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RoshanKetab +98(21) 66963783-8

V l l U L
I I I V I I I
Y3 I I I V I I I
Y3 V I I

GENETICS IN MEDICINE
Seventh E d i t ~ o n

Robert L. Nussbaum, M D
Holly Smith Distinguished Professor in Science and Medicine
Chief, Division of Medical Genetics
Department of Medicine and The Institute for Human Genetics
University of California, San Francisco
San Francisco, California

Roderick R. McInnes, MD, PhD, FRS(C)

University Professor
Anne and Max Tanenbaum Chair in Molecular Medicine
Professor of Pediatrics and Molecular and Medical Genetics
University of Toronto and The Hospital for Sick Children
Toronto, Ontario, Canada
Scientific Director, Institute of Genetics
Canadian Institutes of Health Research

Huntington F. Willard, PhD

Director
Institute for Genome Sciences and Policy
Vice Chancellor for Genome Sciences
Nanaline H. Duke Professor of Genome Sciences
Duke University
Durham, North Carolina

With Clinical Case Studies updated and new cases prepared by

Ada Hamosh, MD, MPH

Clinical Director
Institute of Genetic Medicine
Scientific Director, O M I M
Associate Professor, Pediatrics
Johns Hopkins University School of Medicine
Baltimore, Maryland
RoshanKetab +98(21) 66963783-8
RoshanKetab +98(21) 66963783-8

Thompson & Thompson

GENETICS IN MEDICINE
Seventh Edit-ion
 RoshanKetab +98(21) 66963783-8

1600 John F. Kennedy Blvd.

Ste 1800
Philadelphia, PA 19103-2899

THOMPSON & THOMPSON GENETICS IN MEDICINE ISBN: 9781416030805

Copyright O 2007,2004,2001,1991, 1986, 1980, 1973,1966 by Saunders, an imprint

of Elsevier Inc.

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Notice

Neither the Publisher nor the Authors assume any responsibility for any loss or injury and/or
damage to persons or property arising out of or related to any use of the material contained in
this book. It is the responsibility of the treating practitioner, relying on independent expertise
and knowledge of the patient, to determine the best treatment and method of application for
the patient.

The Publisher
-
Library of Congress Cataloging-in-Publication Data

Nussbaum, Robert L, 1950-

Thompson & Thompson Genetics in Medicine. - 7th ed. I Robert L. Nussbaum, Roderick R.
McInnes, Huntington F. Willard.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4160-3080-5
1. Medical genetics. I. McInnes, Roderick R. 11. Willard, Huntington F. 111. Thompson,
Margaret W. (Margaret Wilson), 1920 - Thompson & Thompson Genetics in Medicine.
IV. Title. V. Title: Genetics in medicine. VI. Title: Thompson and Thompson Genetics in
Medicine.
[DNLM: 1. Genetics, Medical. QZ 50 N975t 20071
RB155.T52 2007
616'.042-dc22

Acquisitions Editor: Kate Dimock

Developmental Editor: Marybeth Thiel
Publishing Services Manager: Linda Van Pelt
Design Direction: Karen O'Keefe Owens
Cover Design Direction: Karen O'Keefe Owens

Worlung together to grow

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In their preface to the first edition of Genetics in Medi- more examples of how genomics is being used to iden-
cine, published over 40 years ago, James and Margaret tify the contributions made by genetic variation to
Thompson wrote: disease susceptibility and treatment outcomes.
The book is not intended to be a compendium of
Genetics is fundamental t o the basic sciences of
genetic diseases nor is it an encyclopedic treatise on
preclinical medical education and has important
human genetics and genomics in general. Rather, the
applications t o clinical medicine, public health
authors hope that the seventh edition of Genetics in
and medical research. With recognition of the
Medicine will provide students with a framework for
role of genetics in medicine has come the
understanding the field of medical genetics while giving
problem of providing a place for it in the
them a basis on which to establish a program of con-
undergraduate curriculum, a problem which is as
tinuing education in this area. The clinical cases, first
yet only partly solved in most medical schools.
introduced in the last edition to demonstrate and rein-
This book has been written t o introduce the
force general principles of disease inheritance, patho-
medical student t o the principles of genetics as
genesis, diagnosis, management, and counseling,
they apply t o medicine, and t o give him (her) a
continue to be an important feature of the book. We
background for his o w n reading of the extensive
have expanded the set of cases to add more common
and rapidly growing literature in the field. If his
complex disorders to the original set of cases, which
(her) senior colleagues also find it useful, we shall
comprised mostly highly informative and important
be doubly satisfied.
disorders with mendelian inheritance. To enhance
What was true then is even more so now as our knowl- further the teaching value of the Clinical Cases, we
edge of genetics and of the human genome is rapidly have added an additional feature to the seventh edition:
becoming an integral part of public health and the at specific points throughout the text, we provide a case
practice of medicine. This new edition of Genetics in number (highlighted in ) to direct readers to the
Medicine, the seventh, seeks to fulfill the goals of the case in the Clinical Case Studies section that is relevant
previous six by providing an accurate exposition of the to the concepts being discussed at that point in the
fundamental principles of human and medical genetics. text.
Using illustrative examples drawn from medicine, we Any medical or genetic counseling student, advanced
continue to emphasize the genes and molecular mecha- undergraduate, graduate student in genetics, resident in
nisms operating in human diseases. any field of clinical medicine, practicing physician, or
Much has changed, however, since the last edition allied medical professional in nursing or physical
of this book. Completion of the Human Genome Project therapy should find this book to be a thorough but not
provides us with a catalogue of all human genes, their exhaustive (or exhausting!) presentation of the funda-
sequence, and an extensive, and still growing, database mentals of human genetics and genomics as applied to
of human variation. Genomic information has stimu- health and disease.
lated the creation of powerful new tools that are chang-
ing human genetics research and medical genetics
practice. We therefore have expanded the scope of the Robert L. Nussbaum, M D
book to incorporate the concepts of "Personalized Roderick R . McInnes, M D , PhD
Medicine" into Genetics in Medicine by providing Huntington F. Willard, PhD
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Acknowledgments

The authors wish to express their appreciation and Joseph Nevins and Hutton Kearney of Duke University;
gratitude to their many colleagues who, through their John Phillips I11 of the Vanderbilt University School of
ideas, suggestions, and criticisms, improved the seventh Medicine; Jennifer Puck and Me1 Grumbach of the
edition of Genetics i n Medicine. In particular, we are University of California, San Francisco; Eric Shoubridge
grateful to Leslie Biesecker for sharing his knowledge of McGill University; Richard Spielman of the Univer-
and experience in molecular dysmorphology and genet- sity of Pennsylvania; Peter St. George-Hyslop of the
ics in the writing of Chapter 14, "Developmental Genet- University of Toronto; Lyuba Varticovski of the
ics and Birth Defects." We also thank Win Arias of the National Cancer Institute; Paula Waters of the Univer-
National Institutes of Health; Peter Byers and George sity of British Columbia; Huda Zoghbi and Arthur
Stamatoyannopoulos of the University of Washington; Beaudet of the Baylor College of Medicine; and David
Diane Cox of the University of Alberta; Gary Cutting Ledbetter and Christa Lees Martin of Emory Univer-
and David Valle of the Johns Hopkins School of sity. We also thank the many students in the Johns
Medicine; Robert Desnick of the Mount Sinai School HopkinsINIH Genetic Counseling Training Program
of Medicine; Curt Harris of the National Cancer Insti- for their constructive criticisms of the previous edition
tute; Douglas R. Higgs of the Weatherall Institute of during the gestation of this new edition.
Molecular Medicine; Katherine High of the Children's We once again express our deepest gratitude to Dr.
Hospital of Philadelphia; Jennifer Jennings of the Insti- Margaret Thompson for providing us the opportunity
tute of Genetics of the Canadian Institutes of Health to carry on the legacy of the textbook she created 40
Research; Mark Kay of Stanford University; Muin years ago with her late husband, James S. Thompson.
Khoury of the Centers for Disease Control; Joe Clarke, Finally, we again thank our families for their patience
Don Mahuran, Chris Pearson, Peter Ray, and Steve and understanding for the many hours we spent creat-
Scherer of the Hospital for Sick Children, Toronto; ing this, the seventh edition of Genetics i n Medicine.
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Chapter 5

Introduction, 1 Principles o f Clinical Cytogenetics, 59

Genetics and Genomics in Medicine, 1 Introduction to Cytogenetics, 59
Onward, 2 Chromosome Abnormalities, 65
Parent-of-Origin Effects, 77
Studies of Chromosomes in Human Meiosis, 81
Chapter 2 Mendelian Disorders with Cytogenetic Effects, 82
The Human Genome and the Chromosomal
Cytogenetic Analysis in Cancer, 82
Basis o f Heredity, 5
The Human Genome and Its Chapter 6
Chromosomes, 6 Clinical Cytogenetics: Disorders o f the
Cell Division, 13 Autosomes and the Sex Chromosomes, 89
Human Gametogenesis and Fertilization, 20
Medical Relevance of Mitosis and Autosomal Disorders, 89
Meiosis, 22 The Sex Chromosomes and Their
Abnormalities, 98
Disorders of Gonadal and Sexual
Chapter 3 Development, 109
The Human Genome: Gene Structure and
Chapter 7
Function, 25
Information Content of the Human Patterns o f Single-Gene Inheritance, 115
Genome, 25 Overview and Concepts, 115
The Central Dogma: Mendelian Inheritance, 118
DNA + RNA -+ Protein, 26 Factors Affecting Pedigree Patterns, 119
Gene Organization and Structure, 28 Correlating Genotype and Phenotype, 121
Fundamentals of Gene Expression, 30 Autosomal Patterns of Mendelian
Gene Expression in Action: The P-Globin Inheritance, 122
Gene, 33 X-Linked Inheritance, 129
Gene Regulation and Changes in Activity of the Pseudoautosomal Inheritance, 135
Genome, 36 Mosaicism, 135
Variation in Gene Expression and its Relevance Imprinting In Pedigrees, 137
to Medicine, 38 Unstable Repeat Expansions, 139
Conditions that May Mimic Mendelian
Inheritance of Single-Gene Disorders, 144
Chapter 4
Maternal Inheritance of Disorders Caused by
Tools o f Human Molecular Genetics, 41 Mutations in the Mitochondria1 Genome, 144
Analysis of Individual DNA and RNA Family History as Personalized Medicine, 146
Sequences, 41
Methods of Nucleic Acid Analysis, 48 Chapter 8
The Polymerase Chain Reaction, 50
DNA Sequence Analysis, 53 Genetics o f Common Disorders with Complex
Advanced Techniques Using Digital Image Inheritance, 151
Capture of Fluorescence-Tagged Qualitative and Quantitative Traits, 152
Nucleotides, 55 Genetic and Environmental Modifiers of
Western Blot Analysis of Proteins, 5 7 Single-Gene Disorders, 159
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Contents - --
--
-

