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Molecular Hematology
Molecular
Hematology
FOURTH EDITION
Edited by
Drew Provan MD FRCP FRCPath
Emeritus Reader in Autoimmune Haematology
Department of Haematology
Barts and The London School of Medicine and Dentistry
Queen Mary University of London, UK
John G. Gribben MD DSc FRCP FRCPath FMedSci

Professor of Medical Oncology
Barts Cancer Institute
Barts and The London School of Medicine and Dentistry
Queen Mary University of London, UK
This edition first published 2020
© 2020 by John Wiley & Sons
Edition History [3rd edition, 2010]
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Library of Congress Cataloging-in-Publication Data
Names: Provan, Drew, editor. | Gribben, John editor.
Title: Molecular hematology / edited by Drew Provan, John G. Gribben.
Description: Fourth edition. | Hoboken, NJ : Wiley-Blackwell, 2020. | Includes bibliographical
references and index.
Identifiers: LCCN 2019034376 (print) | LCCN 2019034377 (ebook) | ISBN 9781119252870 (hardback) |
ISBN 9781119252955 (adobe pdf) | ISBN 9781119252931 (epub)
Subjects: MESH: Hematologic Diseases | Molecular Biology–methods
Classification: LCC RC636 (print) | LCC RC636 (ebook) | NLM WH 120 | DDC 616.1/5–dc23
LC record available at https://lccn.loc.gov/2019034376
LC ebook record available at https://lccn.loc.gov/2019034377
Cover Design: Wiley
Cover Image: © JUAN GAERTNER/SCIENCE PHOTO LIBRARY/Getty Images
Set in 10/12pt MinionPro by Aptara Inc., New Delhi, India
10 9 8 7 6 5 4 3 2 1
Dedication
We would like to dedicate this book to two people: our dear friend and colleague, Professor Sir David Weatherall, who sadly
passed away on 8 December 2018. He was truly a pioneer of molecular biology and was the first physician scientist to use
molecular techniques to study hematological disease. We will all miss him very much.
In addition, we would like to dedicate the book to Val Provan. Always in our thoughts and much missed.
Contents
Contributors, ix 13 The molecular basis of iron metabolism, 161

Preface to the fourth edition, xiii Nancy C. Andrews & Tomas Ganz
Further reading, xv 14 Hemoglobinopathies due to structural mutations, 173

D. Mark Layton & Steven Okoli
Acknowledgments, xvi
15 Molecular pathogenesis of malaria, 193
David J. Roberts, Arnab Pain & Chetan E. Chitnis
1 Beginnings: the molecular pathology of hemoglobin, 1
16 Molecular coagulation and thrombophilia, 207
David Weatherall
Björn Dahlbäck & Andreas Hillarp
2 Stem cells, 21
17 The molecular basis of hemophilia, 221
David T. Scadden
Daniel P. Hart & Paul L.F. Giangrande
3 The genetics of acute myeloid leukemias, 37
18 The molecular basis of von Willebrand disease, 235
Amy M. Trottier & Carolyn J. Owen
Luciano Baronciani
4 Molecular diagnostics and risk assessment in
19 Platelet disorders, 251
myeloid malignancies, 49
Kenneth J. Clemetson
Christian Scharenberg & Torsten Haferlach
20 The molecular basis of blood cell alloantigens, 267
5 Molecular basis of acute lymphoblastic leukemia, 59
Cristina Navarrete, Louise Tilley, Winnie Chong
Bela Patel & Fiona Fernando
& Colin J. Brown
6 Chronic myeloid leukemia, 71
21 Functions of blood group antigens, 285
Hagop Kantarjian, Jorge Cortes, Elias Jabbour &
Jonathan S. Stamler & Marilyn J. Telen
Susan O’Brien
22 Autoimmune hematological disorders, 297
7 Myeloproliferative neoplasms, 87
Drew Provan & John W. Semple
Jyoti Nangalia, Anthony J. Bench, Anthony R.
Green & Anna L. Godfrey 23 Molecular therapeutics in hematology: gene
therapy, 319
8 Lymphoma genetics, 101
William M. McKillop & Jeffrey A. Medin
Jennifer L. Crombie, Anthony Letai & John G. Gribben
24 Pharmacogenomics, 339
9 The molecular biology of chronic lymphocytic
Leo Kager & William E. Evans
leukemia, 111
John G. Gribben 25 History and development of molecular biology, 353
Paul Moss
10 The molecular biology of multiple myeloma, 121
Wee Joo Chng & P. Leif Bergsagel 26 Cancer stem cells, 363
Sara Ali & Dominique Bonnet
11 The molecular basis of bone marrow failure
syndromes and red cell enzymopathies, 131 27 Molecular basis of transplantation, 373
Deena Iskander, Lucio Luzzatto & Anastasios Francesco Dazzi & Antonio Galleu
Karadimitris
12 Anemia of chronic disease, 155 Index, 389
Tomas Ganz
vii
Contributors
Sara Ali MD Kenneth J. Clemetson PhD, ScD, CChem, FRSC

Haematopoietic Stem Cell Laboratory, The Francis Crick Department of Haematology, Inselspital, University of Berne,
Institute, London, UK Berne, Switzerland
Nancy C. Andrews MD, PhD Jorge Cortes MD

Duke University School of Medicine, Durham, NC, USA Department of Leukemia, University of Texas MD Anderson
Cancer Center, Houston, TX, USA
Luciano Baronciani PhD
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlin- Jennifer L. Crombie MD
ico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Department of Medical Oncology, Dana-Farber Cancer
Center, Milan, Italy Institute, Harvard Medical School, Boston, MA, USA
Anthony J. Bench MA, PhD Björn Dahlbäck MD, PhD

Laboratory Medicine, NHS Lothian, Edinburgh, UK Department of Translational Medicine, Section of Clinical
Chemistry, Lund University, University Hospital, Malmö,
P. Leif Bergsagel MD Sweden
Division of Hematology-Oncology, Comprehensive Cancer
Center, Mayo Clinic Arizona, Scottsdale, AZ, USA Francesco Dazzi MD, PhD
School of Cancer & Pharmaceutical Sciences, King’s College
Dominique Bonnet PhD London; King’s Health Partners Cancer Research UK Centre,
Haematopoietic Stem Cell Laboratory, The Francis Crick London, UK
Institute, London, UK
William E. Evans PharmD
Colin J. Brown PhD, FRCPath St Jude Children’s Research Hospital, Memphis, TN, USA
Histocompatibility and Immunogenetics Laboratory, NHS
Blood and Transplant; Faculty of Life Sciences & Medicine,
Fiona Fernando MD
King’s College London, London, UK
Centre of Haemato-Oncology, Barts Cancer Institute, Queen
Mary University of London, London, UK
Chetan E. Chitnis MSc, MA, PhD
Malaria Group, Pasteur Institute, Paris, France
Antonio Galleu MD, PhD
School of Cancer & Pharmaceutical Sciences, King’s College
Wee Joo Chng MB ChB, MRCP, FRCPath London; King’s Health Partners Cancer Research UK Centre,
National University Cancer Institute, National Univer- London, UK
sity Health System of Singapore; University of Singapore,
National University Hospital, Singapore
Tomas Ganz PhD, MD
Department of Medicine, David Geffen School of Medicine
Winnie Chong PhD
at UCLA, Los Angeles, CA, USA
Histocompatibility and Immunogenetics Service Develop-
ment Laboratory, NHS Blood and Transplant, London, UK
ix
x Contributors
Paul L.F. Giangrande MD, FRCP, FRCPath, FRCPCH Anthony Letai MD, PhD
Formerly of Oxford Haemophilia and Thrombosis Centre, Department of Medical Oncology, Dana-Farber Cancer
Churchill Hospital, Oxford, UK Institute, Harvard Medical School, Boston, MA, USA
Anna L. Godfrey PhD, MRCP, FRCPath Lucio Luzzatto MD

Department of Haematology, Cambridge University Hospi- Department of Haematology and Blood Transfusion,
tals NHS Foundation Trust, Cambridge, UK Muhimbili University College of Health Sciences, Dar-es-
Salaam, Tanzania
Anthony R. Green PhD, FRCP, FRCPath, FMedSci
Department of Haematology, Cambridge Institute for Medi- William M. McKillop PhD
cal Research; Wellcome Medical Research Council Stem Cell Department of Pediatrics, Medical College of Wisconsin,
Institute, Cambridge, UK Milwaukee, WI, USA
John G. Gribben MD, DSc, FRCP, FRCPath, FMedSci Jeffrey A. Medin PhD
Barts Cancer Institute, Barts and The London School of Departments of Pediatrics and Biochemistry, Medical Col-
Medicine and Dentistry, Queen Mary University of London, lege of Wisconsin, Milwaukee, WI, USA
London, UK
Paul Moss MD, PhD
Torsten Haferlach MD School of Cancer Sciences, University of Birmingham, Birm-
MLL Munich Leukemia Laboratory, Munich, Germany ingham, UK
Daniel P. Hart FRCP, FRCPath, PhD
Jyoti Nangalia PhD, MRCP, FRCPath
The Royal London Hospital Haemophilia Centre, Barts and
Welcome Sanger Institute, Hinxton; Department of Haema-
The London School of Medicine and Dentistry, Queen Mary
tology, University of Cambridge; Wellcome-Medical
University of London, London, UK
Research Council Cambridge Stem Cell Institute, Cam-
bridge, UK
Andreas Hillarp PhD
Department of Clinical Chemistry and Transfusion
Cristina Navarrete PhD, FRCPath
Medicine, Halland County Hospital, Halmstad, Sweden
Histocompatibility and Immunogenetics Service Develop-
ment Department, NHS Blood and Transplant; Department
Deena Iskander MD, PhD, MRCP
of Immunology and Molecular Pathology, University College
Centre for Haematology, Imperial College London, Ham-
London, London, UK
mersmith Hospital, London, UK
Elias Jabbour MD Susan O’Brien MD

Department of Leukemia, University of Texas MD Anderson Department of Leukemia, University of Texas MD Anderson
Cancer Center, Houston, TX, USA Cancer Center, Houston, TX, USA
Leo Kager MD Steven Okoli MBChB, FRCP, FRCPath

Department of Pediatrics, St. Anna Children’s Hospital, Center for Hematology, Imperial College London, London,
Medical University Vienna, Austria UK
Hagop Kantarjian MD Carolyn J. Owen MD, MDres(UK), FRCPC

Department of Leukemia, University of Texas MD Anderson Division of Hematology and Hematological Malignancies,
Cancer Center, Houston, TX, USA University of Calgary, Foothills Medical Centre, Calgary,
Canada
Anastasios Karadimitris PhD, MRCP, FRCPath
Department of Haematology and Blood Transfusion, Arnab Pain PhD
Muhimbili University College of Health Sciences, Dar-es- Biological and Environmental Sciences and Engineering
Salaam, Tanzania (BESE) Division, King Abdullah University of Science and
Technology, Jeddah, Saudi Arabia; Nuffield Division of Clin-
D. Mark Layton MB BS, FRCP, FRCPCH ical Laboratory Sciences (NDCLS), The John Radcliffe Hos-
Center for Hematology, Imperial College London, London, pital, University of Oxford, Headington, Oxford, UK
UK
Contributors xi
Bela Patel MD, FRCPath, MD(res) Jonathan S. Stamler MD

Centre of Haemato-Oncology, Barts Cancer Institute, Queen Harrington Discovery Institute and Institute of Transfor-
Mary University of London, London, UK mative Molecular Medicine, University Hospitals Cleveland
Medical Center and Case Western Reserve University, Cleve-
Drew Provan MD, FRCP, FRCPath land, OH, USA
Blizard Institute, Barts and The London School of Medicine
and Dentistry, Queen Mary University of London, London, Marilyn J. Telen MD
UK Department of Medicine, Division of Hematology, Duke
University Medical Center, Durham, NC, USA
David J. Roberts DPhil, MRCP, FRCPath
National Health Service Blood and Transplant (Oxford), The Louise Tilley PhD
John Radcliffe Hospital, Oxford, UK International Blood Group Reference Laboratory, NHS
Blood and Transplant, Bristol, UK
David T. Scadden MD
Department of Stem Cell and Regenerative Biology, Harvard Amy M. Trottier MSc, MD, FRCPC
Stem Cell Institute, Harvard University; Center for Regenera- Division of Hematology and Hematological Malignancies,
tive Medicine, Massachusetts General Hospital, Boston, MA, University of Calgary, Foothills Medical Centre, Calgary,
USA Canada
Christian Scharenberg MD, PhD David Weatherall MD, FRCP, FRS

