f 'essences' , a s suggeste d b y Hippocrate s ove r 200 0 year s different allele s are heterozygotes .
before. But , unlike fluid essences tha t should blend in the offspring i n The secon d filial , o r F2 , generatio n i s compose d o f th e grand -
all proportions , Mende l showe d tha t th e instruction s for contrastin g children of the original couple, resulting from mating of their offspring
characters segregat e an d recombin e i n simpl e mathematica l propor - with partner s of simila r genotype. In eac h cas e bot h parent s ar e het-
tions. He therefore suggested that the hereditary factors are particulate. erozygotes, s o both produce F and /gamete s i n equal numbers . This
Mendel postulated fou r new principles concerning uni t inheritance, creates three genotypes in the F2: FF, //(identical lofF) andff, in the
dominance, segregation and independent assortment that appl y t o ratio: 1:2:1.
most genes of all diploid organisms . Due to the dominance of F over/, dominant homozygotes arepheno-
typicallythe sam e as heterozygotes, s o there ar e three offsprin g wit h
The principle o f unit inheritance free earlobe s to each on e with attached. Thephenotypic ratio 3:1 is
Hereditary characters are determined by indivisible units of informa- characteristic of the offspring of two heterozygotes.
tion (which we now call genes). An allele is one version of a gene.
The principle o f independent assortmen t
The principle of dominance Different genes control different phenotypic characters and the
Alleles occur in pairs in each individual, but the effects of one allele
alleles of different genes reassort independently of one another.
may be masked by those of a dominant partner allele.

The principle o f segregation Example

During formation of the gametes the members of each pair ofalleles Auburn an d 'red ' hai r occu r naturall y onl y i n individual s wh o ar e
separate, so that each gamete carries only one allele of each pair. homozygous fo r a recessive allel e r . Non-re d i s dominant , wit h th e
Allele pairs are restored at fertilization. symbol R . Al l red-haire d peopl e ar e therefor e rr , whil e non-re d ar e
either RR or Rr.
Example Consider the mating between an individual with red hair and attached
The earlobes of some people have an elongated attachmen t t o the neck earlobes (rrff )and a partner wh o i s heterozygous a t both genetic loc i
while others are free, a distinction determined by two alleles of the same (RrFf). Th e recessiv e homozygot e ca n produc e onl y on e kin d o f
gene,/for attached, F for free. gamete, o f genotyp e rf, bu t th e doubl e heterozygot e ca n produc e
Consider a man carrying two copies of F (i.e. FF), with free earlobes, gametes of fou r genotypes : RF , Rf, r F an d rf . Offsprin g o f fou r geno -
married to a woman with attached earlobes and two copies of/(i.e. ff) . types are produced: RrFf, Rrff, rrFfand rrff an d these are i n the ratio
Both ca n produc e onl y one kin d o f gamete , F fo r th e man,/fo r th e 1:1:1:1.

38 Medical genetics
 Mating of a double heterozygote with a double Mating of a double hetero^g ote wth a
recessive homozygote double dominant homozygote