Examples of Multifactorial Traits for which Defects in Receptor Proteins, 360

Genetic and Environmental Factors Are Transport Defects, 364
Known, 160 Disorders of Structural Proteins, 367
Neurodegenerative Disorders, 377
Chapter 9
C h a p t e r 13
Genetic Variation in Individuals and
Populations: Mutation and The Treatment o f Genetic Disease, 393
Polymorphism, 175 The Current State of Treatment of Genetic
Mutation, 175 Disease, 393
Types of Mutations and Their Consequences, 177 Special Considerations in Treating Genetic
Human Genetic Diversity, 183 Disease, 395
Inherited Variation and Polymorphism in Treatment Strategies, 396
DNA, 184 The Molecular Treatment of Disease, 399
Inherited Variation and Polymorphism in
Proteins, 186
Genotypes and Phenotypes in Populations, 192 'hapter 14
Factors that Disturb Hardy-Weinberg
Developmental Genetics and Birth
Equilibrium, 195
Ethnic Differences in the Frequency of Various Defects, 419
Genetic Diseases, 199 (with the assistance of Leslie G . Biesecker, M D )

Developmental Biology in Medicine, 419

C h a p t e r 10
Introduction to Developmental Biology, 422
Human Gene Mapping and Disease Gene Genes and Environment in Development, 424
Identification, 207 Basic Concepts of Developmental Biology, 426
Cellular and Molecular Mechanisms in
The Genetic Landscape of the Human Development, 434
Genome, 207 Interaction of Developmental Mechanisms in
Mapping Human Genes by Linkage Embryogenesis, 440
Analysis, 217
Mapping of Complex Traits, 222
From Gene Mapping to Gene Identification, Chapter 15

Prenatal Diagnosis, 443

Clinical Case Studies Illustrating Genetic
Indications for Prenatal Diagnosis by Invasive
Principles, 231
Testing, 443
Methods of Prenatal Diagnosis, 444
C h a p t e r 11 Laboratory Studies, 453
Emerging Technologies for Prenatal
Principles o f Molecular Disease: Lessons from Diagnosis, 456
the Hemoglobinopathies, 323 Prenatal Prevention and Management of Genetic
The Effect of Mutation on Protein Function, 323 Disease, 457
How Mutations Disrupt the Formation of Genetic Counseling for Prenatal Diagnosis, 458
Biologically Normal Proteins, 325
The Hemoglobins, 326
Chapter 16
The Hemoglobinopathies, 329
Cancer Genetics and Genomics, 461
Chapter 12 Genetic Basis of Cancer, 461
Oncogenes, 464
The Molecular, Biochemical, and Cellular Tumor-Suppressor Genes, 467
Basis o f Genetic Disease, 345 Tumor Progression, 479
Diseases due to Mutations in Different Classes of Applying Genomics to Individualize Cancer
Proteins, 345 Therapy, 479
Diseases Involving Enzymes, 348 Cancer and the Environment, 482
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C h a p t e r 17 Application of Molecular Genetics to

Determination of Recurrence Risks, 516
Personalized Genetic Medicine, 4 8 5
Empirical Recurrence Risks, 519
Family History as Personalized Genetic
Medicine, 485
Genetic Screening in Populations, 487 C h a p t e r 20
Screening for Genetic Susceptibility to Ethical Issues i n Medical Genetics, 5 2 3
Disease, 490
Ethical Dilemmas Arising in Medical
Genetics, 523
- C h a p t e r 18

Pharmacogenetics a n d
Eugenic and Dysgenic Effects of Medical
Genetics, 528
Genetics in Medicine, 529
Pharmacogenomics, 4 9 7
Using Risk Information to Improve Care:
Pharmacogenetics, 497 Glossary, 531
Pharmacogenomics, 504 Answers to Problems, 551
Role of Ethnicity and Race in Personalized
Medicine, 504 Index, 567

C h a p t e r 19

Genetic Counseling a n d Risk Assessment, 5 0 7

The Process of Genetic Counseling, 507
Determining Recurrence Risks, 509
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Introduction

O GENETICS A N D GENOMICS I N to a medical disorder allows the risk in other family

MEDICINE members to be estimated so that proper management,
prevention, and counseling can be offered to the patient
Genetics in medicine had its start at the beginning of and the family.
the 20th century, with the recognition by Garrod and In the past few years, the Human Genome Project
others that Mendel's laws of inheritance could explain has made available the complete sequence of all human
the recurrence of certain disorders in families. During DNA; knowledge of the complete sequence allows the
the ensuing 100 years, medical genetics grew from a identification of all human genes, a determination of
small subspecialty concerned with a few rare hereditary the extent of variation in these genes in different popu-
disorders to a recognized medical specialty whose con- lations, and, ultimately, the delineation of how varia-
cepts and approaches are important components of the tion in these genes contributes to health and disease. In
diagnosis and management of many disorders, both partnership with all the other disciplines of modern
common and rare. This is even more the case now at biology, the Human Genome Project has revolutionized
the beginning of the 21st century, with the completion human and medical genetics by providing fundamental
of the Human Genome Project, an international effort insights into many diseases and promoting the develop-
to determine the complete content of the human genome, ment of far better diagnostic tools, preventive mea-
defined as the sum total of the genetic information of sures, and therapeutic methods based on a comprehensive
our species (the suffix -ome is from the Greek for "all" view of the genome.
or "complete"). We can now study the human genome Genetics is rapidly becoming a central organizing
as an entity, rather than one gene at a time. Medical principle in medical practice. Here are just a few exam-
genetics has become part of the broader field of genomic ples of the vast array of applications of genetics and
medicine, which seeks to apply a large-scale analysis of genomics to medicine today:
the human genome, including the control of gene
expression, human gene variation, and interactions A child who has multiple congenital malformations
between genes and the environment, to improve medical and a normal routine chromosome analysis under-
care. goes a high-resolution genomic test for submicro-
Medical genetics focuses not only on the patient scopic chromosomal deletions or duplications.
but also on the entire family. A comprehensive family A young woman with a family history of breast
history is an important first step in the analysis of any cancer receives education, test interpretation, and
disorder, whether or not the disorder is known to be support from a counselor specializing in hereditary
genetic. As pointed out by Childs, "to fail to take a breast cancer.
good family history is bad medicine." A family history An obstetrician sends a chorionic villus sample taken
is important because it can be critical in diagnosis, may from a 38-year-old pregnant woman to a cytogenet-
show that a disorder is hereditary, can provide informa- ics laboratory for examination for abnormalities in
tion about the natural history of a disease and variation the number or structure of the fetal chromosomes.
in its expression, and can clarify the pattern of inheri- A hematologist combines family and medical history
tance. Furthermore, recognizing a familial component with gene testing of a young adult with deep venous
 RoshanKetab +98(21) 66963783-8