Department of Hematology, Skaraborgs Hospital, Skövde; Formerly of Weatherall Institute of Molecular Medicine, The
Department of Cell and Molecular Biology, Karolinska Insti- John Radcliffe Hospital, Oxford, UK
tute, Stockholm, Sweden
John W. Semple PhD

Division of Hematology and Transfusion Medicine, Lund
University, Lund, Sweden
Preface to the fourth edition
Hematology is a fast-moving discipline with innovation both ative neoplasms, myeloma, and myelodysplastic syndromes.
diagnostically and therapeutically. In the 19 years since the The huge array of biological markers makes stratification and
first edition of Molecular Hematology was published, many treatment much more sophisticated than ever before. All the
advances have been made. Molecular techniques have helped chapters dealing with malignant blood diseases have been
explain the basis of many diseases, starting initially with red thoroughly revised and brought up to date.
cell disorders and hemostasis. However, thanks to the use of However, despite the growing complexity in terms of
molecular biology we can now diagnose and stratify patients pathogenesis, diagnosis, and management of patients with
with diseases such as leukemia, myeloma, myeloproliferative blood diseases, the ethos of the book remains the same –
neoplasms, and others. Such advances in technology have not namely, to provide a succinct account of the molecular biol-
only helped explain the underlying basis of the diseases, but ogy of hematological disease written at a level where it should
have also provided targets for treatment. be of benefit to both the seasoned molecular biologist and
The world of red cells started the whole specialty of molec- the practicing clinician alike. We have retained the original
ular medicine and, using molecular biology techniques, structure for the chapters, high-quality artwork, and Further
many of the phenotypic features of red cell disorders have Reading sections in order to make the book visually appealing
been explained. This is discussed eloquently by the late Pro- and relevant to modern hematology practice.
fessor Sir David Weatherall at the beginning of the book. We very much hope you enjoy this edition and, as always,
Other non-malignant areas which have been updated include we welcome any comments or suggestions from readers,
the Functions of Blood Group Antigens, von Willebrand Dis- which we will attempt to incorporate into the next edition.
ease, and Platelet Disorders.
Undoubtedly, hemato-oncology has seen the biggest Drew Provan
explosion in terms of understanding the molecular basis of John Gribben
diseases such as leukemias, lymphomas, the myeloprolifer-
xiii
Further reading
Anderson, K.C. and Ness, P.M. (eds.) (2000). Scientific Basis of Transfu- Mullis, K.B. (1990). The unusual origin of the polymerase chain reac-
sion Medicine: Implications for Clinical Practice, 2e. Philadelphia, PA: tion. Scientific American 262: 56–65.
WB Saunders. Roitt, I. (2001). Roitt’s Essential Immunology, 10e. Oxford: Blackwell Sci-
Beutler, E. and Lichtman, M.A. (eds.). Williams’ Hematology, 6e. New ence.
York: McGraw-Hill. Stamatoyannopoulos, G., Nienhuis, A.W., Majerus, P.W., and Varmus,
Cooper, G.M. (1997). The Cell: A Molecular Approach. Washington, DC: H. (eds.) (2000). The Molecular Basise of Blood Diseases, 2e. Philadel-
ASM Press. phia, PA: W.B. Saunders.
Cox, T.M. and Sinclair, J. (1997). Molecular Biology in Medicine. Oxford: Watson, J.D., Gilman, M., Witkowski, J., and Zoller, M. (eds.) (1992).
Blackwell Science. Recombinant DNA, 2e. New York: Scientific American Books.
Jameson, J.L. (ed.) (1998). Principles of Molecular Medicine. New York:
Humana Press.
xv
Acknowledgments
We would like to express thanks to Claire Bonnett, Publisher, and Deirdre Barry, Senior Editorial Assistant, for their help with
this work.
xvi
Chapter 1 Beginnings: the molecular
pathology of hemoglobin
David Weatherall
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
Historical background, 1 Molecular aspects of the high frequency of the hemoglobin variants, 17
The structure, genetic control, and synthesis of normal hemoglobin, 2 Molecular aspects of the prevention and management of the
The molecular pathology of hemoglobin, 6 hemoglobin disorders, 18
Genotype–phenotype relationships in the thalassemias, 12 Postscript, 18
Structural hemoglobin variants, 16 Further reading, 18
within bacteria. The steady improvement in the proper-

Historical background ties of cloning vectors made it possible to generate libraries
of human DNA growing in bacterial cultures. Ingenious
Linus Pauling first used the term “molecular disease” in 1949,
approaches were developed to scan the libraries to detect
after the discovery that the structure of sickle cell hemoglobin
genes of interest; once pinpointed, the appropriate bacte-
differed from that of normal hemoglobin. Indeed, it was this
rial colonies could be grown to generate larger quantities of
seminal observation that led to the concept of molecular
DNA carrying a particular gene. Later it became possible
medicine, the description of disease mechanisms at the level
to sequence these genes, persuade them to synthesize their
of cells and molecules. However, until the development of
products in microorganisms, cultured cells, or even other
recombinant DNA technology in the mid-1970s, knowledge
species, and hence to define their key regulatory regions.
of events inside the cell nucleus, notably how genes function,
The early work in the field of human molecular genet-
could only be the subject of guesswork based on the structure
ics focused on diseases in which there was some knowl-
and function of their protein products. However, as soon as
edge of the genetic defect at the protein or biochemical level.
it became possible to isolate human genes and to study their
However, once linkage maps of the human genome became
properties, the picture changed dramatically.
available, following the identification of highly polymorphic
Progress over the last 30 years has been driven by techno-
regions of DNA, it was possible to search for any gene for a
logical advances in molecular biology. At first it was possible
disease, even where the cause was completely unknown. This
only to obtain indirect information about the structure and
approach, first called reverse genetics and later rechristened
function of genes by DNA/DNA and DNA/RNA hybridiza-
positional cloning, led to the discovery of genes for many
tion; that is, by probing the quantity or structure of RNA
important diseases.
or DNA by annealing reactions with molecular probes. The
As methods for sequencing were improved and automated,
next major advance was the ability to fractionate DNA into
thoughts turned to the next major goal in this field, which was
pieces of predictable size with bacterial restriction enzymes.
to determine the complete sequence of the bases that con-
This led to the invention of a technique that played a central
stitute our genes and all that lies between them: the Human
role in the early development of human molecular genetics,
Genome Project. This remarkable endeavor was finally com-
called Southern blotting after the name of its developer, Edwin
pleted in 2006. The further understanding of the functions
Southern. This method allowed the structure and organiza-
and regulation of our genes will require multidisciplinary
tion of genes to be studied directly for the first time and led
research encompassing many different fields. The next stage
to the definition of a number of different forms of molecular
in the Human Genome Project, called genome annotation,
pathology.
entails analyzing the raw DNA sequence in order to deter-
Once it was possible to fractionate DNA, it soon became
mine its biological significance. One of the main ventures
feasible to insert the pieces into vectors able to divide
in the era of functional genomics will be in what is termed
proteomics, the large-scale analysis of the protein products of
Molecular Hematology, 4th Edition. Edited by Drew Provan and John G. Gribben.
genes. The ultimate goal will be to try to define the protein
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
1
2 Molecular Hematology
complement, or proteome, of cells and how the many dif-

ferent proteins interact with one another. To this end, large-
The structure, genetic control, and
scale facilities are being established for isolating and purify-
synthesis of normal hemoglobin
ing the protein products of genes that have been expressed
in bacteria. Their structure can then be studied by a vari- Structure and function
ety of different techniques, notably X-ray crystallography
The varying oxygen requirements during embryonic, fetal,
and nuclear magnetic resonance spectroscopy. The crys-
and adult life are reflected in the synthesis of different
tallographic analysis of proteins is being greatly facilitated
structural hemoglobins at each stage of human development.
by the use of X-ray beams from a synchrotron radiation
However, they all have the same general tetrameric struc-
source.
ture, consisting of two different pairs of globin chains, each
In the last few years both the utility and extreme com-
attached to one heme molecule. Adult and fetal hemoglobins
plexity of the fruits of the genome project have become
have α chains combined with β chains (Hb A, α2 β2 ),
apparent. The existence of thousands of single-nucleotide
δ chains (Hb A2 , α2 δ2 ), and γ chains (Hb F, α2 γ2 ). In
polymorphisms (SNPs) has made it possible to search for
embryos, α-like chains called ζ chains combine with γ
genes of biological or medical significance. The discovery of
chains to produce Hb Portland (ζ2 γ2 ), or with ε chains to
families of regulatory RNAs and proteins is starting to shed
make Hb Gower 1 (ζ2 ε2 ), while α and ε chains form Hb
light on how the functions of the genome are controlled,
Gower 2 (α2 ε2 ). Fetal hemoglobin is heterogeneous; there
and studies of acquired changes in its structure, epigenetics,
are two varieties of γ chain that differ only in their amino
promise to provide similar information. Recent develop-
acid composition at position 136, which may be occupied by
ments in new-generation sequencing of DNA and RNA are
either glycine or alanine; γ chains containing glycine at this
also providing invaluable information about many aspects
position are called G γ chains, those with alanine A γ chains
of gene regulation.
(Figure 1.1).
During this remarkable period of technical advance, con-
The synthesis of hemoglobin tetramers consisting of two
siderable progress has been made toward an understanding
unlike pairs of globin chains is absolutely essential for the
of the pathology of disease at the molecular level. This has
effective function of hemoglobin as an oxygen carrier. The
had a particular impact on hematology, leading to advances
classical sigmoid shape of the oxygen dissociation curve,
in the understanding of gene function and disease mecha-
which reflects the allosteric properties of the hemoglobin
nisms in almost every aspect of the field.
molecule, ensures that, at high oxygen tensions in the lungs,
The inherited disorders of hemoglobin – the thalassemias
oxygen is readily taken up and later released effectively at the
and structural hemoglobin variants, the commonest human
lower tensions encountered in the tissues. The shape of the
monogenic diseases – were the first to be studied systemati-
curve is quite different to that of myoglobin, a molecule that
cally at the molecular level and a great deal is known about
consists of a single globin chain with heme attached to it,
their genotype–phenotype relationships. This field led the
which, like abnormal hemoglobins that consist of homote-
way to molecular hematology and, indeed, to the develop-
tramers of like chains, has a hyperbolic oxygen dissociation
ment of molecular medicine. Thus, even though the genet-
curve.
ics of hemoglobin is complicated by the fact that different
The transition from a hyperbolic to a sigmoid oxygen
varieties are produced at particular stages of human devel-
dissociation curve, which is absolutely critical for normal
opment, the molecular pathology of the hemoglobinopathies
oxygen delivery, reflects cooperativity between the four
provides an excellent model system for understanding any
heme molecules and their globin subunits. When one of
monogenic disease and the complex interactions between
them takes on oxygen, the affinity of the remaining three
genotype and environment that underlie many multigenic
increases markedly; this happens because hemoglobin can
disorders.
exist in two configurations, deoxy(T) and oxy(R), where T
In this chapter I consider the structure, synthesis, and
and R represent the tight and relaxed states, respectively.
genetic control of the human hemoglobins, describe the
The T configuration has a lower affinity than the R for
molecular pathology of the thalassemias, and discuss briefly
ligands such as oxygen. At some point during the addition
how the complex interactions of their different genotypes
of oxygen to the hemes, the transition from the T to the R
produce a remarkably diverse family of clinical phenotypes;
configuration occurs and the oxygen affinity of the partially
the structural hemoglobin variants are discussed in more
liganded molecule increases dramatically. These allosteric
detail in Chapter 14. Readers who wish to learn more about
changes result from interactions between the iron of the
the methods of molecular genetics, particularly as applied to
heme groups and various bonds within the hemoglobin
the study of hemoglobin disorders, are referred to the reviews
tetramer, which lead to subtle spatial changes as oxygen is
cited at the end of this chapter.
taken on or given up.
Beginnings: the molecular pathology of hemoglobin 3
1 Kb
31 32 99 100 30 31 104 105
ζ ψζ ψα2 ψα1 α2 α1 θ1 ε Gγ Aγ ψβ δ β
16 11
ζ2ε2 ζ2γ2 α2ε2 α2γ2 α2β2 α2δ2