Matings between double heterozygotes

These offspring also have phenotype s tha t ar e all different: non-re d 1a child with non-red hai r and free earlobes (R-F-), a s 9/16;
with fre e earlobes , non-red wit h attached, red wit h free, an d red wit h 2a child with non-red hai r and attached earlobes (R-ff), a s 3/16;
attached, respectively. 3a child with red hair and free earlobes (rrF-), a s 3/16; and
4a child with red hair and attached earlobes (rrff), a s 1/16.
The test-mating
The mating described above , in which one partner is a double recessive Biological support for Mendel's laws
homozygote (rrff), constitute s a test-mating, a s hi s o r he r recessiv e The behaviour of Mendel's factors (alleles) coincides with the observed
alleles allow expression o f all the alleles of the partner . properties and behaviour of the chromosomes: (i ) both occur in homol-
The valu e of such a test i s revealed by comparison with mating s i n ogous pairs; (ii) at meiosis both separate, but reunite at fertilization; and
which the recessive partner i s replaced by a double dominan t homozy - (iii) the homologues o f both segregate and recombine independently o f
gote (RRFF). Th e new partner can produce only one kind of gamete, of one another . This coincidence is because th e genes ar e components of
genotype RF, and fou r genotypically different offsprin g ar e produced, the chromosomes .
again in equal proportions: RRFF, RRFf, RrFF an d RrFf. H owever, due
to dominance all have non-red hair and free earlobes, so the genotype of Exceptions to Mendel's law s
the heterozygous parent remains obscure. 1 Sex-relate d effects (see Chapter 20) .
2 Mitochondria l inheritance (see Chapter 20).
Matings between double heterozygotes 3 Geneti c linkag e (see Chapter 27) .
The triumphant mathematica l proo f o f Mendel law s wa s provided b y 4 Polygeni c condition s (se e Chapters 22, 23).
matings between pairs of double heterozygotes. Each ca n produce four 5 Incomplet e penetranc e (se e Chapter 19) .
kinds of gametes: RF , Rf, r F and rf, whic h combined at random produc e 6 Genomi c imprinting (see Chapter 19).
nine differen t genotypi c combinations . Due t o dominance there ar e 7 Dynami c mutations (see Chapter 19) .
four phenotypes, i n the ratio 9:3:3:1 (total = 16). This allow s us to
predict the odds of producing:

Mendel's laws 3 9
17 Autosoma l dominant inheritanc e

P^rt of original pedigree for braehydaetyly AchondropJasfa Risk of transmi00iofi of

achondroplasia In a marriage
between two achondropfaslcs

Es-fcimatlon of risk for ofPspring*

autosomal dominant fntieritance
Marfsti syndrome

Overview The pedigree diagram

The best way to represent the distribution of affected individuals within Females are symbolized by circles (O), males by squares (D), persons
a family is with a pedigree diagra m (se e Chapter 35). From thi s the of unknown sex by diamonds (O). Individuals affected b y the disorder
mode of inheritance can often be easily deduced. are represente d b y solid symbol s (•, •) , thos e unaffected , b y open