thrombosis to assess the benefits and risks of initiat- even though no individual gene on the chromosome is
ing and maintaining anticoagulant therapy. abnormal. As a group, chromosome disorders are
Gene expression array analysis of a tumor sample is common, affecting about 7 per 1000 liveborn infants
used to determine prognosis and to guide therapeutic and accounting for about half of all spontaneous first-
decision-making. trimester abortions. These disorders are discussed in
An oncologist tests her patients for genetic variations Chapter 6.
that can predict a good response or an adverse reac- Single-gene defects are caused by individual mutant
tion to a chemotherapeutic agent. genes. The mutation may be present on only one chro-
A forensic pathologist uses databases of genetic poly- mosome of a pair (matched with a normal allele on the
morphism~in his analysis of DNA samples obtained homologous chromosome) or on both chromosomes of
from victims' personal items and surviving relatives the pair. In a few cases, the mutation is in the mito-
to identify remains from the September 11, 2001 chondrial rather than in the nuclear genome. In any
World Trade Center attack. case, the cause is a critical error in the genetic informa-
Discovery of an oncogenic signaling pathway inap- tion carried by a single gene. Single-gene disorders such
propriately reactivated by a somatic mutation in a as cystic fibrosis, sickle cell anemia, and Marfan syn-
form of cancer leads to the development of a specific drome usually exhibit obvious and characteristic pedi-
and powerful inhibitor of that pathway that success- gree patterns. Most such defects are rare, with a
fully treats the cancer. frequency that may be as high as 1 in 500 to 1000
Genetic principles and approaches are not restricted individuals but is usually much less. Although individu-
to any one medical specialty or subspecialty but are ally rare, single-gene disorders as a group are responsi-
permeating many areas of medicine. To give patients ble for a significant proportion of disease and death.
and their families the full benefit of expanding genetic Taking the population as a whole, single-gene disorders
knowledge, all physicians and their colleagues in the affect 2% of the population sometime during an entire
health professions need to understand the underlying life span. In a population study of more than 1 million
principles of human genetics. These principles include live births, the incidence of serious single-gene disor-
the existence of alternative forms of a gene (alleles) in ders in the pediatric population was estimated to be
the population; the occurrence of similar phenotypes 0.36%; among hospitalized children, 6% to 8% prob-
developing from mutation and variation at different ably have single-gene disorders. These disorders are
loci; the recognition that familial disorders may arise discussed in Chapter 7.
from gene variants that cause susceptibility to diseases Multifactorial inheritance is responsible for the
in the setting of gene-gene and gene-environmental majority of diseases, all of which have a genetic contri-
interactions; the role of somatic mutation in cancer and bution, as evidenced by increased risk for recurrence in
aging; the feasibility of prenatal diagnosis, presymp- relatives of affected individuals or by increased fre-
tomatic testing, and population screening; and the quency in identical twins, and yet show inheritance
promise of powerful gene-based therapies. These con- patterns in families that do not fit the characteristic
cepts now influence all medical practice and will only patterns seen in single-gene defects. Multifactorial dis-
become more important in the future. eases include prenatal developmental disorders, result-
ing in congenital malformations such as Hirschsprung
Classification of Genetic Disorders disease, cleft lip and palate, or congenital heart defects,
as well as many common disorders of adult life, such
In clinical practice, the chief significance of genetics is as Alzheimer disease, diabetes, and hypertension. There
in elucidating the role of genetic variation and mutation appears to be no single error in the genetic information
in predisposing to disease, modifying the course of in many of these conditions. Rather, the disease is the
disease, or causing the disease itself. Virtually any result of one, two, or more different genes that together
disease is the result of the combined action of genes and can produce or predispose to a serious defect, often in
environment, but the relative role of the genetic com- concert with environmental factors. Estimates of the
ponent may be large or small. Among disorders caused impact of multifactorial disease range from 5% in the
wholly or partly by genetic factors, three main types pediatric population to more than 60% in the
are recognized: chromosome disorders, single-gene dis- entire population. These disorders are the subject of
orders, and multifactorial disorders. Chapter 8.
In chromosome disorders, the defect is due not to
a single mistake in the genetic blueprint but to an excess
or a deficiency of the genes contained in whole chro- 6 ONWARD
mosomes or chromosome segments. For example, the
presence of an extra copy of one chromosome, chromo- During the SO-year professional life of today's profes-
some 21, produces a specific disorder, Down syndrome, sional and graduate students, extensive changes are
 RoshanKetab +98(21) 66963783-8

1
CHAPTER Introduction
-

likely to take place in the discovery, development, and appreciation of the genetic and genomic perspective on
use of genetic and genomic knowledge and tools in health and disease will form a framework for lifelong
medicine. It is difficult to imagine that any ~ e r i o dcould learning that is part of every health professional's
encompass changes greater than those seen in the past career.
50 years, during which the field has gone from first
recognizing the identity of DNA as the active agent of
inheritance, to uncovering the molecular structure of
DNA and chromosomes and determining the complete 43 GENERAL REFERENCES
code of the human genome. And yet, judging from the
quickening pace of discovery within only the past Guttmacher AE, Collins FS: Genomic medicine-a primer. N Engl
J Med 347:1512-1520, 2002.
decade, it is certain that we are just at the Peltonen L, McKusick VA: Genomics and medicine. Dissecting
beginning of a revolution in integrating knowledge of human disease in the postgenomic era. Science 291:1224-1229,
genetics and the genome into public health and the 2001.
Willard HF, Angrist M, Ginsburg GS: Genomic medicine: genetic
practice An the language variation and its impact on the future of health care. Philos Trans
and concepts of human and medical genetics and an R S ~ Lond
C B Biol Sci 360:1543-1550,2005.
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The Human Genome and the

Chromosomal Basis o f Heredity

Appreciation of the importance of genetics to medicine The study of chromosomes, their structure, and
requires an understanding of the nature of the heredi- their inheritance is called cytogenetics. The science of
tary material, how it is packaged into the human modern human cytogenetics dates from 1956, when it
genome, and how it is transmitted from cell to cell was first established that the normal human chromo-
during cell division and from generation to generation some number is 46. Since that time, much has been
during reproduction. The human genome consists of learned about human chromosomes, their normal
large amounts of the chemical deoxyribonucleic acid structure, their molecular composition, the locations of
(DNA) that contains within its structure the genetic the genes that they contain, and their numerous and
information needed to specify all aspects of embryo- varied abnormalities.
genesis, development, growth, metabolism, and repro- Chromosome and genome analysis has become an
duction-essentially all aspects of what makes a human important diagnostic procedure in clinical medicine. As
being a functional organism. Every nucleated cell in the described more fully in subsequent chapters, some of
body carries its own copy of the human genome, which these applications include the following:
contains, by current estimates, about 25,000 genes. Clinical Diagnosis Numerous medical disorders,
Genes, which at this point we define simply as units of including some that are common, such as Down syn-
genetic information, are encoded in the DNA of the drome, are associated with microscopically visible
genome, organized into a number of rod-shaped orga- changes in chromosome number or structure and
nelles called chromosomes in the nucleus of each cell. require chromosome or genome analysis for diagnosis
The influence of genes and genetics on states of health and genetic counseling (see Chapters 5 and 6).
and disease is profound, and its roots are found in the
information encoded in the DNA that makes up the Gene Mapping and Identification A major goal of
human genome. Our knowledge of the nature and iden- medical genetics today is the mapping of specific genes
tity of genes and the composition of the human genome to chromosomes and elucidating their roles in health
has increased exponentially during the past several and disease. This topic is referred to repeatedly but is
decades, culminating in the determination of the DNA discussed in detail in Chapter 10.
sequence of virtually the entire human genome in Cancer Cytogenetics Genomic and chromosomal
2003. changes in somatic cells are involved in the initiation
Each species has a characteristic chromosome com- and progression of many types of cancer (see Chapter
plement (karyotype) in terms of the number and the 16).
morphology of the chromosomes that make up its
genome. The genes are in linear order along the chro- Prenatal Diagnosis Chromosome and genome analy-
mosomes, each gene having a precise position or locus. sis is an essential procedure in prenatal diagnosis (see
A gene map is the map of the chromosomal location of Chapter 15).
the genes and is characteristic of each species and the The ability to interpret a chromosome report and
individuals within a species. some knowledge of the methodology, the scope, and the
 RoshanKetab +98(21) 66963783-8

Thnmncnn R Thnmncnn CFNFTICZ IN MFnlCINE - - - -

- - -

limitations of chromosome studies are essential skills 46 chromosomes, arranged in 23 pairs (Fig. 2-1). Of
for physicians and others working with patients with those 23 pairs, 22 are alike in males and females and
birth defects, mental retardation, disorders of sexual are called autosomes, numbered from the largest to the
development, and many types of cancer. smallest. The remaining pair comprises the sex chro-
mosomes: two X chromosomes in females and an X
and a Y chromosome in males. Each chromosome
Q THE HUMAN GENOME AND ITS carries a different subset of -genes that are arranged
-
CHROMOSOMES linearly along its DNA. Members of a pair of chromo-
somes (referred to as homologous chromosomes or
With the exception of cells that develop into gametes homologues) carry matching genetic information; that
(the germline), all cells that contribute to one's body are is, they have the same genes in the same sequence. At
called somatic cells (soma, body). The genome con- any specific locus, however, they may have either identi-
tained in the nucleus of human somatic cells consists of cal or slightly different forms of the same gene, called

x Nuclear chromosomes c:,..,, 7 1

w The human genome,
encoded on both nuclear and mitochon-
drial chromosomes. (Modified from
Brown TA: Genomes, 2nd ed. New York,
Wiley-Liss, 2002.)

...CAGGTCTTAGCCAlTCGGAAT
CGTACGCTAGCAATTCTTATGG
AAACTGTGAAGGCTTATAAT.. .
Human Genome Sequence
 RoshanKetab +98(21) 66963783-8

- - - CHAPTER2 The Human Genome and the Chromosomal Basis o f Heredity

Purines Pyrimidines
NH2 0
II

r. ~-.-.
w The four bases of DNA ti I
and the general structure of a nucleotide H
in DNA. Each of the four bases bonds Adenine (A) Thymine (T)
with deoxyribose (through the nitrogen
shown in blue) and a phosphate group to
form the corresponding nucleotides.
OH H
Phosphate Deoxyribose