Hb Gower 1 Hb Portland Hb Gower 2 HbF HbA HbA2
Embryo Fetus Adult

Fig. 1.1 The genetic control of human hemoglobin production in embryonic, fetal, and adult life. The standard names for these genes
are as follows: Alpha genes HBA1 and HBA2, Beta gene HBB, Gamma genes HBG1 and HBG2, Delta gene HBD, and the embryonic genes HBE1
and HBZ.
The precise tetrameric structures of the different human In short, oxygen transport can be modified by a variety
hemoglobins, which reflect the primary amino acid of adaptive features in the red cell that include interactions
sequences of their individual globin chains, are also vital between the different heme molecules, the effects of CO2 , and
for the various adaptive changes that are required to ensure differential affinities for 2,3-BPG. These changes, together
adequate tissue oxygenation. The position of the oxygen with more general mechanisms involving the cardiorespira-
dissociation curve can be modified in several ways. For tory system, provide the main basis for physiological adapta-
example, oxygen affinity decreases with increasing CO2 ten- tion to anemia.
sion (the Bohr effect). This facilitates oxygen loading to the
tissues, where a drop in pH due to CO2 influx lowers oxygen
affinity; the opposite effect occurs in the lungs. Oxygen affin- Genetic control of hemoglobin
ity is also modified by the level of 2,3-diphosphoglycerate The α- and β-like globin chains are the products of two dif-
(2,3-BPG) in the red cell. Increasing concentrations shift ferent gene families which are found on different chromo-
the oxygen dissociation curve to the right (i.e. they reduce somes (Figure 1.1). The β-like globin genes form a linked
oxygen affinity), while diminishing concentrations have the cluster on chromosome 11, spread over approximately 60 kb
opposite effect. 2,3-BPG fits into the gap between the two β (kilobase or 1000 nucleotide bases). The different genes that
chains when it widens during deoxygenation, and interacts form this cluster are arranged in the order 5′ –ε–G γ–A γ–
with several specific binding sites in the central cavity of ψβ–δ–β–3′ . The α-like genes also form a linked cluster, in
the molecule. In the deoxy configuration the gap between this case on chromosome 16, in the order 5′ –ζ–ψζ–ψα1–
the two β chains narrows and the molecule cannot be α2–α1–3′ . The ψβ, ψζ, and ψα genes are pseudogenes; that
accommodated. With increasing concentrations of 2,3-BPG, is, they have strong sequence homology with the β, ζ, and
which are found in various hypoxic and anemic states, α genes, but contain a number of differences that prevent
more hemoglobin molecules tend to be held in the deoxy them from directing the synthesis of any products. They may
configuration and the oxygen dissociation curve is therefore reflect remnants of genes that were functional at an earlier
shifted to the right, with more effective release of oxygen. stage of human evolution.
Fetal red cells have greater oxygen affinity than adult The structure of the human globin genes is, in essence,
red cells, although, interestingly, purified fetal hemoglobin similar to that of all mammalian genes. They consist of long
has an oxygen dissociation curve similar to that of adult strings of nucleotides that are divided into coding regions,
hemoglobin. These differences, which are adapted to the oxy- or exons, and non-coding inserts called intervening sequences
gen requirements of fetal life, reflect the relative inability of (IVSs) or introns. The β-like globin genes contain two
Hb F to interact with 2,3-BPG compared with Hb A. This is introns, one of 122–130 base pairs between codons 30 and 31
because the γ chains of Hb F lack specific binding sites for and one of 850–900 base pairs between codons 104 and 105
2,3-BPG. (the exon codons are numbered sequentially from the 5′ to
the 3′ end of the gene, i.e. from left to right). Similar, though promoter elements: enhancers (regulatory sequences that
smaller, introns are found in the α and ζ globin genes. These increase gene expression despite being located at a con-
introns and exons, together with short non-coding sequences siderable distance from the genes) and “master” regulatory
at the 5′ and 3′ ends of the genes, represent the major func- sequences called, in the case of the β globin gene cluster, the
tional regions of the particular genes. However, there are also locus control region (LCR) and, in the case of the α genes,
extremely important regulatory sequences which subserve HS40 (a nuclease-hypersensitive site in DNA 40 kb from the
these functions that lie outside the genes themselves. α globin genes). Each of these sequences has a modular struc-
At the 5′ non-coding (flanking) regions of the globin ture made up of an array of short motifs that represent the
genes, as in all mammalian genes, there are blocks of binding sites for transcriptional activators or repressors.
nucleotide homology. The first, the ATA box, is about 30
bases upstream (to the left) of the initiation codon; that is, the
Gene action and globin synthesis
start word for the beginning of protein synthesis (see later).
The second, the CCAAT box, is about 70 base pairs upstream The flow of information between DNA and protein is sum-
from the 5′ end of the genes. About 80–100 bases further marized in Figure 1.2. When a globin gene is transcribed,
upstream there is the sequence GGGGTG, or CACCC, which messenger RNA (mRNA) is synthesized from one of its
may be inverted or duplicated. These three highly conserved strands, a process which begins with the formation of a tran-
DNA sequences, called promoter elements, are involved in scription complex consisting of a variety of regulatory pro-
the initiation of transcription of the individual genes. Finally, teins together with an enzyme called RNA polymerase (see
in the 3′ non-coding region of all the globin genes there later). The primary transcript is a large mRNA precursor
is the sequence AATAAA, which is the signal for cleavage which contains both intron and exon sequences. While in
and polyA addition to RNA transcripts (see Gene Action and the nucleus, this molecule undergoes a variety of modifica-
Globin Synthesis). tions. First, the introns are removed and the exons are spliced
The globin gene clusters also contain several sequences together. The intron/exon junctions always have the same
that constitute regulatory elements, which interact to pro- sequence: GT at their 5′ end, and AG at their 3′ end. This
mote erythroid-specific gene expression and coordination appears to be essential for accurate splicing; if there is a muta-
of the changes in globin gene activity during develop- tion at these sites this process does not occur. Splicing reflects
ment. These include the globin genes themselves and their a complex series of intermediary stages and the interaction
A
C C A
A C T T
C A A A T A
C A T T A A
C T A G A A
Flanking IVS 1 IVS 2 Flanking Gene
NC GT AG GT AG NC
5' 3' mRNA precursor
5' CAP Excision of introns

AAAA-A Splicing of exons
AAAA-A Processed mRNA
Nucleus
Cytoplasm
AAAA-A Translation
AUG UG
Ribosome ACC UUC UAA
U AC G AAG
Transfer RNA
Amino
acid Growing
chain
Finished
chain
Processed Fig. 1.2 The mechanisms of globin gene
chain transcription and translation.
of a number of different nuclear proteins. After the exons are the mRNA from left to right, and the growing peptide chain
joined, the mRNAs are modified and stabilized; at their 5′ end is transferred from one incoming tRNA to the next; that is,
a complex CAP structure is formed, while at their 3′ end a the mRNA is translated from 5′ to 3′ . During this time the
string of adenylic acid residues (polyA) is added. The mRNA tRNAs are held in appropriate steric configuration with the
processed in this way moves into the cytoplasm, where it mRNA by the two ribosomal subunits. There are specific
acts as a template for globin chain production. Because of initiation (AUG) and termination (UAA, UAG, and UGA)
the rules of base pairing – that is, cytosine always pairs with codons. When the ribosomes reach the termination codon,
thymine, and guanine with adenine – the structure of the translation ceases, the completed globin chains are released,
mRNA reflects a faithful copy of the DNA codons from which and the ribosomal subunits are recycled. Individual globin
it is synthesized; the only difference is that, in RNA, uracil (U) chains combine with heme, which has been synthesized
replaces thymine (T). through a separate pathway, and then interact with one like
Amino acids are transported to the mRNA template on chain and two unlike chains to form a complete hemoglobin
carriers called transfer RNAs (tRNAs); there are specific tetramer.
tRNAs for each amino acid. Furthermore, because the genetic
code is redundant (i.e. more than one codon can encode a
Regulation of hemoglobin synthesis
particular amino acid), for some of the amino acids there are
several different individual tRNAs. Their order in the globin The regulation of globin gene expression is mediated mainly
chain is determined by the order of codons in the mRNA. at the transcriptional level, with some fine tuning during
The tRNAs contain three bases, which together constitute an translation and post-translational modification of the gene
anticodon; these anticodons are complementary to mRNA products. DNA that is not involved in transcription is held
codons for particular amino acids. They carry amino acids tightly packaged in a compact, chemically modified form that
to the template, where they find the appropriate positioning is inaccessible to transcription factors and polymerases and is
by codon–anticodon base pairing. When the first tRNA is heavily methylated. Activation of a particular gene is reflected
in position, an initiation complex is formed between several by changes in the structure of the surrounding chromatin,
protein initiation factors together with the two subunits that which can be identified by enhanced sensitivity to nucleases.
constitute the ribosomes. A second tRNA moves in along- Erythroid lineage-specific nuclease-hypersensitive sites are
side and the two amino acids that they are carrying form found at several locations in the β globin gene cluster. Four
a peptide bond between them; the globin chain is now two are distributed over 20 kb upstream from the ε globin gene
amino acid residues long. This process is continued along in the region of the β globin LCR (Figure 1.3). This vital
–20 0 20 40 60 kb
5' HS 3' HS
4 3 2 1 1
ε Gγ Aγ δ β
Chromosome 11
LCR
–40 –20 0 20 40 kb
HS–40
ζ α2 α1
Chromosome 16
Fig. 1.3 The positions of the major regulatory regions in the β and α globin gene clusters. The arrows indicate the position of the
erythroid lineage-specific nuclease-hypersensitive sites. HS, hypersensitive.
regulatory region is able to establish a transcriptionally active Regulation of developmental changes

domain spanning the entire β globin gene cluster. Several in globin gene expression
enhancer sequences have been identified in this cluster. A
During development, the site of red cell production moves
variety of regulatory proteins bind to the LCR, and to the
from the yolk sac to the fetal liver and spleen, and thence
promoter regions of the globin genes and to the enhancer
to bone marrow in the adult. Embryonic, fetal, and adult
sequences. It is thought that the LCR and other enhancer
hemoglobin synthesis is approximately related in time to
regions become opposed to the promoters to increase
these changes in the site of erythropoiesis, although it is quite
the rate of transcription of the genes to which they are
clear that the various switches, between embryonic and fetal
related.
and between fetal and adult hemoglobin synthesis, are beau-
These regulatory regions contain sequence motifs for
tifully synchronized throughout these different sites. Fetal
various ubiquitous and erythroid-restricted transcription
hemoglobin synthesis declines during the later months of
factors. Binding sites for these factors have been identified in
gestation, and Hb F is replaced by Hb A and Hb A2 by the
each of the globin gene promoters and at the hypersensitive
end of the first year of life.
site regions of the various regulatory elements. A number
Although the exact mechanism of the switch from fetal to
of the factors which bind to these areas are found in all cell
adult hemoglobin is still not understood, recent studies of
types. They include Sp1, Yy1, and Usf. In contrast, a number
patients with unusually high levels of HbF and genome-wide
of transcription factors have been identified, including
association studies (GWAS) have yielded extremely promis-
GATA-1, EKLF, and NF-E2, which are restricted in their
ing information about some of the regulatory genes involved.
distribution to erythroid cells and, in some cases, megakary-
They include BCL11A, MYB, and KLF1. It is clear from stud-
ocytes, and mast cells. The overlapping of erythroid-specific
ies of these and related genes that they are involved directly in
and ubiquitous-factor binding sites in several cases suggests
the regulation of hemoglobin switching, work which is yield-
that competitive binding may play an important part in
ing great promise for the development of future technology
the regulation of erythroid-specific genes. Another binding
for increasing HbF synthesis to modify the phenotype of tha-
factor, SSP, the stage selector protein, appears to interact
lassemias and sickle cell anemia.
specifically with ε and γ genes. Several elements involving
the chromatin and histone acetylation required for access of
these regulatory proteins have been identified.
The binding of hematopoietic-specific factors activates the The molecular pathology
LCR, which renders the entire β globin gene cluster tran- of hemoglobin
scriptionally active. These factors also bind to the enhancer
and promoter sequences, which work in tandem to regu- As is the case for many monogenic diseases, the inherited dis-
late the expression of the individual genes in the clusters. It orders of hemoglobin fall into two major classes. First, there
is likely that some of the transcriptional factors are devel- are those that result from reduced output of one or other
opmental stage specific, and hence may be responsible for globin genes, the thalassemias. Second, there is a wide range
the differential expression of the embryonic, fetal, and adult of conditions that result from the production of structurally
globin genes. The α globin gene cluster also contains an ele- abnormal globin chains; the type of disease depends on how
ment, HS40, which has some structural features in common the particular alteration in protein structure interferes with
with the β LCR, although it is different in aspects of its struc- its stability or function. Of course, no biological classifica-
ture. A number of enhancer-like sequences have been identi- tion is entirely satisfactory and those which attempt to define
fied, although it is becoming clear that there are fundamental the hemoglobin disorders are no exception. There are some
differences in the pattern of regulation of the two globin gene structural hemoglobin variants which happen to be synthe-
clusters. sized at a reduced rate and hence are associated with a clini-
In addition to the different regulatory sequences outlined, cal picture similar to thalassemia. And there are other classes
there are also sequences which may be involved specifically of mutations which simply interfere with the normal tran-
with “silencing” of genes, notably those for the embryonic sition from fetal to adult hemoglobin synthesis, a family of
hemoglobins, during development. conditions given the general title hereditary persistence of fetal
Some degree of regulation is mediated by differences in hemoglobin (HPFH). Furthermore, because these diseases are
the rates of initiation and translation of the different mRNAs, all so common and occur together in particular populations,
and at the post-transcriptional level by differential affinity it is not uncommon for an individual to inherit a gene for
for different protein subunits. However, this kind of post- one or other form of thalassemia and a structural hemoglobin
transcriptional fine tuning probably plays a relatively small variant. The heterogeneous group of conditions that results
role in determining the overall output of the globin gene from these different mutations and interactions is summa-
products. rized in Table 1.1.
Table 1.1 The thalassemias and related disorders