40 Medical genetics
symbols (O , D). Marriages or matings are indicated b y horizontal line s Unaffected member s of affecte d familie s ar e normal homozygote s
linking mal e an d femal e symbols . Offsprin g ar e show n beneat h th e and so do not transmit the condition: bbxbb — > bb
parental symbols, in order of birth from left to right, linked to the mating
line by a vertical, and numbered (1,2, 3, etc.) from left to right in Arabic Estimation of risk
numerals. Th e generation s ar e indicate d i n Roma n numeral s (I , II , In simply inherited autosomal dominant conditions where the diagnosis
III, etc. ) fro m to p t o botto m o n th e left , wit h th e earlies t generatio n is secure, estimation of risk for the offspring of a family member can be
labelled I. based simpl y on the predictions o f Mendel's laws . For example :
The patien t wh o stimulate d th e investigation , th e propositu s 1 Fo r the offspring o f a heterozygote an d a normal homozygot e (B b x
(female: proposita), proband , o r index case, is shown by an arrow (71) bb^lBb; \bb};
with the letter P. The individual who sought genetic advice (the consult- risk of B- =1/2, or 50% .
and) i s show n b y a n arro w withou t th e P . (N.B . i n olde r text s 2 Fo r the offspring of two heterozygotes (BbxBb - > IBB; 2Bb; \bb}\
the proband is indicated by an arrow alone). A diagonal line through the risk of £- = 3/4, or 75%.
symbol indicates death. 3 Fo r the offspring of a dominant homozygote wit h a normal partner
(BBxbb^(Bb);
Rules for autosomal dominant inheritanc e risk of B- =1, or 100% .
The followin g ar e th e rule s fo r simpl e autosoma l dominan t Calculations involving dominant conditions can, however, be problem-
inheritance. atical a s w e usuall y d o no t kno w whethe r a n affecte d offsprin g i s
1 Both males and females express the allele and can transmit it homozygous or heterozygous (see Chapter 36).
equally to sons and daughters.
2 Excludin g ne w mutation s an d non-penetranc e (se e Chapte r 19) , Clinical examples
every affected person ha s a n affected parent ('vertical ' patter n o f Over 4000 autosomal dominan t diseases ar e known, although few are
expression i n the pedigree). Direct transmission through three gen- common (> 1/5000; see also Chapter 35) .
erations is practically diagnostic of a dominant.
3 In offected families, the ratio of affected to unaffected children is Achondroplasia (achondroplastic dwarfism)
almost always 1:1. Achondroplasia cause s sever e shortenin g o f th e lon g bone s o f th e
4 If both parents are unaffected, all the children are unaffected. limbs, depression o f the bridge of the nose and lumbar lordosis (exag-
gerated forwar d curvatur e of the spine). It is due to mutations in fibro-
Example blast growt h facto r receptor , FGF R 3 , an d i s letha l prenatall y i n
The firs t conditio n i n humans fo r whic h th e mod e of inheritanc e wa s homozygotes. Livebor n offspring of two persons wit h achondroplasi a
elucidated was brachydactyly, characterize d by abnormally short pha- (Ac ac ) therefor e hav e a two-third s ris k o f bein g affected , not three -
langes (distal joints of fingers and toes). quarters (see figure).
In Mendelia n symbols , the dominant allele B cause s brachydactyly
and ever y affecte d individua l i s eithe r a homozygot e (BB), o r a Acute intermittent porphyria
heterozygote (Bb). I n practice most are heterozygotes, becaus e brachy- The porphyria s ar e characterized b y occasional excretio n o f red por -
dactyly i s a rare trait (i.e . < 1/5000 births), as are almost al l dominant phyrin in the urine. Much of the time they are asymptomatic, but severe
disease alleles. Unrelate d marriage partners are therefore usually reces- neurological symptom s can occur during starvation, or following con -
sive homozygotes (bb} an d the mating can be represented : sumption of certain chemicals. It is therefore an example of a pharma-
Bbxbb cogenetic trai t (se e Chapter 19) .
I
Bb,bb Marfan syndrome
1: 1 Patients ar e tall, with long, thi n limb s an d fingers and dislocate d ey e
lenses, pectus excavatum (funnel chest ) and a high-arched palate. The
Dominant disease allele s ar e kept at low frequency sinc e their carriers aorta is susceptible to aneurysm (swelling) which if left untreate d may
are less fit than normal homozygotes. lead to rupture. The underlying defect is in the protein fibrillin-1, in the
Matings between heterozygote s ar e the onl y kind that can produc e periosteum, an d connectiv e tissue . Expressio n i s variabl e an d onl y
homozygous offspring: some features ma y occur in any patient (see figure).
BbxBb
I Estimation of mutation rate
BB, Bb, bb The frequenc y o f dominan t diseases i n familie s wit h n o prio r case s
1:2:1, i.e. 3 affected: 1 unaffected . can b e use d t o estimate the natura l frequenc y of new poin t mutations
(see Chapter 29) . This varies widely between genes , but averages abou t
Dominant disease allele homozygotes are rare and with many
one even t i n an y specifi c gen e pe r 50000 0 zygotes . Almost al l point
disease alleles homozygosity i s lethal. Mating s between heterozygote s
mutations aris e i n sperm , eac h containin g aroun d 4000 0 gene s (se e
may involve inbreeding (see Chapter 18) , or occur when patients have
Chapter 4) . Ther e ar e therefor e abou t 40000 mutation s pe r 50000 0
met as a consequence of their disability (e.g . at a clinic for the disorder).
sperm an d w e ca n expec t aroun d 8% o f viabl e sperm (an d babies) t o
All offspring of affected homozygotes are affected:
carry a new genetic mutation. However, only a minority of these occurs
BBxbb within genes that produce clinically significant effects, or would behave
I as dominant traits.
Bb
Autosomal dominant inheritance 4 1
18 Autosoma l recessive inheritanc e