Guanine (G) Cytosine (C)

alleles. One member of each pair of chromosomes is moiety, polymerize into long polynucleotide chains by
inherited from the father, the other from the mother. 5'-3' phosphodiester bonds formed between adjacent
Normally, the members of a pair of autosomes are deoxyribose units (Fig. 2-3). In the human genome,
microscopically indistinguishable from each other. In these polynucleotide chains (in the form of a double
females, the sex chromosomes, the two X chromo- helix; Fig. 2-4) are hundreds of millions of nucleotides
somes, are likewise largely indistinguishable. In males, long, ranging in size from approximately 50 million
however, the sex chromosomes differ. One is an X, base pairs (for the smallest chromosome, chromosome
identical to the X's of the female, inherited by a male 21) to 250 million base pairs (for the largest chromo-
from his mother and transmitted to his daughters; the some, chromosome 1).
other, the Y chromosome, is inherited from his father The anatomical structure of DNA carries the chem-
and transmitted to his sons. In Chapter 6, we look at ical information that allows the exact transmission of
some exceptions to the simple and almost universal rule genetic information from one cell to its daughter cells
that human females are X X and human males are and from one generation to the next. At the same time,
XY. the primary structure of DNA specifies the amino acid
In addition to the nuclear genome, a small but sequences of the polypeptide chains of proteins, as
important part of the human genome resides in mito- described in the next chapter. DNA has elegant features
chondria in the cytoplasm (see Fig. 2-1). The mitochon- that give it these properties. The native state of DNA,
drial chromosome, to be described later in this chapter, as elucidated by James Watson and Francis Crick in
has a number of unusual features that distinguish it 1953, is a double helix (see Fig. 2-4). The helical struc-
from the rest of the human genome. ture resembles a right-handed spiral staircase in which
its two polynucleotide chains run in opposite direc-
DNA Structure: A Brief Review tions, held together by hydrogen bonds between pairs
of bases: A of one chain paired with T of the other, and
Before the organization of the human genome and its G with C. The specific nature of the genetic informa-
chromosomes is considered in detail, it is necessary to tion encoded in the human genome lies in the sequence
review the nature of the DNA that makes up the genome. of C'S, A's, G's, and T's on the two strands of the double
DNA is a polymeric nucleic acid macromolecule com- helix along each of the chromosomes, both in the
posed of three types of units: a five-carbon sugar, nucleus and in mitochondria (see Fig. 2-1). Because of
deoxyribose; a nitrogen-containing base; and a phos- the complementary nature of the two strands of DNA,
phate group (Fig. 2-2). The bases are of two types, knowledge of the sequence of nucleotide bases on one
purines and pyrimidines. In DNA, there are two purine strand automatically allows one to determine the
bases, adenine (A) and guanine (G), and two pyrimi- sequence of bases on the other strand. The double-
dine bases, thymine (T) and cytosine (C). Nucleotides, stranded structure of DNA molecules allows them to
each composed of a base, a phosphate, and a sugar replicate precisely by separation of the two strands,
 RoshanKetab +98(21) 66963783-8

Thompson &Thomason GENETICS IN MEDICINE

followed by synthesis of two new complementary

5' end strands, in accordance with the sequence of the original
template strands (Fig. 2-5). Similarly, when necessary,
the base complementarity allows efficient and correct
I Base 1
repair of damaged DNA molecules.

Organization of Human Chromosomes

The composition of genes in the human genome, as well
as the determinants of their expression, is specified in
the DNA of the 46 human chromosomes in the nucleus
plus the mitochondria1 chromosome. Each human
chromosome consists of a single, continuous DNA
double helix; that is, each chromosome in the nucleus
is a long, linear double-stranded DNA molecule, and
the nuclear genome consists, therefore, of 46 DNA mol-
ecules, totaling more than 6 billion nucleotides (see Fig.
2-1).
Chromosomes are not naked DNA double helices,
however. Within each cell, the genome is packaged as
I Base 2 chromatin, in which genomic DNA is complexed with
several classes of chromosomal proteins. Except during
3' end
cell division, chromatin is distributed throughout the
3' 5:-5: nucleus and is relatively homogeneous in appearance
under the microscope. When a cell divides, however, its
Figure 2-3 1 A portion of a DNA polynucleotide chain, genome condenses to appear as microscopically visible
showing the 3'-5' phosphodiester bonds that link adjacent chromosomes. Chromosomes are thus visible as dis-
nucleotides. crete structures only in dividing cells, although they
retain their integrity between cell divisions.
The DNA molecule of a chromosome exists in
chromatin as a complex with a family of basic chromo-
somal proteins called histones and with a heteroge-

The structure of DNA.

Lelr, LWU-dimensional
A representation of
the two complementary strands of DNA,
showing the AT and GC base pairs. Note
that the orientation of the two strands is
antiparallel. Right, The double-helix
model of DNA, as proposed by Watson
and Crick. The horizontal "rungs" repre-
sent the paired bases. The helix is said to
be right-handed because the strand going
from lower left to upper right crosses over
the opposite strand. (Based on Watson
JD, Crick FHC: Molecular structure of
nucleic acids-a structure for deoxyribose
nucleic acid. Nature 171:737-738, 1953.)
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La Palisse.—On the Bèbre; is a small town, with a large château of the
fifteenth and sixteenth centuries.
Varennes-sur-Allier.—A small place, with quaint houses.
S t . É t ienne owes its prosperity to its extensive coalfields, covering
about 100 square miles. The annual production of the mines is given as
from 3,000,000 to 4,000,000 tons. The town also employs thousands of men
in the iron foundries, where armour-plate and machinery and all sorts of
large castings are made. A very large output of rifles and revolvers is
another source of wealth to the town, and the ribbon industry, largely
carried on in the homes of the workmen, keeps 40,000 men employed. The
weavers, as a rule, show their looms to visitors without the least objection.
The Palais des Beaux Arts contains a good picture-gallery and a museum
of gun-making and looms, but otherwise there is little to see in this town,
consisting mainly of one very long street.
THE ROAD TO ROANNE
From St. Étienne until one reaches Fontainebleau the towns and villages
have fewer antiquities and, on
 No. 22. ST. ÉTIENNE TO MOULINS.

the whole, less picturesqueness than farther south, and if time is running
short this portion of the tour can be hurried over with less fear of missing
good things than any other part of the route described. The scenery is
delightful in some districts, but comparatively tame in others.
At the red-roofed village of L a F ouillous e the tramway from St.
Étienne stops. The valley, although containing so many factories and such a
busy town, is extraordinarily free from smoke, and the fields are as clean
and bright as though there were no industrial activities for many miles.
At the end of the valley the distant peep of mountains, snow-covered
until May, is delightful on a sunny morning. The road goes nearly due
northwards through the flat, marshy Plaine-du-Forez, through which the
Loire winds a snaky course. Hills surround the plain on all sides, and the
pastoral scenes of grazing cattle, backed by the snowy ridges to the west,
are most paintable.
At the village of Meyl i eu - Montr ond there is a complete shell of a
castle on the right bank of the Loire. The reddish-coloured road keeps very
straight between rows of poplars, and in a short time brings one to F eur s , a
busy little place where, among other things, they make sabots.
There was a town here called Forus in Gallo-Roman times, but there are
no remains to interest the passing traveller beyond a few old houses.
Balb i gny is an uninteresting village on the Loire, just where the road
leaves the level ground and begins to enter the tumble of hills enclosing the
northern end of the plain. The views obtained are most exhilarating all the
way to Roanne, and one frequently has great panoramic views of the Loire,
which appears as a huge blue serpent in the midst of the green and reddish-
brown fields.
The road passes through the villages of Neulise, Vendranges, and
l’Hôpital, and then drops down to the red-roofed town of
ROANNE
There is nothing to detain visitors in this busy manufacturing town, for
all that was interesting or picturesque, beyond a few houses of the sixteenth
century, has disappeared. The streets are narrow and not beautiful.
North of Roanne the vine appears again, after having disappeared since
leaving the Rhone Valley.
The enormous plain of the Loire extends to the north, with mountains on
the western horizon, dominated by the silvery grey peaks of the Auvergnes.
 THE TOUR DE L’HORLOGE AT MOULINS.
Built in the fifteenth century. The spires of the cathedral are
modern work by Viollet-le-Duc. (Page 365.)
 Town Plan No. 28.—Roanne.

L a P acaudi èr e is a picturesque village, with a conspicuously

attractive old house on the left, having a steeply pitched turreted roof of
dark brown tiles, and a carved stone doorway of the sixteenth century. One
notices the gradual disappearance of the low-pitched roof as one goes
northwards.
L a P al isse is a picturesque town on the pretty River Bèbre. The
turreted château on the right above the road and river dates from the
fifteenth or sixteenth centuries, and has a Flamboyant Gothic chapel,
containing the tombs of the family of Chabannes. Jacques de Chabannes,
often called La Palisse, became Marshal of France, and was killed at the
Battle of Pavia in 1525.
The road crosses the river opposite the château, and then goes out of the
village westwards along a beautiful road, bordered by tall and stately
poplars, standing like rows of pillars on the short, close-growing turf on
each side of the way. Small flocks of sheep, feeding on the roadside grass,
and tended by girls, who fill up their time with industrious knitting, are
often passed.
All the low-pitched roofs have been left behind, and the villages are
picturesque with thatch and weather-worn tiles and little hipped dormers.
The country is slightly undulating and green, and to the south the strangely
shaped peaks of the volcanic mountains of the Auvergne group are seldom
out of sight.
Farther on one reaches the shallow depression in which, on sunny days,
the River Allier sparkles between its low banks.
The men of this part of the centre of France wear black felt hats and blue
smocks, and have side-whiskers and clean-shaven lips and chins, after the
fashion of the peasants of Normandy.
Var ennes- sur- Al l i er is a quietly picturesque little town, with many
old roofs and overhanging eaves, supported with wooden brackets.
In the pretty village of B essay there is a bad caniveau across the road,
but otherwise there is little calling for comment on the rest of the way to
Moulins.
 SECTION XXIII