Defective β globin gene transcription
There are a variety of mechanisms that interfere with nor-
α Thalassemia γ Thalassemia mal transcription of the β globin genes. First, the genes may
α0 be either completely or partially deleted. Overall, deletions
α+ δ Thalassemia
of the β globin genes are not commonly found in patients
Deletion (−α)
with β thalassemia, with one exception: a 619-bp deletion
Non-deletion (αT ) εγδβ Thalassemia
involving the 3′ end of the gene is found frequently in the
β Thalassemia Hereditary persistence of Sind populations of India and Pakistan, where it constitutes
β0 fetal hemoglobin about 30% of the β thalassemia alleles. Other deletions are
β+ Deletion
extremely rare.
Normal Hb A2 (δβ)0
A much more common group of mutations, which results
“Silent” Non-deletion
Dominant Linked to β globin genes
in a moderate decrease in the rate of transcription of the
β globin genes, involves single-nucleotide substitutions in
δβ Thalassemia G γβ+
or near the TATA box at about −30 nucleotides (nt) from
(δβ)+ A γβ+
the transcription start site, or in the proximal or distal pro-
(δβ)0 Unlinked to β globin genes
moter elements at −90 and −105 nt. These mutations result
(A γδβ)0
in decreased β globin mRNA production, ranging from 10%
to 25% of the normal output. Thus, they are usually associ-
Over recent years, determination of the molecular pathol- ated with the mild forms of β+ thalassemia. They are particu-
ogy of the two common forms of thalassemia, α and β, has larly common in African populations, an observation which
provided a remarkable picture of the repertoire of mutations explains the unusual mildness of β thalassemia in this racial
that can underlie human monogenic disease. In the sections group. One particular mutation, C → T at position −101 nt
that follow I describe, in outline, the different forms of molec- to the β globin gene, causes an extremely mild deficit of β
ular pathology that underlie these conditions. globin mRNA. Indeed, this allele is so mild that it is com-
pletely silent in carriers and can only be identified by its inter-
The β thalassemias action with more severe β thalassemia alleles in compound
heterozygotes.
There are two main classes of β thalassemia, β0 thalassemia,
in which there is an absence of β globin chain production,
Mutations that cause abnormal processing
and β+ thalassemia, in which there is a variable reduction
of mRNA
in the output of β globin chains. As shown in Figure 1.4,
mutations of the β globin genes may cause a reduced output As mentioned earlier, the boundaries between exons and
of gene product at the level of transcription or mRNA introns are marked by the invariant dinucleotides GT at the
processing, or translation, or through the stability of the donor (5′ ) site and AG at the acceptor (3′ ) site. Mutations that
globin gene product. affect either of these sites completely abolish normal splicing
Deletions
I IVSI 2 IVS 2 3
PR C I FS SPL SPL FS SPL SPL FS Poly A

NS NS NS
100 bp
Point mutations
Fig. 1.4 The mutations of the β globin gene that underlie β thalassemia. The heavy black lines indicate the length of the deletions. The
point mutations are designated as follows: PR, promoter; C, CAP site; I, initiation codon; FS, frameshift and nonsense mutations; SPL, splice
mutations; Poly A, poly A addition site mutations.
and produce the phenotype of β0 thalassemia. The transcrip- globin mRNA and hence in the clinical phenotype of severe
tion of genes carrying these mutations appears to be normal, β thalassemia. Interestingly, mutations at codons 19, 26, and
but there is complete inactivation of splicing at the altered 27 result in both reduced production of normal mRNA (due
junction. to abnormal splicing) and an amino acid substitution when
Another family of mutations involves what are called splice the mRNA which is spliced normally is translated into pro-
site consensus sequences. Although only the GT dinucleotide tein. The abnormal hemoglobins produced are Hb Malay, Hb
is invariant at the donor splice site, there is conservation E, and Hb Knossos, respectively. All these variants are associ-
of adjacent nucleotides and a common, or consensus, ated with a mild β+ thalassemia-like phenotype. These muta-
sequence of these regions can be identified. Mutations tions illustrate how sequence changes in coding rather than
within this sequence can reduce the efficiency of splicing IVS influence RNA processing, and underline the impor-
to varying degrees, because they lead to alternate splicing tance of competition between potential splice site sequences
at the surrounding cryptic sites. For example, mutations of in generating both normal and abnormal varieties of β globin
the nucleotide at position 5 of IVS-1 (the first intervening mRNA.
sequence), G → C or T, result in a marked reduction of Cryptic splice sites in introns may also carry mutations
β chain production and in the phenotype of severe β+ that activate them even though the normal splice sites remain
thalassemia. On the other hand, the substitution of C for T intact. A common mutation of this kind in Mediterranean
at position 6 in IVS-1 leads to only a mild reduction in the populations involves a base substitution at position 110 in
output of β chains. IVS-1. This region contains a sequence similar to a 3′ accep-
Another mechanism that leads to abnormal splicing tor site, though it lacks the invariant AG dinucleotide. The
involves cryptic splice sites. These are regions of DNA which, change of the G to A at position 110 creates this dinucleotide.
if mutated, assume the function of a splice site at an inappro- The result is that about 90% of the RNA transcript splices to
priate region of the mRNA precursor. For example, a variety this particular site and only 10% to the normal site, again pro-
of mutations activate a cryptic site which spans codons 24– ducing the phenotype of severe β+ thalassemia (Figure 1.5).
27 of exon 1 of the β globin gene. This site contains a GT Several other β thalassemia mutations have been described
dinucleotide, and adjacent substitutions that alter it so that it which generate new donor sites within IVS-2 of the β globin
more closely resembles the consensus donor splice site result gene.
in its activation, even though the normal splice site is intact. A Another family of mutations that interferes with β globin
mutation at codon 24 GGT → GGA, though it does not alter gene processing involves the sequence AAUAAA in the 3′
the amino acid which is normally found in this position in untranslated regions, which is the signal for cleavage and
the β globin chain (glycine), allows some splicing to occur polyadenylation of the β globin gene transcript. Somehow,
at this site instead of the exon–intron boundary. This results these mutations destabilize the transcript. For example, a
in the production of both normal and abnormally spliced β T → C substitution in this sequence leads to only one-tenth of
Normal splicing
GT IVS1 AG GT IVS2 AG
β gene
TTGGTCT
10%
β+ thalassemia Fig. 1.5 The generation of a new splice site in
an intron as the mechanism for a form of β+
90% thalassemia. For details see text.
the normal amount of β globin mRNA transcript, and hence absence of mRNA from the cytoplasm of red cell precursors.
to the phenotype of a moderately severe β+ thalassemia. This appears to be an adaptive mechanism, called nonsense-
Another example of a mutation which probably leads to mediated decay, whereby abnormal mRNA of this type is not
defective processing of the function of β globin mRNA is the transported to the cytoplasm, where it would act as a tem-
single-base substitution A → C in the CAP site. It is not yet plate for the production of truncated gene products. How-
understood how this mutation causes a reduced rate of tran- ever, in the case of exon III mutations, apparently because
scription of the β globin gene. this process requires the presence of an intact upstream exon,
There is another small subset of rare mutations that involve the abnormal mRNA is transported into the cytoplasm and
the 3′ untranslated region of the β globin gene, and these are hence can act as a template for the production of unstable
associated with relatively mild forms of β thalassemia. It is β globin chains. The latter precipitate in the red cell pre-
thought that these interfere in some way with transcription, cursors together with excess α chains to form large inclu-
but the mechanism is unknown. sion bodies, and hence there is enough globin chain imbal-
ance in heterozygotes to produce a moderately severe degree
of anemia.
Mutations that result in abnormal
translation of β globin mRNA
The α thalassemias
There are three main classes of mutations of this kind.
Base substitutions that change an amino acid codon to a The molecular pathology of the α thalassemias is more com-
chain termination codon prevent the translation of β globin plicated than that of the β thalassemias, simply because there
mRNA and result in the phenotype of β0 thalassemia. Several are two α globin genes per haploid genome. Thus, the normal
mutations of this kind have been described; the common- α globin genotype can be written αα/αα. As in the case of β
est, involving codon 17, occurs widely throughout South- thalassemia, there are two major varieties of α thalassemia,
east Asia. Similarly, a codon 39 mutation is encountered fre- α+ and α0 thalassemia. In α+ thalassemia one of the linked α
quently in the Mediterranean region. globin genes is lost, either by deletion (−) or mutation (T); the
The second class involves the insertion or deletion of heterozygous genotype can be written –α/αα or αT α/αα.
one, two, or four nucleotides in the coding region of the β In α0 thalassemia the loss of both α globin genes nearly
globin gene. These disrupt the normal reading frame, cause always results from a deletion; the heterozygous genotype is
a frameshift, and hence interfere with the translation of β therefore written − −/αα. In populations where specific dele-
globin mRNA. The end result is the insertion of anomalous tions are particularly common, Southeast Asia (SEA) or the
amino acids after the frameshift until a termination codon Mediterranean region (MED), it is useful to add the appropri-
is reached in the new reading frame. This type of mutation ate superscript as follows: – –SEA /αα or – –MED /αα. It follows
always leads to the phenotype of β0 thalassemia. that when we speak of an “α thalassemia gene,” what we are
Finally, there are several mutations which involve the β really referring to is a haplotype; that is, the state and function
globin gene initiation codon and which, presumably, reduce of both of the linked α globin genes.
the efficiency of translation.
α0 thalassemia
Unstable β globin chain variants
Three main molecular pathologies, all involving deletions,
Some forms of β thalassemia result from the synthesis of have been found to underlie the α0 thalassemia phenotype.
highly unstable β globin chains which are incapable of form- The majority of cases result from deletions that remove both
ing hemoglobin tetramers and which are rapidly degraded, α globin genes and a varying length of the α globin gene
leading to the phenotype of β0 thalassemia. Indeed, in many cluster (Figure 1.6). Occasionally, however, the α globin gene
of these conditions no abnormal globin chain product can be cluster is intact, but is inactivated by a deletion which involves
demonstrated by protein analysis, and the molecular pathol- the major regulatory region HS40, 40 kb upstream from the
ogy has to be interpreted simply on the basis of a derived α globin genes, or the α globin genes may be lost as part of a
sequence of the variant β chain obtained by DNA analysis. truncation of the tip of the short arm of chromosome 16.
Recent studies have provided some interesting insights As well as providing us with an understanding of the
into how complex clinical phenotypes may result from the molecular basis for α0 thalassemia, detailed studies of these
synthesis of unstable β globin products. For example, there deletions have yielded more general information about the
is a spectrum of disorders that result from mutations in exon mechanisms that underlie this form of molecular pathology.
3 which give rise to a moderately severe form of β tha- For example, it has been found that the 5′ breakpoints of a
lassemia in heterozygotes. It has been found that nonsense or number of deletions of the α globin gene cluster are located
frameshift mutations in exons I and II are associated with the approximately the same distance apart and in the same order
–50 –10 0 10 20 30
ζ2 ψζ1 ψα2 ψα1 α2 α1 θ1
Inter-ζHVR 3'HVR
Fig. 1.6 Some of the deletions that underlie α0