First-cousin marriage between heterozygotes Degrees of relationship with proband

Marriage between recessive homozygote and

heterozygote
Marriage between recessiv e homozygote s

Cumulative postnatal mortalities among 3442 A family pedigree showing two kind s of
offspring of first cousins and 5224 offspring of recessive deafness
unrelated parents

Overview 4 When both parents are affected all the children are affected.
The pedigree diagram for a family in which autosomal recessive diseas e 5 Affected individuals with normal partners usually have only
is present differs markedly fro m those with other form s of inheritance . normal children.
Recessive diseases ca n be relatively common, as heterozygous carriers
can preserve an d transmit disease allele s without adverse selection . Example
Homozygotes for oculocutaneous albinism (albinos) represen t around
Rules o f autosomal recessiv e inheritanc e 1 in 10 000 births. They have very pale hair and skin, blue or pink irides
The followin g ar e th e rule s fo r simpl e autosoma l recessiv e and red pupils. They suffer fro m photophobia (avoidanc e of light) and
inheritance: involuntary eye movements called nystagmus, relate d t o faults in the
1 Both males and females are affected. neural connections between eye and brain. Their biochemica l defec t is
2 There are breaks in the pedigree an d typically the pattern of expres- in the enzyme tyrosinase, which normally convert s tyrosine , throug h
sion is 'horizontal' (i.e . sibs are affected, bu t parents are not). dihydroxy-phenylalanine (DOPA), into DOPA quinone, a precursor of
3 Affected children can be born to normal parents, usually in the ratio the dark pigment, melanin (se e Chapter 39).
of one affected to three unaffected. Every albin o is a recessive homozygot e (aa) and most ar e born t o