MOULINS TO BRIARE, 87 MILES

(140 KILOMETRES)
DISTANCES ALONG THE ROUTE
Kil. Miles.
Moulins to St. Pierre-le-Moutier 32 20
St. Pierre-le-Moutier to Nevers 23 14¼
Nevers to La Charité 25 15½
La Charité to Pouilly 14 8¾
Pouilly to Cosne 15 9¼
Cosne to Briare 31 19¼
NOTES FOR DRIVERS
Moulins to St. Imbert.—Level, and afterwards long undulations to
Nevers, and a good many moderate hills as far as La Marche.
La Marche to Pouilly-sur Loire.—Level, but a long hill follows Pouilly,
with a descent of 4 kilometres to Cosne.
From Cosne to Briare the road follows the Loire, and is level.
Ousson.—Has a cassis or caniveau.
PLACES OF INTEREST ON THE ROUTE
Moulins.—A picturesque town, containing—(1) Several old houses; (2)
clock-tower, built in 1455; (3) portions of the château of the Dukes of
Bourbon; (4) cathedral, with choir built in 1463, containing coeval
glass; (5) tomb of Henri, Duc de Montmorenci, in the Lycée.
Sauvigny.—Twelve kilometres west of Moulins; has a splendid
Romanesque church, containing several Bourbon tombs.
St. Pierre-le-Moutier.—An interesting little town, with fifteenth-century
houses, portions of its ramparts, and a gateway; twelfth-century church,
with richly carved north door.
Nevers (pron. Nervair).—A large and very pleasantly situated town on the
Loire, with—(1) Walls, gateways, and towers dating from the eleventh
to the sixteenth century; (2) the Ducal Palace, now the Palais de Justice,
built in 1475; (3) Cathedral of St. Cyr, with eastern and western apses,
and examples of nearly every period of architecture from 1028 to the
sixteenth century; (4) Church of St. Étienne, an extremely fine example
of the Romanesque Burgundian style.
La Charité.—A very attractive little town on the Loire, with—(1) Several
old houses; (2) walls and towers of its fortifications; (3) Church of Ste.
Croix, a magnificent example of eleventh to twelfth century work.
Mesves.—A pretty village with a twelfth-century barn.
Pouilly.—A picturesque little town with a seventeenth-century château.
Cosne.—A town with iron foundries and three churches (one disused); the
most interesting is that of St. Aignan, with a fine Romanesque apse.
Myennes.—A roadside hamlet.
Bonny-sur-Loire.—A village with a quaint church spire.
Mo u li ns is a picturesque and attractive town on high ground above the
River Allier. The first
 Town Plan No. 29.—Moulins.

conspicuous feature reached on entering from the south is the Tour de

l’Horloge, built in 1455, with moving figures in its curiously designed
lantern. The narrow streets contain several good houses of the sixteenth and
seventeenth centuries, and many of the brick fronts are ornamented with
lozenges in darker brick. One house behind the clock-tower is noticeable
for its beautiful little gazebo on the roof, with carved corbels and pilasters.
The nave and towers of the Cathedr al are modern, having been built
under the direction of Viollet le Duc. The spires add to the appearance of
the town, as they stand out boldly from a hundred points of view. The
beautiful choir was built by Agnes de Bourgogne in 1463, and it has been
fortunate in preserving its fine fifteenth to sixteenth century glass. In the
sacristy on the north side there is a fine triptych, showing, on the inside, the
Virgin surrounded with angels, and Pierre II. de Bourbon and his wife,
Anne of France (died 1522), a daughter of Louis XI. On the south side of
the choir there is a beautiful spiral stone staircase, and near it, in a chapel, is
a gruesome memorial representing the horrors of worms consuming a
human body.
Adjoining the cathedral is all that now remains of the Castle of th e
D u k es of B our bon, now unfortunately converted into a prison. From the
river-side the walls tower up to a great height.
In the Lycée, formerly a convent of the Visitation, one is shown the
sumptuous tomb of Carrara marble put up by his widow to the famous
Henri, Duc de Montmorenci, who was executed at Toulouse in 1632 on a
charge of treason against Louis XIII.
Lord Clarendon wrote a portion of his ‘History of
the Great Rebellion’ while he was staying at Moulins,
and James FitzJames, Duke of Berwick, Marshal and
Peer of France, and a natural son of James II., was
born here in 1670.
As one goes out of Moulins one notices two
massive pillars marking the position of the town
walls which have disappeared. The poplar-bordered
road gives pretty views of the Allier on the left, and
the fresh green of the roadside grass is a pleasant
contrast to the

No. 23. MOULINS TO

BRIARE.
 THE FIFTEENTH-CENTURY FIREPLACE IN THE
HÔTEL DU GRAND CERF AT LE GRAND ANDELY.
(Page 409.)

dust farther south. Picturesque timber-framed houses with dark browny-red

roofs begin to abound, and the villages increase in charm. Large farmhouses
with big stone barns, here and there buildings with quaint crows’ steps to
the gables, and two or three windmills, are passed, all adding considerably
to the charm of the scenery.
S t . P i er r e- le- Mout i er is a delightful old place. It retains portions of
its ramparts, round towers, and a gateway, made more interesting when one
remembers that this was one of the towns of the Loire Valley taken by
Jeanne d’Arc in 1429. The church belonged to the Cluniac priory of St.
Martin d’Autun, and is a very interesting example of the style of the latter
half of the twelfth century. The north doorway, with its richly sculptured
tympanum showing Christ in the midst of angels, should be seen. The town
contains some picturesque houses of the fifteenth century and later.
NEVERS
On approaching this town there is a fine view of its cathedral rising
above the old roofs with the Loire in the foreground, and the confluence
with the Allier two or three miles to the left.
All remains of the Roman town of Nevirnum, which was of so much
strength that Cæsar kept his military stores there, have entirely disappeared,
with the exception of a few objects in the Library of the town.

Town Plan No. 30.—Nevers.

The medieval remains are, on the other hand, of great interest. On the
town walls there remain—(1) The Porte de Croux, a most picturesque
gateway dating from 1393-1396; it has corner turrets and three openings for
the drawbridge supports; (2) the Loire gateway, the lower part of which is
as early as the eleventh century; (3) the Tour Goguin, twelfth century; and
(4) the Tour St. Eloi, sixteenth century.
The D ucal P al ace , now the Palais de Justice, was built in 1475 by
Jean de Clamecy, Comte de Nevers, and its Renaissance character was
given during the next century, when the Clèves family, and afterwards the
Gonzogas of Mantua, held Nevers. In front of the palace there are pleasant
gardens, with a view southwards towards Moulins, and to the right (when
one faces this prospect) is the Cathed r al of S t. Cyr . It has a square
tower of the Flamboyant period, rather severe in outline, but encrusted with
beautiful panelling and statuary, and the south porch belongs to the same
period. The curious, almost bizarre, feature of the interior is the apsidal
termination at both the east and west ends. At the east end there is a
beautiful vaulted ambulatory of the fourteenth century, erected outside the
eastern apse of the Romanesque cathedral, built in 1028 and restored and
altered in 1194. The early wall-paintings were fortunately preserved by the
Gothic architect.
At the west end, the Romanesque crypt remains beneath an apse rebuilt
in the sixteenth century. The Saint Sépulcre in the crypt is a hideous group
of painted figures bending over a representation of Christ. The beautiful
nave, rebuilt in 1188, is enriched with caryatides and sculptured figures.
Before leaving Nevers the very fine Chur ch of the Cluniac P r io r y
o f S t . É t ien ne , begun in 1063 by William I., Count of Nevers, and
finished in 1097, should be seen. It is a remarkably fine example of the
Burgundian-Romanesque style. The cloisters belong to the thirteenth
century.
Bernadette Soubirous, the unfortunate heroine of the Lourdes apparition
of the Virgin, spent her last years, and died at the early age of thirty-five, in
the nunnery of St. Gildard at Nevers. Throughout most of her life, and
especially towards the end, her physical infirmities were a great burden to
the poor girl. Her grave is in the convent garden, and one marvels that the
Roman Catholic authorities did not order a sumptuous tomb in the
pilgrimage church at Lourdes! (See p. 235.)
The road goes northwards through P ougues- les- E aux , and runs close
to the Loire from the hamlet of La Marche for a considerable distance. The
river is broken up with sandy islands covered with low green bushes and
thin wire-grass.
L a Char i té is a very picturesque and cheerful little town with several
good old houses, and an old stone bridge across the river. The extremely
interesting and beautiful Romanesque church belonged to one of the most
important Cluniac priories in France, so famed for its good deeds that the
place received the name it now bears. A town sprang up round the abbey,
and ramparts defended with several towers were built in 1184, but the
fortifications standing to-day were rebuilt in 1364. It is surprising that there
are any of the defences left when one reads of the frequent sieges and
sackings the town endured, particularly during the religious wars of the
sixteenth century.
T h e C hur ch of S t e. C r oix , just mentioned, was consecrated in 1107
by Pope Pascal II., but not finished until some years later. The nave and
south-west tower were ruined in 1557 during the religious wars. The choir,
with picturesque stilted arches, the transepts, and the central tower, are all
that remain of one of the finest Romanesque basilicas in France.
The road goes northwards through the mossy-roofed village of Mesves ,
which has a twelfth-century barn, and for mile after mile the Loire appears
on the left as a blue ribbon threaded through the lacework of the intervening
trees.
P o u i l ly is a cheerful little town with high-pitched roofs and stone
walls, a seventeenth-century château, and a partially Gothic church. The
white wine of the neighbourhood is considered exceedingly good.
COSNE
is a considerable town with iron foundries, barracks, and a hospital. The
church of St. Aignan has a fine Romanesque apse with richly carved
capitals to its pillars, and a greatly enriched west door of the same period.
Pope Pius VII., when in France under Napoleon’s orders, stayed at the
Hôtel du Grand Cerf.
One passes through the village of Myennes , with the houses standing
back from the road, and two or three hamlets, including Bonny- su r-
L o i r e , with the oddest spire to its church, and then enters the village of
B r iar e , where the road to Orleans goes off to the left.
The quaint Hôtel de France, with a courtyard, can furnish a modest
déjeuner.
 SECTION XXIV

BRIARE TO MELUN, 64 MILES

(103 KILOMETRES)
DISTANCES ALONG THE ROUTE
Kil. Miles.
Briare to Montargis 41 25½
Montargis to Nemours 32 20
Nemours to Fontainebleau 15 9¼
Fontainebleau to Melun 15 9¼
TWO ALTERNATIVE ROUTES
Kil. Miles.
1.Briare to Orleans via Gien,
70 43½
Ouzouer-sur-Loire, and Châteauneuf
For the route from Orleans to Rouen,
Havre, Dieppe, and Calais,
see Sections I. to IV.
2.Fontainebleau to Chartres 97 60¼
Fontainebleau to Milly 18 11¼
Milly to Maisse 5 3
Maisse to Étampes 18 11¼
Étampes to Authon-la-Plaine 16 10
Authon-la-Plaine to Ablis 13 8
Ablis to Chartres 27 16¾
NOTES FOR DRIVERS
 Ascent from Briare fairly steep; after that level to Montargis.
Montargis to Fontainebleau.—Practically a flat road, chiefly in the valley of the Loing.