and α+ thalassemia. The colored rectangles
beneath the α globin gene cluster indicate the
lengths of the deletions. The unshaded regions
indicate uncertainty about the precise breakpoints.
The three small deletions at the bottom of the figure
represent the common α+ thalassemia deletions.
HVR, highly variable regions.
along the chromosome as their respective 3′ breakpoints; α globin gene region, a finding that provides a completely
similar findings have been observed in deletions of the β new mechanism for genetic disease. In another case of α0
globin gene cluster. These deletions seem to have resulted thalassemia, in which no molecular defects could be detected
from illegitimate recombination events, which have led to the in the α globin gene cluster, a gain-of-function regulatory
deletion of an integral number of chromatin loops as they polymorphism was found in the region between the α globin
pass through their nuclear attachment points during chro- genes and their upstream regulatory elements. This alteration
mosomal replication. Another long deletion has been charac- creates a new promoter-like element that interferes with the
terized in which a new piece of DNA bridges the two break- normal activation of all downstream α-like globin genes.
points in the α globin gene cluster. The inserted sequence In short, detailed analysis of the molecular pathology of
originates upstream from the α globin gene cluster, where the α0 thalassemias has provided valuable evidence not only
normally it is found in an inverted orientation with respect about how large deletions of gene clusters are caused, but also
to that found between the breakpoints of the deletion. Thus about some of the complex mechanisms that may underlie
it appears to have been incorporated into the junction in a cases in which the α gene clusters remain intact, but in which
way that reflects its close proximity to the deletion breakpoint their function is completely suppressed.
region during replication. Other deletions seem to be related
to the family of Alu-repeats, simple repeat sequences that
α+ thalassemia
are widely dispersed throughout the genome; one deletion
appears to have resulted from a simple homologous recombi- As mentioned earlier, the α+ thalassemias result from the
nation between two repeats of this kind that are usually 62 kb inactivation of one of the duplicated α globin genes, by either
apart. deletion or point mutation.
A number of forms of α0 thalassemia result from terminal 𝛼 + Thalassemia due to gene deletions. There are two com-
truncations of the short arm of chromosome 16 to a site about mon forms of α+ thalassemia that are due to loss of one
50 kb distal to the α globin genes. The telomeric consensus or other of the duplicated α globin genes, −α3.7 and −α4.2 ,
sequence TTAGGGn has been added directly to the site of the where 3.7 and 4.2 indicate the size of the deletions. The way
break. Since these mutations are stably inherited, it appears in which these deletions have been generated, approximately
that telomeric DNA alone is sufficient to stabilize the ends of 4 kb long, was probably generated by an ancient duplication
broken chromosomes. event. The homologous regions, which are divided by small
Quite recently, two other molecular mechanisms have inserts, are designated X, Y, and Z. The duplicated Z boxes
been identified as the cause of α0 thalassemia which, though are 3.7 kb apart and the X boxes are 4.2 kb apart. The result
rare, may have important implications for an understand- of misalignment reflects the underlying structure of the α
ing of the molecular pathology of other genetic diseases. In globin gene complex (Figure 1.7). Each α gene lies within
one case, a deletion in the α globin gene cluster resulted a boundary of homology and reciprocal crossover between
in a widely expressed gene (LUC7L) becoming juxtaposed these segments at meiosis, a chromosome is produced with
to a structurally normal α globin gene. Although the latter either a single (−α) or triplicated (ααα) α globin gene. As
retained all its important regulatory elements, its expression shown in Figure 1.7, if a crossover occurs between homol-
was silenced. It was found in a transgenic mouse model that ogous Z boxes 3.7 kb of DNA are lost, an event which is
transcription of antisense RNA mediated the silencing of the described as a rightward deletion, −α3.7 . A similar crossover
ψα1 α2 α1
X Y Z X Y Z
(a)
ψα1 α2 α1
3.7
αααanti
ψα1 α2 α1
3.7
–α
(b) Rightward crossover
ψα1 α2 α1
4.2
αααanti
Fig. 1.7 Mechanisms of the generation of the
common deletion forms of α+ thalassemia. (a)
The normal arrangement of the α globin genes, ψα1 α2 α1
4.2
with the regions of homology X, Y, and Z. (b) The –α
crossover that generates the −α3.7 deletion. (c) The
crossover that generates the −α4.2 deletion. (c) Leftward crossover
between the two X boxes deletes 4.2 kb, the leftward deletion gene, although there is considerable evidence that it in some
−α4.2 . The corresponding triplicated α gene arrangements way destabilizes the mRNA.
are called αααanti 3.7 and αααanti 4.2 . A variety of different
points of crossing over within the Z boxes give rise to differ-
α thalassemia/mental retardation syndromes
ent length deletions, still involving 3.7 kb.
Non-deletion types of 𝛼 + thalassemia. These disorders There is a family of mild forms of α thalassemia which is
result from single or oligonucleotide mutations of the par- quite different to that described in the previous section and
ticular α globin gene. Most of them involve the α2 gene but, which is associated with varying degrees of mental retarda-
since the output from this locus is two to three times greater tion. Recent studies indicate that there are two quite different
than that from the α1 gene, this may simply reflect ascertain- varieties of this condition, one encoded on chromosome 16
ment bias due to the greater phenotypic effect and, possibly, (ATR-16) and the other on the X chromosome (ATR-X).
a greater selective advantage. The ATR-16 syndrome is characterized by relatively mild
Overall, these mutations interfere with α globin gene mental disability with a variable constellation of facial and
function in a similar way to those that affect the β globin skeletal dysmorphisms. These individuals have long dele-
genes. They affect the transcription, translation, or post- tions involving the α globin gene cluster, but removing
translational stability of the gene product. Since the prin- at least 1–2 Mb. This condition can arise in several ways,
ciples are the same as for β thalassemia, we do not need including unbalanced translocation involving chromosome
to describe them in detail, with one exception, a mutation 16, truncation of the tip of chromosome 16, and the loss of
which has not been observed in the β globin gene cluster. the α globin gene cluster and parts of its flanking regions by
It turns out that there is a family of mutations that involves other mechanisms.
the α2 globin gene termination codon, TAA. Each specifi- The ATR-X syndrome results from mutations in a gene on
cally changes this codon so that an amino acid is inserted the X chromosome, Xq13.1–q21.1. The product of this gene
instead of the chain terminating. This is followed by “read- is one of a family of proteins involved in chromatin-mediated
through” of α globin mRNA, which is not normally trans- transcriptional regulation. It is expressed ubiquitously dur-
lated until another in-phase termination codon is reached. ing development and at interphase it is found entirely within
The result is an elongated α chain with 31 additional residues the nucleus in association with pericentromeric heterochro-
at the C-terminal end. Five hemoglobin variants of this type matin. In metaphase, it is similarly found close to the cen-
have been identified. The commonest, Hb Constant Spring, tromeres of many chromosomes but, in addition, occurs at
occurs at a high frequency in many parts of Southeast Asia. the stalks of acrocentric chromosomes, where the sequences
It is not absolutely clear why the read-through of normally for ribosomal RNA are located. These locations provide
untranslated mRNAs leads to a reduced output from the α2 important clues to the potential role of this protein in the
establishment and/or maintenance of methylation of the are left intact and the deletion simply removes the δ and β
genome. Although it is clear that ATR-X is involved in α globin genes; in these cases both the G γ and the A γ globin
globin transcription, it also must be an important player in gene remain functional. For some reason, these long dele-
early fetal development, particularly of the urogenital system tions allow persistent synthesis of the γ globin genes at a
and brain. Many different mutations of this gene have been relatively high level during adult life, which helps to com-
discovered in association with the widespread morphologi- pensate for the absence of β and δ globin chain production.
cal and developmental abnormalities which characterize the They are classified according to the kind of fetal hemoglobin
ATR-X syndrome. that is produced, and hence into two varieties, G γ(A γδβ)0
and G γA γ(δβ)0 thalassemia; in line with other forms of tha-
lassemia, they are best described by what is not produced:
α thalassemia and the myelodysplastic syndrome
(A γδβ)0 and (δβ)0 thalassemia, respectively. Homozygotes
Since the first description of Hb H (see later section) in the red produce only fetal hemoglobin, while heterozygotes have a
cells of a patient with leukemia, many examples of this asso- thalassemic blood picture together with about 5–15% Hb F.
ciation have been reported. The condition usually is reflected
in a mild form of Hb H disease, with typical Hb H inclusions
Hereditary persistence of fetal hemoglobin
in a proportion of the red cells and varying amounts of Hb H
demonstrable by hemoglobin electrophoresis. The hemato- Genetically determined persistent fetal hemoglobin synthe-
logical findings are usually those of one or other form of the sis in adult life is of no clinical importance, except that its
myelodysplastic syndrome. The condition occurs predomi- genetic determinants can interact with the β thalassemias or
nantly in males in older age groups. Very recently it has been structural hemoglobin variants; the resulting high level of Hb
found that some patients with this condition have mutations F production often ameliorates these conditions. The differ-
involving ATR-X. The relationship of these mutations to the ent forms of HPFH result from either long deletions involv-
associated myelodysplasia remains to be determined. ing the δβ globin gene cluster, similar to those that cause
(δβ)0 thalassemia, or point mutations that involve the pro-
moters of the G γ or A γ globin gene. In the former case there
Rarer forms of thalassemia and related
is no β globin chain synthesis and therefore these condi-
disorders
tions are classified as (δβ)0 HPFH. In cases in which there
There are a variety of other conditions that involve the β are promoter mutations involving the γ globin genes, there is
globin gene cluster which, although less common than the increased γ globin chain production in adult life associated
β thalassemias, provide some important information about with some β and δ chain synthesis in cis (i.e. directed by the
mechanisms of molecular pathology and therefore should be same chromosome) to the HPFH mutations. Thus, depend-
mentioned briefly. ing on whether the point mutations involve the promoter of
the G γ or A γ globin gene, these conditions are called G γ β+
HPFH and A γ β+ HPFH, respectively.
The δβ thalassemias
There is another family of HPFH-like disorders in which
Like the β thalassemias, the δβ thalassemias, which result the genetic determinant is not encoded in the β chain clus-
from defective δ and β chain synthesis, are subdivided into ter. In one case the determinant encodes on chromosome 6,
the (δβ)+ and (δβ)0 forms. although its nature has not yet been determined.
The (δβ)+ thalassemias result from unequal crossover It should be pointed out that all these conditions are very
between the δ and β globin gene loci at meiosis with the heterogeneous and that many different deletions or point
production of δβ fusion genes. The resulting δβ fusion mutations have been discovered that produce the rather sim-
chain products combine with α chains to form a family of ilar phenotypes of (δβ)0 or G γ or A γ β+ HPFH.
hemoglobin variants called the hemoglobin Lepores, after the
family name of the first patient of this kind to be discovered.
Because the synthesis of these variants is directed by genes Genotype–phenotype relationships in
with the 5′ sequences of the δ globin genes, which have defec- the thalassemias
tive promoters, they are synthesized at a reduced rate and
result in the phenotype of a moderately severe form of δβ It is now necessary briefly to relate the remarkably diverse
thalassemia. molecular pathology described in the previous sections to
The (δβ)0 thalassemias nearly all result from long dele- the phenotypes observed in patients with these diseases.
tions involving the β globin gene complex. Sometimes they It is not possible to describe all these complex issues here.
involve the A γ globin chains and hence the only active locus Rather, I shall focus on those aspects that illustrate the more
remaining is the G γ locus. In other cases the G γ and A γ loci general principles of how abnormal gene action is reflected
in a particular clinical picture. Perhaps the most important membrane causes alterations in its structure, and their degra-
question that I will address is why patients with apparently dation products, notably heme, hemin (oxidized heme), and
identical genetic lesions have widely differing disorders, iron, result in oxidative damage to the red cell contents
a problem that still bedevils the whole field of medical and membrane. These interactions result in intramedullary
genetics, even in the molecular era. destruction of red cell precursors and in shortened survival
of such cells as they reach the peripheral blood. The end
result is anemia of varying severity. This, in turn, causes tis-
The β thalassemias sue hypoxia and the production of relatively large amounts of
As we have seen, the basic defect that results from the 200 erythropoietin; this leads to a massive expansion of the inef-
or more different mutations that underlie these conditions is fective bone marrow, resulting in bone deformity, a hyperme-
reduced β globin chain production. Synthesis of the α globin tabolic state with wasting and malaise, and bone fragility.
chain proceeds normally and hence there is imbalanced A large proportion of hemoglobin in the blood of β tha-
globin chain output with an excess of α chains (Figure 1.8). lassemics is of the fetal variety. Normal individuals produce
Unpaired α chains precipitate in both red cell precursors and about 1% of Hb F, unevenly distributed among their red cells.
their progeny with the production of inclusion bodies. These In the bone marrow of β thalassemics, any red cell precursors
interfere with normal red cell maturation and survival in a that synthesize γ chains come under strong selection because
variety of complex ways. Their attachment to the red cell they combine with α chains to produce fetal hemoglobin, and
α
Ex
ce
γ ss
β
α2γ2 Denaturation
HbF Degradation
Selective survival of
HbF-containing Hemolysis Destruction of RBC
precursors precursors
Increased levels of Splenomegaly Ineffective