42 Medical genetics
phenotypically norma l parents, who can also produce norma l homozy- Phenylketonuria
gotes an d heterozygote s i n th e rati o o f on e dominan t homozygot e t o In phenylketonuria, levels of phenylalanine and its breakdown product s
two pigmented heterozygote s t o one albino: are elevate d i n th e urin e and blood , causin g sever e menta l handicap ,
muscular hypertonicit y an d reduce d pigmentation . Th e mos t usua l
AaxAa — » \A A : 2Aa: laa; three pigmented : one albin o
defect i s i n phenylalanin e hydroxylase , whic h normall y convert s
Matings betwee n albino s produce onl y albino babies: dietary phenylalanine into tyrosine. Screening i s routinely carried ou t at
birth and homozygotes ar e given phenylalanine-free diet s (see Chapter
aa x aa — > aa
42).
Albinos wit h normall y pigmente d partner s usuall y produc e onl y
pigmented offsprin g as the albinism allele i s relatively rare: Congenital deafnes s
There ar e man y (>30 ) non-syndromic, autosoma l recessiv e form s o f
aaxAA -^ Aa
congenital deafnes s tha t mimi c on e anothe r a t th e gros s phenotypi c
Occasionally, however , a normally pigmented partne r is a heterozygot e level in that all homozygotes ar e deaf. The frequenc y of heterozygote s
and a half of the children of such matings are recessive homozygotes : is abou t 10% . The children o f tw o deaf parents ma y have perfect
hearing if the parents are homozygous for mutant recessive alleles at
aaxAa —>Aa,aa; 1 pigmented: 1 albino
different loci.
Superficially th e latte r patter n resemble s tha t du e t o dominan t If allele s d an d e bot h caus e deafnes s i n th e homozygou s state , a
heterozygotes with normal partner s (se e Chapter 17 ) and so is referre d mating between two deaf homozygotes coul d be represented:
to as 'pseudodominance'.
dd£E x DDe e
Recessive diseases can be common i n reproductively close d popula -
deaf dea f
tions and molecula r test s ar e used t o identif y unaffected carriers . Th e
frequency of heterozygotes can be calculated from that of homozygotes
4
DdEe
by the Hardy-Weinberg law (see Chapter 26).
all offspring have normal hearing.
Estimation o f risk
Recessive homozygote s ar e produce d b y thre e kind s o f mating ,
Consanguineous mating s
Consanguinity mean s tha t partner s shar e a t leas t on e ancestor .
although the first of these is by far the most common .
Inbreeding between consanguineou s partners is potentially harmful as
1 Tw o heterozygotes: AaxAa— > \AA:2Aa: laa;risk = 1/4,0.25 or 25%.
it bring s recessive allele s 'identica l b y descent ' int o th e homozygou s
2 Recessiv e homozygot e an d heterozygote : a a x A a —> lAa: laa;
state i n th e offspring . Incestuou s matings , e.g. between paren t an d
risk= 1/2 , 0.5 or 50% .
child, o r sib s (brothe r an d sister ) involve the greates t risk . Th e prob -
3 Tw o recessive homozygotes: aa x aa — > aa; ris k = 1 or 100% .
ability that a particular allele present in one individual is present also in
an incestuou s partne r i s 0.5 . I f eac h o f u s i s heterozygou s fo r on e
Clinical example s (se e also Chapter 35)
Cystic fibrosis harmful (bu t non-lethal) recessive allele, the probabilit y of a homozy-
Cystic fibrosi s i s th e mos t commo n recessiv e diseas e i n Europeans , gous recessive offspring resulting from incestuou s mating is:
affecting on e i n 1800-250 0 live births . It affects many system s o f th e 0.5x0.25 = 0.125, or 1/8.
body, but especiall y th e lung s and pancrea s an d i s letha l if untreated.
The basic defect i s in chloride ion transport. For marriage s betwee n firs t cousins , the equivalen t figures are 1/ 8
that a n allele i s shared and 1/3 2 (3%) that a homozygous bab y wil l b e
Tay-Sachs diseas e produced. Thi s accord s wit h th e observe d frequenc y o f recessiv e
The incidenc e o f Tay-Sach s diseas e i n American non-Jew s i s on e i n disease among offsprin g of first-cousin marriages, althoug h tha t figure
360000, but i t is a hundred times as common ( 1 i n 3600) in American excludes early miscarriages.
Ashkenazi Jews . I t affect s th e entir e nervou s syste m an d i s lethal , Recessive diseas e occurs in outbred marriage s at one-quarter o f the
usually b y th e ag e o f 2 years . Th e basi c defec t i s a deficienc y i n square o f th e heterozygot e frequenc y (see Chapter 26 ) an d average s
hexosaminidase A (see Chapter 39). about 2% ' overall . I n general, th e rare r the disease and th e greate r th e
frequency o f consanguineou s marriages, th e highe r the proportio n o f
Spinal muscular atroph y recessive homozygotes produce d b y them.
Spinal muscula r atroph y i s a progressiv e muscula r weaknes s du e t o The offsprin g o f first-cousin marriage s have 2.5 times as many con-
degeneration of the anterior horn cells of the spinal cord. The infantile genital malformations and 70% higher postnatal mortality than those of
form ha s a carrier frequency of 1/3 0 and is lethal by the age of 3 years. outbred matings, both features of decreased vigour , known as inbreed -
Juvenile forms ar e less common an d progress more slowly . The collec- ing depression.
tive incidence i s 1/1000 0 births.

Autosomal recessive inheritance 4 3

19 Intermediat e inheritance

PomJttince and codominance in the A simplified pedigree for ectrodactyty, showing

AEQ blood groups incomplete penetrance

Age of onset of Huntiftgtoii disease

Causation of FmderHWH an4 An0efman syndromes

44 Medical genetics
acted

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MAMMALS ARAB a
Photo and English

their Zoological we

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117

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124
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107
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Baden it illustration

fish there
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in TERRIERS The

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48

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