PLACES OF INTEREST ON THE ROUTE

Briare.—A village at the junction of the roads from Orleans and Paris.
La Boussière.—A hamlet with a small château in a park.
Mormant.—A small village with a Romanesque church.
Montargis.—An old and historic town; gateway of château, two towers of town walls, and interesting church
with twelfth-century nave, and a fine choir of Transitional Gothic and Renaissance.
Souppes.—A village with a twelfth-century church.
Nemours.—A small town on the River Loing; picturesque castle, containing a museum; church with thirteenth-
century tower, and the rest sixteenth to seventeenth century.
Fontainebleau.—A small town, which has grown up on one side of the huge Palace of Fontainebleau, built by
François I. and succeeding Kings.

Br iar e is the Roman Brivodurum, but it is now a quiet, uninteresting little town where buttons are manufactured.
After passing through the old-fashioned village of L a B o ussi èr e , one turns to the left towards the château,
at a corner where a board indicates the ‘Route de Paris.’ The yellow-coloured road, with a fine surface, goes on
through a well-wooded country to N og ent- su r- Ver ni sso n , a village without interest, and soon afterwards
Mor m ant , a hamlet with a small Romanesque church.
MONTARGIS
This historic town has, unfortunately, only preserved a gateway of its twelfth-century château, at one time
called le Berceau des Enfants de France, owing to the French queens coming thither, before the building of
Fontainebleau, when they were about to become mothers. Two circular towers of the medieval fortifications are the
only relics of the walls that resisted the English army under the Earl of Warwick during the Hundred Years’ War.
The church has a fine twelfth-century nave, an ornate west end, and an exceedingly graceful and unusually
designed choir, built between 1540 and 1618. The tall pillars of the ambulatory are without capitals, and they
support roofs of equal height above the choir and the ambulatory. Interior and exterior show the change from the
Gothic to the Classic style.
The long canal extending from Briare to the Loing passes through Montargis, which was at one time
surrounded by marshy country, now drained and cultivated.
On leaving the town one passes a statue of Mirabeau, and, after crossing three bridges, the road to
Fontainebleau turns sharply to the left past the goods entrance of the railway-station, and then keeps to the western
side of the fairly extensive forest of Montargis.
 No. 24. BRIARE TO
MELUN.

Mistletoe grows luxuriantly in this district, and all the way from Moulins the trees are tufted with the curious
parasitic plant, which English folk buy from the French in huge quantities as each Christmas festival approaches.
At the hamlet of F ontenay one goes to the right at the fork, and the road continues through a scattered forest,
with prodigious quantities of mistletoe, and at a point 13½ kilometres from Nemours there is a caniveau in the
middle of the village.
After passing S ou pp es, a hamlet with a twelfth-century church, the scenery changes. On the right great
isolated masses of rock stand on the grassy slopes, and on the left the shallow little valley of the Loing is
beautified with the picturesque mills and weirs on the river. The low wooded hills on the left, full of faint purples
and browny greens in spring-time, form a delightful background to the bright green of the grass near at hand. The
rocky slopes on the right are often covered with juniper, and here and there pines scent the atmosphere.
Nem our s is a quiet little town, with a collegiate church of the Gothic and Renaissance periods, with the
lower part of the tower of the thirteenth century; but the château, built in the twelfth and fifteenth centuries, is the
most interesting and picturesque feature. It has circular towers, with conical roofs at each corner, and another
tower (the keep) to the north is joined to the main building with a passage three stories in height. The castle has
been converted into a museum, and the whole of the interior is shown to visitors by an indefatigable old gardienne,
who insists on showing the view over the surrounding forests, which can be seen from the donjon tower.
It was at Nemours, in July, 1585, that Catherine de Medici, on behalf of Henri III., signed the treaty revoking
all edicts in favour of the Protestants, and enforcing the universal profession of Catholicism.
At the present time the title of Duc de Nemours is borne by the second son of Louis-Philippe.
On leaving Nemours the road keeps to the west of the Loing, and almost at once enters the F or est of
F ontainebleau . Most of the trees are without any beauty, being thin and tall and of an average size. There are no
suggestions of the primeval, such as every English forest contains, including even the Londoner’s paradise of
Epping. The only feature of this great tree-grown area which is interesting, apart from its associations, is the
strange appearance of great lumps of rock, tilted up at curious angles, and sprawling about among the trees in such
an odd fashion that in the twilight the forest seems full of giant sloths and other prehistoric beasts!
FONTAINEBLEAU
The town of Fontainebleau stands in the midst of the forest, with the palace and park on the east side.
The palace is open to visitors every day between 11 a.m. and 4 p.m.
 As long ago as 1137 a French king—Louis le Jeune—dated an Act ‘apud fontem Bleaudi.’ François I., that
mighty builder of Renaissance palaces, was, however, the real creator of the Fontainebleau of to-day. He planned,
and to a considerable extent carried out, a structure he desired to be the finest palace in the world. The Galerie de
François I. and that called after and decorated by Henri II. were built by François, and so were the Chapelle de la
Sainte Trinité, the Chapelle St. Saturnin, and the magnificent Salon de François I. Henri II., Henri IV., and various
other sovereigns carried on the building of the immense pile, Fontainebleau being popular for various reasons,
particularly on account of the hunting in the great forest.
Perhaps it is the figure of Napoleon in the midst of the accumulated royal splendours of Fontainebleau that
appeals most to the imagination. The young Corsican soldier, transformed into an Emperor, and dwelling with his
Empress wife in palaces such as this, causes one to gaze with more than ordinary interest at the sumptuous
apartments, with their gilded furnishings, their heavy silken coverings, their thrones, bedsteads, mirrors, and a
thousand features, all of which were backgrounds to the short, dark-haired, and clean-shaven man who had put the
States of Europe, with one notable exception, into the melting-pot of his ambition. One is shown the little round
table upon which ‘the Usurper’ signed his abdication, and the famous horseshoe-shaped staircase where he said
good-bye to the weeping soldiers of the Old Guard.
THE ROAD TO MELUN
goes northwards through the forest, and about 8 kilometres from Fontainebleau passes the stone Tab le d u R oi,
dated 1723. On emerging from the forest Melun is close at hand.
 SECTION XXV

MELUN TO ST. GERMAIN-EN-LAYE,

45¼ MILES
(73 KILOMETRES)
DISTANCES ALONG THE ROUTE

Kil. Miles.
Melun to Villeneuve 27 16¾
Villeneuve to Choisy-le-Roi 5 3
Choisy-le-Roi to Versailles 27 16¾
Versailles to St. Germain-en-Laye 14 8¾

TO PARIS, DIEPPE, AND CALAIS

DISTANCES ALONG THE ROUTE

Kil. Miles.
Melun to Paris 40 25
Paris to Dieppe via Pontoise, Beauvais, and Gournay-en-Bray 186 115¾
Paris to Calais via Beauvais, Abbeville, and Montreuil 279 173½

NOTES FOR DRIVERS

Melun to Choisy-le-Roi.—Level.
Choisy-le-Roi to Versailles.—Has a few sections of paved road, but this route avoids any bad or continuous
stretches.
Versailles to St. Germain.—A steep ascent at Rocquencourt, and at the fork at the Grille Royale turn to the
right to avoid the steep descent to Marly-le-Roi.

PLACES OF INTEREST ON THE ROUTE

Melun.—An old town on the Seine, with the Church of Notre Dame on the island (eleventh century and later),
and St. Aspais on the north bank of the river, a graceful late Gothic church.
Versailles.—A considerable town; the huge royal palace is on the west side, with the gardens and park extending
beyond.
St. Germain-en-Laye.—A pleasant little town, built by François I., also having a royal palace and a forest
attached to it; the terrace on the east side of the park has a splendid view over Paris.

The interests of Melun to the passing stranger are summed up in the two churches of Notre Dame and St. Aspais.
The first is on the island formed by the Seine, and is a curious specimen of eleventh-century architecture, with
alterations and additions made in the twelfth, fifteenth, and later centuries. The Tour de César, also on the island, is
a relic of the royal castle demolished in 1740. The Church of St. Aspais, on the north side of the river, is an
irregularly shaped building of the fifteenth and sixteenth centuries, with a beautiful choir, having a fine vaulted
ambulatory.
Henry V. captured Melun in 1420, but ten years later Joan of Arc stirred up the people to regain their liberty,
and with her help the English were expelled.
 Town Plan No. 31.—Melun.