HbF in red cells (pooling, plasma erythropoiesis
volume expansion)
High
oxygen affinity of Anemia
red cells
R
O ed u e
c su a
2 d
eli ed Tis poxi
ve h y
ry
Erythropoietin
Transfusion
Marrow
expansion
Inc
r
ab ease
so d
rp iro
tio n
Skeletal deformity n Iron loading
Increased metabolic rate
Wasting
Gout
Folate deficiency
Endocrine deficiencies
Cirrhosis
Fig. 1.8 The pathophysiology of β thalassemia. Cardiac failure
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With an exquisite dexterity of address the Countess contrived to
introduce an allusion to the situation of Penelope Primrose; and as
neither the young lady nor her aunt was in full possession of the
circumstances in which Mr Primrose was at that time, they both had
the impression on their minds that there was no other immediate
prospect for his daughter than the exertion of her own talents and
acquirements to provide her with the means of support. The worthy
rector had not as yet been long enough in the grave to give
Penelope an opportunity of feeling the difference of Mrs Greendale’s
manner towards her; but she had penetration enough to foresee
what must be her situation so long as she remained under the same
roof as her aunt. With the utmost readiness did she therefore listen
to the Countess, when speaking of the various employments to
which a young person situated as she was might turn her attention.
“Lord Smatterton,” said the Countess, “has frequently mentioned
the subject to me, and he recommends a situation in a private family.
There are certainly some advantages and some disadvantages in
such a situation: very much depends upon the temper and
disposition of almost every individual in the family. It is possible that
you may meet with a family consisting of reasonable beings, but it is
more than probable that you may have to encounter arrogance or
ignorance; these are not excluded from any rank.”
This language seemed to Penelope as an intimation that a school
would be a more desirable sphere in which to make profitable use of
her acquisitions. It was not for her to oppose any objections to the
implied recommendations of so good and so great a friend as her
ladyship; but she felt considerable reluctance to that kind of
employment, which she fancied had been suggested. Her reply was
embarrassed but respectful, intimating that she was ready to adopt
any mode of employment which the Countess might be pleased to
suggest. Her ladyship gave a smile of approbation to the
acquiescent disposition which the young lady manifested, and
added:
“If Miss Primrose could conquer a little feeling of timidity, which
might naturally enough be experienced by one so retired in her
habits, it would be possible for her, with her great vocal powers and
musical talent, not only to find means of maintenance, but to arrive at
a competent independence, by adopting the musical profession.
Then she would also enjoy the pleasure of good society. If such
arrangement be agreeable, I will most willingly charge myself with
providing the preparatory instruction under a distinguished professor.
What does my young friend think of such occupation?”
Had sincerity been the readiest road to the patronage and
friendship of the great, this question might have been very readily
and easily answered. But Penelope knew better than to suppose that
any advantage could arise from a direct opposition to the wishes of a
patron. Repugnant as she was to the proposal, she dared not to
whisper the least syllable of contradiction, on the ground of dislike, to
the profession; but after a blush of mortification, which the Countess
mistook for a symptom of diffidence, she replied:
“I fear that your ladyship is disposed to estimate rather too highly
the humble talents I may possess, and that I shall not answer the
expectations which so distinguished patronage might raise.”
The Countess was not altogether pleased with this shadow of an
objection; for it seemed to call in question her own discernment. She
therefore replied with some quickness:
“I beg your pardon, Miss Primrose: I have usually been considered
as something of a judge in these matters; and, if I do not greatly
mistake, you are peculiarly qualified for the profession; and, if you
would condescend to adopt my recommendation, I will be
answerable for its success.”
The Countess, with all her kindness and considerateness, had not
the slightest idea that there could be in a young person, situated as
Penelope, any feeling of pride or thought of degradation. But pride
was in being before titles were invented; and even republics, which,
in the arrogance of equality, may repel from their political vocabulary
all distinctions of fellow citizens, cannot eradicate pride from the
human heart. In a civilized country there is not perhaps an individual
to be found who is incapable of the sensation of degradation. Miss
Primrose thought it degrading to become a public singer; she felt that
it would be publishing to the world that she was not independent.
The world cares little about such matters. Right or wrong, however,
this feeling took possession of the young lady’s mind; and as pride
does not enter the mind by means of reasoning, it will not be
expelled by any process of ratiocination. For all this, however, the
worthy Countess could make no allowance; and it appeared to her
that if a young person were under the necessity of serving her
superiors in rank for the sake of maintenance, it signified very little
what mode of servitude were applied to.
There was also another consideration which weighed not a little
with the Countess, in almost insisting upon Miss Primrose’s adopting
the musical profession. Her ladyship was a distinguished patroness,
and a most excellent judge of musical talent; and there was a rival
patroness who had never yet been able to produce, under her
auspices, anything at all equal to Penelope Primrose. The
mortification or defeat of a rival is a matter of great moment to minds
of every description. Whenever there is the weakness of rivalry there
must be of necessity also the vanity of triumph, and to that
occasionally much will be sacrificed.
Mrs Greendale, who was present at this discussion, sided most
cordially with the Countess; but had the proposal come from any
other quarter, in all human probability it would have been resented
as an indignity. Penelope was also well aware that it was absolutely
necessary that she should leave the asylum in which so many of her
few days had been spent, and she therefore, with as good a grace
as her feelings permitted, gave assent to the proposal which the
Countess had made. And thereby her generous patroness was
softened.
The discussion of this question occupied no inconsiderable portion
of time, though we have not thought it necessary to repeat at length
the very common-place dialogue which passed on the subject. Our
readers must have very languid imaginations if they cannot supply
the omission for themselves. Suffice it to say, that the arguments
used by the Countess of Smatterton were much stronger than the
objections which arose in the mind of Penelope Primrose; and the
consideration of these arguments, backed by the reflection that she
had no other immediately available resource, determined the
dependent one to acquiesce in that which her soul abhorred. It was
all very true, as the amiable Countess observed, that an occupation
which introduced the person so employed to the notice and into the
saloons of the nobility, could not be essentially degrading; it was also
very true that there could be no moral objection to a profession
which had been ornamented by some of the purest and most
virtuous characters. All this was very true; but notwithstanding this
and much more than this which was urged by the Countess, still
Penelope did not like it. There is no accounting for tastes.
Some young ladies there are who think that, if they should be
situated as Penelope was, they would not suffer any inducement to
lead them to a compliance with such a proposal. They imagine that
no earthly consideration whatever should compel them to that which
they abhorred or disapproved. They cannot think that Penelope
deserved the title of heroine, if she could thus easily surrender her
judgment and bend her will to the dictation of a patroness. But let
these young ladies be informed, that in this compliance lay no small
portion of the heroism of Penelope’s character. She gained a victory
over herself; she did not gratify a pert self-will at the expense of
propriety and decorum, and she had no inclination to play the part of
a Quixote.
It is an easy thing for a young man to set himself up as
independent. The world with all its various occupations is before him.
He may engage in as many freaks as suit his fancy; he may dwell
and live where and how he pleases; but the case is widely different
with a young woman delicately brought up, respectably connected,
and desirous of retaining a respectable condition and the
countenance of her friends. She is truly dependent, and must
oftentimes sacrifice her judgment and feelings to avoid more serious
and important sacrifices.
Penelope used to talk about dependence while under the roof of
her benevolent and kind-hearted relative, now no more. But she felt
it not then, as she felt it when her uncle had departed from life. Then
it was merely a name, now it became a reality.
When the Countess had prevailed upon Penelope to give her
assent to the proposal of publicly displaying her musical talents, her
ladyship was in exceeding good humour; and when a lady of high
rank is in good humour, her condescension, her affability, her wit, her
wisdom, and whatever she pleases to assume or affect of the
agreeable and praiseworthy, are infinitely above all language of
commendation to such a person as Mrs Greendale. The widow
therefore was quite charmed with the exquisitely lady-like manners
of the Countess, astonished at her great good sense; and, had the
Countess requested it, Mrs Greendale herself would have become a
public singer.
While this negociation was going on at the castle at Smatterton,
another discussion concerning Penelope was passing at the rectory
at Neverden.
“Well, papa,” said Miss Darnley, “I took particular notice of
Penelope Primrose yesterday, and purposely mentioned the name of
Lord Spoonbill, to see whether it would produce any emotion, and I
did not observe anything that led me to suppose what you suspect.”
“Very likely, my child, you could not discern it. That was not a time
for the expression of any such feelings. Her thoughts were then
otherwise engaged. But I can say that, from what I have observed, I
have no reason whatever to doubt that her affections are not as they
were with respect to your brother. You know that Robert wrote to her
by the same conveyance which brought us a letter, and although I
gave every opportunity and hint I could to that purpose, Miss
Primrose did not mention having heard.”
“But, my dear papa,” replied Miss Darnley, still unwilling to think
unfavourably of so valued a friend as Penelope, “might not her
thoughts be otherwise engaged at the time, when you visited her; for
you recollect that your call was much sooner after Dr Greendale’s
death than our’s was.”
Mr Darnley smiled with a look of incredulity, and said, “You are
very charitable in your judgment, my dear, but I think in this instance
you extend your candour rather too far. I did not only observe
symptoms of alienation, but had, I tell you, almost a proof of the fact.
I went so far as to allude to her engagement and to offer our house
as an asylum; and her reply was, that she would be at the direction
of Lady Smatterton. Whether she be vain and conceited enough to
aspire to Lord Spoonbill’s hand, I will not pretend to say, but I am
abundantly convinced that she does not regard your brother with the
same affection that she did some time ago; and there certainly have
been symptoms to that effect in the course of her correspondence,
or Robert would never have used such language, or made such
enquiries as he has in his last letter. And I think it would be but an act
of kindness, or even of justice, to let your brother know what are our
suspicions.”
Now Mary Darnley, who was rather inclined to be blue-stockingish,
and had of course, a mighty admiration for wisdom, and learning,
and science, thought it not unlikely that if Penelope had changed her
mind, and transferred her affections to another, that other was more
likely to be Mr Kipperson than Lord Spoonbill. For, she reasoned, it
was not probable that a young woman so brought up as Penelope
had been, should be at all pleased with a character so profligate as
Lord Spoonbill was generally supposed to be. Then Mr Kipperson,
though he was double Penelope’s age, yet was a very agreeable
man, and far superior to the common run of farmers; and he was a
man of very extensive information and of great reading. The
reasoning then went on very consequentially to prove, that as
Penelope loved reading, and as Mr Kipperson loved reading,
therefore Penelope must love Mr Kipperson. This perhaps was not
the best kind of reasoning in the world, yet it might do in default of a
better to support a theory.
The truth of the matter is, that Miss Mary Darnley herself was a
little disposed to admire Mr Kipperson, in virtue of his literary and
scientific character; and the truth also is, that Mr Kipperson had
really manifested symptoms of admiration towards Penelope
Primrose; and last, but not least, is the truth, that Miss Mary Darnley
was somewhat inclined to be jealous of the attention which the
literary and scientific Mr Kipperson had recently paid to Miss
Primrose.
This theory of Miss Mary Darnley seemed the most plausible, and
it was therefore adopted by her mother and sisters, and by them it
was unanimously concluded that Penelope was not unfavourable to
the suit of Mr Kipperson; and then they thought that the young lady
had behaved, or was behaving very ill to their brother; and then they
thought that their brother might do much better for himself; and then
they thought that Mr Kipperson was at least fifty, though till then it
had been the common opinion that he was but forty; and then they
thought that no dependence could be placed on any one; and then
they made many wise remarks on the unexpectedness of human
events, not considering that the experience of millions, and the
events of centuries, have conspired to shew that events take any
other direction than that which is expected. Ann Darnley was sorry
for it, Martha laughed at it, and Mary was angry with it.
As for Mr Darnley himself, he was not much moved; but he could
not admit of the idea that he was wrong in his conjecture that Miss
Primrose was partial to Lord Spoonbill, therefore he could not see
the force of the reasoning which went to prove, that the transfer of
Penelope’s affections was not from Robert Darnley to Lord
Spoonbill, but to Mr Kipperson.
“Beside,” said Mr Darnley, “is it likely that a young woman of such
high notions as Miss Primrose should think of accepting an offer
from Mr Kipperson, who, though he is a man of property and of
literary taste, is still but a farmer, or agriculturist. It is far more likely
that the vanity of the young lady should fix her hopes on Lord
Spoonbill, especially if his lordship has paid her, as is not unlikely,
very marked attentions.”
Although in the family at the rectory of Neverden there was
diversity of opinion as to the person on whom Miss Primrose had
placed her affections, there was at least unanimity in the feeling and
expression of disapprobation. And, in pursuance of this feeling, there
was a diminution, and indeed nearly a cessation of intercourse
between the parties. Many days passed away, and no message and
no visitor from Neverden arrived at Smatterton.
This was deeply and painfully felt by Penelope, and the more so
as it was absolutely impossible for her to ask an explanation. Indeed,
she concluded that no explanation was wanting; the fact that no
letter had been received for so long time, and the circumstance of
the coldness and change in the manners of the young ladies at
Neverden, were sufficient manifestations to Penelope that, for some
cause or other, there was a change in the mind of Robert Darnley
towards her. Then in addition to these things was the reflection, that
she had allowed herself to be persuaded contrary to her own
judgment to adopt the profession of music as a public singer, or at
least as a hired performer. Thus, in a very short time, she was
plunged from the height of hope to the depth of despair. A little while
ago she had been taught to entertain expectations of her father’s
return to England in a state of independence; she had also reason to
hope that, the lapse of a few months, there might come from a
distant land one for whom she did entertain a high esteem, and who
should become her guardian, and guide, and companion through life.
A little while ago also, she had in the society and sympathy of her
worthy and benevolent uncle, Dr Greendale, a refuge from the
storms of life, and some consolation to enable her to bear up aright
under the pressure of life’s evils, its doubts and its fears. All these
hopes were now vanished and dispersed, and she left to the mercy
of a rude world. Her best benefactor was in his grave, and those very
agreeable and pleasant companions in whom he confided as in
relatives, and more than sisters, they also had deserted her. It
required a great effort of mind to bear up under these calamities. Her
mind however had been habituated to exertion, and it had gained
strength from the efforts which it had formerly made; but still her
constitution was not stoical; she had strong and deep feelings. It was
with some considerable effort that she did not yield so far to the
pressure of present circumstances as to lose all elasticity of mind
and to relinquish all love of life. And pity itself need not seek and
cannot find an object more worthy of its tears than one living, who
has lost all relish for life, and ceased to enjoy its brightness or to
dread its darkness.
CHAPTER X.
Some few weeks after Penelope had given her consent to the
arrangement suggested by the Countess of Smatterton, the family at
the castle took their departure for London. Her ladyship did not forget
her promise of providing Miss Primrose with the means of cultivating
and improving her natural talents; but, in a very few days after
arriving in town, negociations were entered into and concluded with
an eminent professor to take under his tuition a young lady
patronized by the Countess of Smatterton.
Great compliments of course were paid to the judgment of the
Countess, and high expectations were raised of the skill and power
of this new vocal prodigy; for countesses never patronize anything
but prodigies, and if the objects of their patronage be not prodigies
by nature, they are very soon made so by art and fashion.
Now the Countess of Smatterton was really a good judge of
musical excellence; her taste was natural, not acquired or affected
as a medium of notoriety, or a stimulus for languid interest in life’s
movements. And when her ladyship had a musical party, which was
indeed not unfrequently, there was not one individual of the whole
assemblage more really and truly delighted with the performances
than herself, and few perhaps were better able to appreciate their
excellence.
At this time but few families were in town, and the winter
assortment of lions, and prodigies, and rages, was not formed or
arranged. Lady Smatterton would have been best pleased to have
burst upon the assembled and astonished world at once with her
new human toy. But the good lady was impatient. She wished to
enjoy as soon as possible the pleasure of exhibiting to her friends
and neighbours and rivals the wonderful talents of Penelope
Primrose. As soon therefore as arrangements could be made with
the professor who was destined to be the instructor of Miss
Primrose, a letter was despatched to Smatterton, desiring the young
lady to make as much haste as possible to town.
This was indeed a sad and painful trial to Penelope. Little did she
think that the plan was so soon to be put in force to which she had
given her reluctant assent. It seemed inconsiderate in her ladyship to
remove Penelope from Mrs Greendale so very soon; not that the
young lady had any very great reluctance to part from Mrs
Greendale; but as she had some reluctance to make the journey to
London for the object which was in view, she felt rather more than
otherwise she would have done the inconvenience to which it
necessarily put her aunt. Having therefore shewn Lady Smatterton’s
letter to the widow, she expressed her concern that the Countess
should be so very hasty in removing her, and said, that if her aunt
wished it she would take the liberty of writing to her ladyship,
requesting a little longer indulgence, that she might render any
assistance which might be needed under present circumstances.
Some persons there are who never will and who never can be
pleased: Mrs Greendale was one of them. Instead of thanking
Penelope for her considerate and kind proposal, her answer was:
“Indeed, Miss Primrose, I think you would be acting very
improperly to question Lady Smatterton’s commands. I know not
who is to provide for you, if you thus turn your back upon your best
friends. I can assure you I have no great need of any of your
assistance, which I dare say you would not be so ready to offer if it
did not suit your own convenience.”
To repeat much such language as this would be wearisome.
Suffice it to say, that there was no form of expression which
Penelope could use, nor any line of conduct which she could
propose, which Mrs Greendale was not ingenious enough to carp at
and object to. It may then be easily imagined that the situation of our
heroine was not much to be envied; nor will it be supposed that she
felt any great reluctance to leave such a companion and friend as
this. With the best grace imaginable, therefore, did Penelope prepare
for yielding obedience to Lady Smatterton’s commands; but it was
still with a heavy heart that she made preparation for her journey.
Before her departure it was absolutely and indispensably
necessary that she should go through the ceremony of taking leave
of her friends. Of several persons, whose names are not here
recorded, Penelope Primrose took leave, with expressions of mutual
regret. There was however no embarrassment and no difficulty in
these cases. When, however, she prepared to take leave of her
friends at Neverden, the case was widely different. Then arose much
perplexity, and then her heart felt such a bitter pang. It was probable
that this would be a final leave. The Darnleys never visited London,
or at least not above once in twenty years. They had recently looked
coldly upon her, and had partially neglected her. It was contrary to
their general practice to act capriciously; there certainly must be a
motive for their behaviour, and what could that motive be but a
change in the intentions of Robert Darnley with respect to herself.
The ground of that change she was at a loss to determine. At all
events she must call and take leave of them.
In pursuance of this determination, Penelope Primrose took, not
the earliest, but the latest opportunity of calling upon Mr Darnley and
the family at Neverden rectory; for it would not be very pleasant to
remain any time in the neighbourhood after a cool and unfriendly
separation from those with whom so many of her pleasantest hours
had been spent, and with whose idea so many of her hopes had
been blended. When she called, the whole family was at home. Her
reception was by no means decidedly unkind, or artificially polite.
There was always indeed a degree of stateliness in the manner of
Mr Darnley, and that stateliness did not appear any less than usual,
nor did it appear quite so tolerable as on former days and on former
occasions.
In the young ladies, notwithstanding their general good sense and
most excellent education, there was towards Penelope that kind of
look, tone, and address, which is so frequently adopted towards
those who once were equals, and whom misfortune has made
inferiors. Those of our readers who cannot understand us here we
sincerely congratulate.
It had been made known to Mr Darnley for what purpose Miss
Primrose was making preparations for a journey to London. But,
though the fact had been communicated, the reason for that step
had not been mentioned; not a word had been said concerning the
pressing importunity of the Countess; nor was there any notice taken
to him of the reluctance with which Penelope had consented to this
arrangement. It appeared therefore to Mr Darnley that the measure
was quite in unison with the young lady’s own wishes; nor did he see
how incongruous such a movement as this must be with his
suspicions of the aspiring views of his late friend’s niece. At all
events, this proceeding on the part of Miss Primrose appeared to
him, and very naturally so, as a tacit relinquishment of the
engagement with his son: as it was impossible for her not to know
how repugnant it must be to the feelings and taste of Mr Robert
Darnley. But as the elder Mr Darnley held the clerical office, of the
sanctity and dignity of which he had very high ideas, he thought it but
part of his duty to administer a word or two of exhortation to the
young lady about to embark in a concern of such a peculiar nature.
Now to render exhortation palatable, or even tolerable, requires a
very considerable share of address and dexterity, more indeed than
usually falls to the lot of clerical or of laical gentry. It is easy enough
to utter most majestically and authoritatively a mass of common
places concerning the dangers to which young people are exposed
in the world. It is easy to say, “Now let me advise you always to be
upon your guard against the allurements of the world, and to conduct
yourself circumspectly, and be very, very attentive to all the proper
decorums and duties of your station.” Such talk as this anybody may
utter; and when young people commence life, they expect to hear
such talk; and for the most part, to say the best of it, it produces no
effect, good, bad, or indifferent. It is also easy to render exhortation
painful and distressing, by making it assume the form of something
humiliating and reproachful; and when it has also a reference to
some departed friend, or to circumstances once bright, but now
gloomy, and when these references are founded on injustice, and
when this injustice cannot be refuted or rectified without some
explanation or explanations more painful still, then it is that
exhortation is doubly painful and distressing. So fell upon the ear
and heart of poor Penelope the exhorting language of Mr Darnley.
When Penelope had first entered the apartment she had
announced the purpose of her call, and had, by the assistance of the
Darnleys, stated the views with which she was going to London: for
so reluctant was she to mention the fact, that its annunciation was
almost extorted from her by those who knew beforehand what were
her intentions. After a very little and very cold common-place talk,
uttered merely from a feeling of the necessity of saying something,
the conversation dropped, and the parties looked awkwardly at one
another. Then did Mr Darnley, assuming a right reverend look,
address himself to Miss Primrose.
“Now, Miss Primrose, before we part, let me as your friend, and as
a friend of your late uncle, give you a little parting advice. I am sorry
that you have determined on taking this step, and had you
condescended to consult me on the subject, I certainly should have
dissuaded you from the undertaking. But, however, that is past.
Though I rather am surprised, I must acknowledge that, recollecting
as you must, how strongly your late worthy uncle used to speak
against this pursuit, you should so soon after his decease resolve to
engage in it. But, however, you are perfectly independent, and have
a right to do as you please. I do not say that in this pursuit there is
anything inconsistent with religion and morality. I would by no means
be so uncharitable. But I should have thought, Miss Primrose, that,
considering your high spirit, you would hardly have condescended to
such an employment; for I may call it condescension, when I
consider the prospects to which you were born: but those, I am sorry
to say, are gone. As you have then fully resolved upon thus making a
public display of your musical talents, which, for anything I know to
the contrary, may be of the highest order—for I do not understand
music myself—you will perhaps excuse me if, as a friend of your late
uncle, and really a well-wisher to yourself, I just take the liberty to
caution you against the snares by which you are surrounded.
Beware of the intoxications of flattery, and do not be unduly
distressed if you should occasionally in the public journals be made
the subject of ill-natured criticism. For I understand there are many
young and inexperienced writers who almost regularly assail by
severe criticism public performers of every kind; and they make use