No. 25. MELUN TO ST. GERMAIN-EN-LAYE, AVOIDING PARIS

Three straight roads lead away from Melun towards Paris, and it is necessary to be careful to take the central
one, going through L ieusaint . This road goes as straight as an arrow to Mon t gér on and Vi ll eneuv e- S t .-
Georges , suburbs of Paris. By using the accompanying map, one will easily find the turning to Choisy-le-Roi,
which crosses the railway to the left of the busy street of Villeneuve.
C hoisy- le- Roi is a manufacturing suburb of Paris. The palace, in which Louis XV. spent his time in
profligacy and debauchery, and where Louis XVI. and Marie-Antoinette often stayed, was destroyed in 1797,
during the Revolution.
Beyond Choisy-le-Roi the road curves and twists frequently, and there are about 4 kilometres of pavée. Near
Chatenay one reaches some straight sections of road, bringing one rapidly to
VERSAILLES
 The town is a large and pleasant outer suburb of Paris, with
wide streets and large open spaces. Louis XV. laid the first stone of
the cathedral in 1743.
The palace of Versailles is the largest royal residence in the
world. It almost tires one to look at the enormous frontage with its
great wings, and the waste of gravel, extending over several acres
outside the gates and railings, gives a dreary appearance to the
town side of the palace. It takes a whole day to go over the
buildings and the park, and on a tour such as this it may be wiser to
leave the historic palace for some other occasion. There is,
unfortunately, no opportunity of including any adequate
description of the buildings and their story here, but the literature
obtainable in handy form on the spot is amply sufficient for all.
It was Louis XIV. who made Versailles the Court residence
instead of St. Germain, and his successors, Louis XV. and Louis
XVI., continued to spend vast sums on the palace, until it became
the wilderness of great apartments through which the tourist is
conducted at the present day. The two small residences in the park
—the Grand Trianon and Petit Trianon—were built for Marie de
Maintenon and Madame du Barry, and were appreciated as retreats
from the immensities of the palace.
ST. GERMAIN-EN-LAYE
MELUN TO ST. GERMAIN-EN-LAYE. is a delightfully situated town commanding beautiful views across
a great loop of the Seine towards Paris. The famous terrace by the
side of the park and above the river has a wonderful prospect towards the east, wherein the capital appears on a
bright, sunny day as one of the most beautiful cities in the world.
The château, built of red brick and stone, belongs to the thirteenth, fourteenth, and sixteenth centuries, and has
only just been subjected to an excess of restoration, leaving the exterior with the freshness of a new building. The
earliest portion of the château is the chapel, a beautiful example of the style prevalent in the reign of St. Louis
(IX.). This was spared when, in 1539, François I. ordered the famous Pierre Chambiges to rebuild the medieval
castle. Henri II. continued the work, but the form of the letter D in the plan probably has no connection with his
beloved Diana de Poitiers, as the plans were prepared several years earlier.
 SECTION XXVI

ST. GERMAIN-EN-LAYE TO GISORS,

37½ MILES
(60 KILOMETRES)
DISTANCES ALONG THE ROUTE

Kil. Miles.
St. Germain to Conflans-Ste. Honorine 11 7
Conflans to Pontoise 8 5
Pontoise to Marines 14 8¾
Marines to Chaumont-en-Vexin 18 11¼
Chaumont-en-Vexin to Trie-Château 5 3
Trie-Château to Gisors 4 2½

NOTES FOR DRIVERS

Pontoise to Bouconvilliers.—On this section of the road there are several stretches of paving, and at the cross-
roads just beyond Lierville (a village just off the road on the left) it is best to go to the right through
Chaumont-en-Vexin, to avoid the paved road that goes direct to Gisors.
Gisors.—On entering there is a bad caniveau.

PLACES OF INTEREST ON THE ROUTE

This portion of the route goes through part of Vexin, a county of ancient France.
Conflans-Ste. Honorine.—A village by the Seine; ruins of two castles; church of twelfth and fifteenth centuries.
Pontoise.—Historic town on the Oise, formerly capital of Vexin; portions of town walls and slight remains of
castle; Hôtel Dieu, rebuilt 1823-1827; two churches—(1) St. Maclou, partly twelfth, but mainly fifteenth and
sixteenth centuries; (2) Notre Dame, Classic, with tomb of St. Gautier, 1146.
Cormeilles-en-Vexin.—Village with picturesque church, twelfth century and later.
Marines.—Small village, with a seventeenth-century château.
Chars.—Village on the Voisne; has church of twelfth and fourteenth centuries.
Chaumont-en-Vexin.—Very picturesquely situated little town; a few old houses, and church of Flamboyant and
Classic periods; remains of eleventh-century castle.
Trie-Château.—Small town; has (1) gateway, tower, and other remains of a fifteenth-century castle; (2)
interesting Hôtel de Ville of twelfth century; (3) church with richly ornamented Romanesque façade.

The Forest of St. Germain-en-Laye, through which the route goes towards Pontoise, occupies practically the whole
of the area enclosed by the third loop of the Seine below Paris, and was formerly part of the immense forest of
Laye, one of those which surrounded Paris in the Middle Ages, and formed a great attraction to the French
monarchs on account of the excellent hunting they provided.
From the long avenue there are interesting views of Paris, with the Eiffel Tower conspicuous, and on fine
sunny days it has the fantastic aspect of a city of palaces and temples.
On emerging from the forest of very indifferent trees, the road crosses the Seine, and one turns to the right at
once for Conf lans- S te. H on or in e , where the ruins of its two castles, with an old tower conspicuous, look out
over the soft green of the willows bordering the river. The late Gothic church, with a tower of the twelfth century,
contains a picture attributed to Zurbaran, a Spanish artist of the seventeenth century who was Court painter to both
Philip III. and Philip IV. The association of Conflans with St. Honorine has been mentioned in connection with
Graville (Section I.).
 About eight kilometres north of Conflans the River Oise is crossed at
PONTOISE,
an historic town picturesquely situated on high ground above the river.
It became the capital of the ancient province of Vexi n when Philippe I. of France united one-half of Vexin to
the Crown, and the castle became a royal residence. The boundaries of the province were, roughly, the Oise, the
Seine, and the Andelle, and dividing it into two portions, known as Vexin Français and Vexin Normand, was the
little River Epte. In the tenth century the Epte was decided upon as the boundary of the Duchy of Normandy, and it
remained so until Philippe Auguste (II.) added the Norman half of Vexin to France. It is an interesting fact that the
French half of Vexin, through having been a possession of the Abbey of St. Denis, gave the viscounts of the
province the right of carrying in battle the celebrated b ann er of the or if l am m e : thus, when Philippe I.
acquired the territory he obtained the privilege, and the oriflamme of St. Denis was transferred to the royal
standard.
There was a bridge at Pontoise in Roman times, for it was then called Pons Iscaræ, and before the present
steel structure made its appearance in recent years there was a stone bridge of five arches.
It is unfortunate that the remains of the Ch âteau are inconsiderable, for its history as a royal residence in
early times is interesting, St. Louis (IX.) having spent much of his youth in its massive walls at the time when his
mother, Blanche of Castile, was endeavouring to keep him from his wife, Marguerite de Provence. It was also at
Pontoise that St. Louis, when ill, vowed that he would lead a Crusade if he recovered. It was the fifth expedition to
the Holy Land which he eventually headed. The town was often besieged in the fourteenth, fifteenth, and sixteenth
centuries, and under Louis XIV. and Louis XV. the Parliament was held there in 1652, 1720, and 1753.
The ramparts still exist in part, but there has apparently been a great deal of reckless destruction in the town,
for it has been robbed of many of its old buildings.
The Hôtel Dieu, built by St. Louis down by the river, was rebuilt in 1823-1827, and its only interest now is the
picture, ‘The Healing of the Paralytic,’ by Philippe de Champaigne, who was one of the artists who helped to
decorate the Luxembourg in Paris for Marie de Medici, the wife of Henri IV.
Bossuet, the most famous man in the Church of France in the seventeenth century, was consecrated Bishop of
Meaux in 1681 in the church of the Cordeliers, which had a splendid refectory. This church, with others, and
several convents has disappeared.
S t. Maclou , the more important of the two which remain, is in part a twelfth-century building, although
mainly of the fifteenth and sixteenth centuries. The west front has a fine Flamboyant porch. Pierre Lemercier, who
was grandfather of Jacques Lemercier, who built the Sorbonne, the Sorbonne church, and the Palais Royale (1585-
1660), was the architect of the Renaissance portions of the church.
 No. 26. ST. GERMAIN-EN-LAYE TO GISORS.

Notr e Dam e, the other church, is chiefly in the Classic style of the latter half of the sixteenth century. It
contains a fine altar-tomb of 1146, bearing the recumbent effigy of St. Gautier, Abbé of Meulan, with four angels
swinging censers. There is also an ancient Madonna which attracts pilgrims to the church.
* * * * * *
Leaving Pontoise by the road to Gisors, one passes through several picturesque villages. The first is
Cor m eilles- en- Vex in , whose church (partly twelfth century), with big flying buttresses and gargoyles, stands
out prominently over the green and wooded country as the village is approached.
There are two or three stretches of paving-stones on this road, necessitating a slow pace to avoid dislocating
every part of the car and its occupants, and there is thus plenty of time to enjoy the rural charm of the red-roofed
villages, the big picturesque farms, and the extensive woods.
Mar ines is a small village with a seventeenth-century château containing a notable staircase. It belonged to
Chancellor Sillory, who was Chancellor of France under Henri IV. In the church is the sixteenth-century chapel of
St. Roch, standing over an octagonal crypt.
Three short stretches of pavé follow after leaving Marines, then the road drops down through a cutting in
yellow sandstone to C har s (on the River Voisne), where there is a church of the twelfth and fourteenth centuries.
The earlier work is worth studying, and there is also an interesting tomb to Jeanne de Ferrières, of the fourteenth
century.
Passing over a level-crossing, the village of Bo uco nv i lli er s lies on the left. It has a large farm of the Sussex
Downs type, sheltered by big trees, a church with a Romanesque tower, and a castle of the time of Louis XIII.
(seventeenth century) on the site of a much earlier one, of which the entrenchments remain.
Just beyond the hamlet of L ier vi ll e (on the left) five roads meet. The direct way to Gisors is straight ahead,
but a notice warns one of bad paving-stones, and recommends going to the right through C haum o nt - en - Vexi n.
By doing so the distance is only slightly increased, and the pavé is entirely avoided.
The road winds down steeply into the leafy hollow in which the little town of Chaumont-en-Vexin stands. Its
church, with a curious Classic tower of stumpy proportions, contains rich Flamboyant work, and is conspicuous on
the shoulder of a hill above the houses.
There are remains of the eleventh-century castle where some of the French kings resided when the Norman
frontiers were defended by a chain of castles. In the chief street there is a picturesque sixteenth-century house of
timber-framing.
 The Pierre-Trouée (or des Druids) is a very fine do lm en , composed of four stones, situated about two
kilometres south-east of Trie-Château. An artificial circular hole has been cut through the base of the side stone,
and Fergusson infers from this that the dolmen was probably never intended to be covered up with earth, or at the
most only partially. The age of dolmens of this type is a matter of the greatest uncertainty. Although in a general
way regarded as prehistoric burial-places, some of them may belong to post-Roman times.
TRIE-CHÂTEAU
is an interesting place. Its Hôtel de Ville is the Maison de Justice of the twelfth century, and it still has its round-
headed windows with small pillars. The Romanesque façade of the church is richly ornamented, and the rest of the
building belongs to the twelfth, thirteenth, and sixteenth centuries.
A fortified gateway (fifteenth century) of the château is passed through on the way to Gisors, and by it is a big
round tower of the same period, although much restored. There can also be seen vaulted underground portions of
this formerly important castle.
Charles François Dupuis, who wrote ‘Origins de tous les Cultes’—a book which did much to precipitate the
irreligious crisis of the Revolution—was born at Trie-Château in 1742.
On entering Gisor s there is a bad caniveau.
 SECTION XXVII