of very authoritative language. Now this kind of criticism would be
very offensive to a person who was not aware that it is the
production of ignorant, conceited boys. I was once acquainted with a
young man who made acknowledgments to me that have given me a
very different view of the critical art from that which I formerly
entertained. But, my good young lady, there are severer trials which
await you than these: you will be very much exposed to the society
of the vicious and dissipated. You will have need of all your caution
and circumspection to take care that your religious and moral
principles be not weakened or impaired. I do not say, indeed, that
your profession is to be esteemed irreligious or immoral; but it
certainly is exposed to many snares, and does require an unusual
share of attention. I hope you will not neglect to attend church
regularly and punctually. It will assuredly be noticed if you neglect
this duty. Many will keep you in countenance should you be disposed
to slight the public ordinances of religion; but there are also not a few
who patronize public musical performances, and who also attend on
religious worship: it is desirable therefore to let these persons see
that you are also attentive to the duties of religion, I must add, Miss
Primrose, that I am concerned to find you so bent upon this scheme.
It would have given me great pleasure, had all things proceeded
rightly, to afford you an asylum in this house till the return of your
father, or till any other change had rendered such accommodation no
longer necessary. But, as circumstances now are, this cannot be.”
It is easy to conceive what effect such language as this must have
had on the sensitive mind and almost broken heart of Penelope
Primrose. It is very true that, in this address to her, Mr Darnley had
no malicious or cruel intention, though every sentence which he
uttered grieved her to the very soul. Well was it for Penelope that
she was partly prepared for something of this kind, and that her
sorrows had crept upon her gradually. Therefore she bore all this
with a most enduring patience, and never attempted to make any
explanation or apology otherwise than by meekly and calmly replying
to the elaborate harangue of Mr Darnley:
“I thank you, sir, for your advice; I hope and trust I shall attend to it;
but I wish you to understand that I am not acting purely according to
my own inclinations in adopting this employment. I am sorry that I
am under the necessity—”
The sentence was unfinished, and the tone in which it was uttered
excited Mr Darnley’s compassion: but he thought it very strange that
Miss Primrose should express any reluctance to engage in a pursuit
which, according to all appearance, she had voluntarily and
unnecessarily adopted. The young ladies also were very sorry for
her, but still they could not help blaming her mentally for her
fickleness towards their brother; for they were sure that he was
attached to her, and they plainly saw, or at least thought they saw,
that she had withdrawn her affections from him. Penelope also was
very well convinced, by this interview with the family, that all her
hopes of Robert Darnley were gone.
To avoid any farther unpleasantness, she then took leave of her
late friends, and, with a very heavy heart, returned to Smatterton to
make immediate preparation for her journey to London. Alas! poor
girl, she was not in a frame of mind favourable to the purposes of
festivity or the notes of gladness. She, in whose heart was no
gladness, was expected to be the means of delighting others. Thus
does it happen, that the tears of one are the smiles of another, and
the pleasures of mankind are founded in each others pains. Never
do the burning words and breathing thoughts of poetry spring with
such powerful energy and sympathy-commanding force, as when
they come from a heart that has felt the bitterness of grief, and that
has been agitated even unto bursting.
Our heroine would then have appeared to the greatest advantage,
and would then have commanded the deepest sympathy in those
moments of solitude, which intervened between the last leave-taking
and her departure for a metropolis of which she had seen nothing,
heard much, and thought little. But now her mind was on the rack of
thought, and so deeply and painfully was it impressed, that her
feeling was of the absolute impossibility of effectually answering the
designs and intentions of her friend the Countess. She could not
bear to look back to the days that were past—she felt an
indescribable reluctance to look forward, but her mind was of
necessity forced in that direction. All that spirit of independence and
feeling of almost pride, which formed no small part of her character,
seemed now to have taken flight, and to have left her a humble,
destitute, helpless creature. It was a pretty conceit that came into her
head, and though it was sorrowful she smiled at it; for she thought
that her end would be swanlike, and that her first song would be her
last, with which she should expire while its notes were trembling on
her lips.
CHAPTER XI.
It was not very considerate of the Countess of Smatterton to let a
young lady like Penelope Primrose take a long and solitary journey
of two hundred miles in a stage-coach without any guide,
companion, or protector. The Earl had a very ample supply of
travelling apparatus, and it would have been quite as easy to have
found room for Penelope in one of the carriages when the family
travelled up to town. But they who do not suffer inconveniences
themselves, can hardly be brought to think that others may.
Penelope felt rather mortified at this neglect, and it was well for her
that she did, as it was the means of taking away her attention from
more serious but remoter evil. It was also productive of another
advantage; for it gave Mr Kipperson an opportunity of exhibiting his
gallantry and politeness. For, the very morning before Penelope was
to leave Smatterton, Mr Kipperson called in person on the young
lady, and stated that imperious business would compel him to visit
the metropolis, and he should have infinite pleasure in
accompanying Miss Primrose on her journey, and perhaps that might
be more agreeable to her than travelling alone or with total
strangers. Penelope could not but acknowledge herself highly
obliged by Mr Kipperson’s politeness, nor did she, with any
affectation or foolery, decline what she might perhaps be compelled
to accept. On the following morning, therefore, Miss Primrose,
escorted by Mr Kipperson, left the sweet village of Smatterton. That
place had been a home to Penelope from almost her earliest
recollections, and all her associations and thoughts were connected
with that place, and with its little neighbour Neverden. Two hundred
miles travelling in a stage-coach is a serious business to one who
has hardly ever travelled but about as many yards. It is also a very
tedious affair even to those who are accustomed to long journies by
such conveyance. In the present instance, however, the journey did
not appear too long to either of our travellers. For Penelope had
looked forward to the commencement of her journey with too much
repugnance to have any very great desire for its completion, and Mr
Kipperson was too happy in the company of Miss Primrose to wish
the wheels of time, or of the coach, to put themselves to the
inconvenience of rolling more rapidly than usual on his account. It
was also an additional happiness to Mr Kipperson that there were in
the coach with him two fellow travellers who had long heard of his
fame, but had never before seen his person; and when they
discovered that they were in company with the great agriculturist,
and the great universal knowledge promoter, Mr Kipperson, they
manifested no small symptoms of satisfaction and admiration.
Now the mind of the scientific agriculturist was so constructed as
to experience peculiar pleasure and delight at aught which came to
his ear in the form of compliment and admiration. And, when Mr
Kipperson was pleased, he was in general very eloquent and
communicative; and he informed his fellow travellers that he was
now hastening up to London on business of the utmost importance.
He had received despatches from town, calling him up to attend the
House of Commons, and to consult with, or rather to advise, certain
committees connected with the agricultural interest. And he, the said
Mr Kipperson, certainly could not decline any call which the deeply
vital interests of agriculture might make upon him. Thereupon he
proceeded to shew that there was no one individual in the kingdom
uniting in himself those rare combinations of talent, which were the
blessing and distinction of the celebrated Mr Kipperson of
Smatterton; and that if he should not pay attention to the bill then
before the House, or at least likely to be before the House, by the
time he should arrive in London, the agricultural interest must be
completely ruined; there could be no remunerating price, and then
the farmers would throw up their farms and leave the country, taking
with them all their implements, skill, forethought, and penetration;
and then all the land would be out of cultivation, and the kingdom
would be but one vast common, only maintaining, and that very
scantily, donkeys and geese.
When the safety of a nation depends upon one individual, that
individual feels himself very naturally of great importance. But
perhaps this is a circumstance not happening quite so often as is
imagined. Strange indeed must it be that, if out of a population of ten
or twelve millions, only one or two can be found on whose wisdom
the state can rely, or from whose councils it can receive benefit. But
as the pleasure of imagining one’s self to be of importance is very
great, that pleasure is very liberally indulged in. And thus the number
of those rarities, called “the only men in the world,” is considerably
increased. Now Mr Kipperson was the only man in the world who
had sagacity and penetration enough to know wherein consisted the
true interest of agriculture; and he was most happy in giving his time
and talents to the sacred cause of high prices. Enough of this: we do
not like to be panegyrical, and it is very probable that our readers will
not be much disappointed if we protest that it is not our intention to
enter very deeply into the subject of political economy. Indeed were
we to enter very deeply into the subject with which Mr Kipperson was
intimate, we should be under the necessity of making an
encyclopedia, or of plundering those already made, beyond the
forbearance of their proprietors.
That must be an exceedingly pleasant mode of travelling which
does not once, during a very long journey, provoke the traveller to
wish himself at his journey’s end. Pleased as was Mr Kipperson at
the opportunity afforded him of behaving politely to Miss Primrose,
and gratified as he was by the respectful veneration with which his
two other fellow travellers received the enunciations of his oracular
wisdom; fearful as was Penelope that her new life would be the
death of her, and mourning as she was under the actual loss of one
most excellent friend, and contemplating the possible loss of others,
still both were pleased to be at their journey’s end.
It would have given Mr Kipperson great pleasure to accompany
Miss Primrose to the Earl of Smatterton’s town residence; but it gave
him much greater pleasure to be able to apologize for this apparent
neglect, by saying that business of a most important nature
demanded his immediate attendance in the city, and from thence to
the House of Commons; but that he should have great pleasure in
calling on the following morning to make enquiries after his fellow
traveller, and to pay his respects to his worthy and right honorable
neighbour, Lord Smatterton. For although my Lord Smatterton was
what the world calls a proud man, yet he did admit of freedom and a
species of familiarity from some sort of people; and a little freedom
with a great man goes a great way with a little man. Now Mr
Kipperson was one of those persons to whom the Earl of Smatterton
was most graciously condescending, and with good reason was he
condescending; for this said Mr Kipperson, wishing to keep up the
respectability of the farming profession, and though being much of a
tenant, and a little of a landlord, but hoping in due time to be more of
a landlord through an anticipated inheritance, he gave all his mind to
impress upon his agricultural neighbours the importance of keeping
up prices, and he paid no small sum for the farm which he tenanted
under the Earl of Smatterton. It may be indeed said with some
degree of truth, that he paid Lord Smatterton exceedingly well for his
condescension; and as his lordship was not much exposed to Mr
Kipperson’s invasions in London, he bore them with great
resignation and address when they did happen. The Countess also
was condescending to Mr Kipperson, being very sensible of his
value to the Smatterton estate; so that the great and scientific
agriculturist appeared to visit this noble family on terms of equality;
and it is a fact that he thought himself quite equal, if not rather
superior, to the Smatterton nobleman. It was a pleasure to Mr
Kipperson to enjoy this conceit; and it did no one any injury, and it is
a pity that he should be disturbed in the possession of the fancy.
The nobility do not act judiciously when they admit of any other
token of distinction than actual rank. When once they adopt any
fanciful distinction from fashion, or ton, or impudence, for they are
nearly the same, the benefit of the civil distinction is at once
renounced, and there is no established immoveable barrier against
innovation. A merchant, or the son of a merchant, may by means of
an imperturbable self-conceit, or by force of commanding
impudence, push himself up into the highest walks of life, and look
down upon nobility. Though the biographer of a deceased statesman
may express his lament that nobility does not admit talent ad
eundem, yet there is danger lest nobility should hold its hereditary
honors with too light a hand. Lord Smatterton indeed was not guilty
of neglecting to preserve upon his own mind, or endeavouring to

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Embryo Fetus Adult

5' CAP Excision of introns

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PR C I FS SPL SPL FS SPL SPL FS Poly A

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Fig. 1.6 Some of the deletions that underlie α0

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