GISORS TO ROUEN, 41 MILES

(66 KILOMETRES)
DISTANCES ALONG THE ROUTE

Kil. Miles.
Gisors to Les Thilliers-en-Vexin 13 8
Les Thilliers to Les Andelys 15 9¼
Les Andelys to Heuqueville 12 7½
Heuqueville to St. Nicholas-de-Pont-St. Pierre 8 5
St. Nicholas-de-Pont-St. Pierre to Boos 9 5½
Boos to Rouen 9 5½

NOTES FOR DRIVERS

Dangu.—There is a steep ascent on the way to Les Thilliers, after which the road is level, until the long and easy
descent of the Gambon Valley to Les Andelys.
Le Petit Andely.—Has a caniveau on entering from Le Grand Andely.
La Vacherie.—Steep, winding ascent from the Seine.
Before reaching Heuqueville.—There is a very steep descent through a wood, which should be taken carefully.
Amfreville-les-Champs.—After leaving, there is a long descent to the Andelle at St. Nicholas-de-Pont-St.
Pierre (caution), and after that village there is a long winding ascent.
Approaching Rouen.—There is a steep descent from Blosseville-Bonsecours.

PLACES OF INTEREST ON THE ROUTE

Gisors.—Exceedingly interesting and picturesque town on the old Norman frontier; Norman castle, built by
William Rufus, Henry I. and II., and Philippe Auguste; streets full of timber-framed houses; beautiful church,
thirteenth, fourteenth, and fifteenth centuries, with Classic west end; Hôtel de Ville, seventeenth century,
formerly a convent.
Dangu.—Interesting château, chiefly of the time of Louis XIII.
Les Thilliers-en-Vexin.—Small hamlet; Château de Bois d’Enemets, sixteenth century, attributed to Mansard.
Harquency.—Hamlet, with small Norman church.
Le Grand Andely.—Small town, with a remarkably fine church, thirteenth to fifteenth centuries, with good
sixteenth-century glass; fountain of Ste. Clotilde; remarkable inn, Le Grand Cerf, built in 1515, rich carving.
Le Petit Andely.—A little town, under the shadow of Château Gaillard; old houses and very interesting
thirteenth-century church.
Château Gaillard.—Imposing ruins of the great fortress, built by Richard Cœur-de-Lion in 1197; fine scenery
and rare wild-flowers.
St. Nicholas-de-Pont-St. Pierre.—Village in the pretty valley of the Andelle, with a fine fifteenth century
château.
Boos.—Small town; ruins of thirteenth-century manor-house, with remarkable pigeon house of sixteenth century.
Blosseville-Bonsecours.—Great panoramic view of Rouen.

Gisor s is an exceedingly picturesque old town possessing a fine castle and a very beautiful church. Standing on
the little River Epte, it was on the frontier of Normandy, and its importance in medieval times was due to this fact.
It was William Rufus who realized the strategic value of the place, and, having obtained possession of it, Robert de
Bellesme in 1097 built him a castle, the keep of which, raised upon an artificial mound, is standing to-day. The
first two Henrys of England strengthened the castle with towers, and in 1196, when Gisors was ceded to Philippe
Auguste at the Treaty of Louviers, still further building was carried out, including a subsidiary keep on the outer
line of defence, now called the Tour du Prisonnier. A considerable portion of the eleventh-century walls of Rufus’s
castle are still standing.
It is worth while to climb the fifteenth-century staircase turret in the Norman keep, and from it see the outer
walls of the castle down below, with the town built close up to it on three sides, and out across the green fields,
about four kilometres to the west, appears the ruined tower of the castle of Neaufles. A subterranean passage, so it
is said, connected the castle of Gisors with N eau f les . During a siege in the thirteenth century a sortie was made
by Queen Blanche of Castile, the mother of St. Louis (IX.), with only a small party, and being cut off from Gisors,
they made for the fortress of Neaufles, which was a ruin even at that time. Night was approaching, so the best plan
was to surround the ruin and make the Queen a prisoner in the morning. But when daylight came there was no sign
of life within the old walls, for the Queen and her men had taken advantage of the secret passage, and had not only
reached Gisors in safety, but had prepared a stronger force, which sallied forth and scattered their amazed enemies.
The salient fact concerning Gisors, which it is not easy to keep in mind, is that this quaint old town was a
feudal stronghold of the English, and that the Epte formed the frontier of English land. It was therefore the scene
of many alarms and excursions and much hard fighting. When it became a French possession through the treaty
already mentioned, Richard Cœur-de-Lion built Château Gaillard, a few miles away, on the Seine, although he had
undertaken not to fortify that spot, for without some such defence Rouen lay at the mercy of the French.
The little chapel in the keep at Gisors was dedicated to St. Thomas of Canterbury; only the foundations remain
to-day, but these, if carefully cleared of grass, weeds, and rubble, would be an interesting addition to the ruin.
In the dungeon of the Tour du Prisonnier there are many curious carvings and scratchings on the stone walls.
The chief of these are attributed to Nicholas Poulain, who, in the fifteenth century, was kept in this hopeless prison
for four years by Louis XI.
The streets of Gisors are full of charm, for, although stucco has been applied far too liberally to quaint
over hanging houses of the sixteenth century, or earlier, their individuality has, in many instances, survived the
treatment, and carved brackets and moulded beams are frequently to be seen. The greenish, and yet transparent,
waters of the Epte flow through the town in the form of a canal, and the covered washing-places for the women are
of exceptional picturesqueness.
T he Hôtel de Ville , dating from the seventeenth century, was formerly a convent of the Carmelites.
T he Chur ch , dedicated to the saints Gervais and Protais, is a building of wonderful charm, and peeps of its
Flamboyant carving, seen through narrow passages between antique timber-framed houses, are some of the
delights of the town. The earliest portion of the building is the choir, with its aisles, built in the thirteenth century
through the generosity of Queen Blanche, who was Regent for her son during his minority, and while he was away
crusading in the Holy Land (see under Pontoise). The nave, chapels, and towers date from the fourteenth to
sixteenth centuries, the wonderfully enriched north portal is Flamboyant, and the west end, with its two unfinished
towers, belongs to the Renaissance period, as at Evreux (Section III.). The towers were stopped at their present
height, for fear that they might be used against the castle if the town were occupied by an enemy.
Jacob’s vision of the angels is shown in a very fine carving over the central west door. The architects of the
church in the sixteenth century were chiefly members of the family of Grappin, and it was Robert Grappin who, in
1530, built the nave in such a hurry that it collapsed, but within a decade it had been rebuilt.
Of the interior there is only space to mention the exceedingly interesting carved pillars; the huge Tree of Jesse
in the baptistery; the chapel, containing a skeleton in stone; twenty-eight sixteenth-century painted panels, showing
legends of the lives of the patron saints of the Church; the beautiful vaulted aisles of the choir; and, finally, the
sixteenth-century glass of the windows.
 No. 27. GISORS TO ROUEN.

The conferences between the English and French kings were held under an elm that grew upon the boundary,
and under its shade, in 1188, Henry II. of England and Philippe Auguste held a peace conference, at which the
aged Archbishop of Tyre appeared, and implored the monarchs to lead armies to aid in driving the infidels from the
Holy City. It was agreed that both should lead a crusade in two years’ time; but in the following year, having fallen
out, they were at war again, and Philippe soon afterwards cut down the tree.
Going out of Gisors by the street that leads approximately southwards, a tributary of the Epte is crossed by a
bridge bearing a gilded statue to Our Lady, and just afterwards a level-crossing, where one turns to the right by the
railway, soon afterwards passing (on the right) a very interesting example of the fortified farm, having a squat
round tower at each corner. Further off, beyond the river, appears the ruined tower of the cast le of Neauf l es .
After crossing the Epte the road climbs up through the village of Dang u , whose château on the left among
the woods above the river was at one time of the greatest importance. The Norman structure has been demolished,
and the existing castle dates back no further than the fifteenth century, some of it only to 1567, and part is modern,
but a large portion is older than the time of Louis XIII.—a contemporary of Charles I.—when it was owned by the
Comte de Bouteville, of whom Mr. Dearmer tells the following story in his admirable work on Normandy:

‘This gentleman has a place in history for his defiance of the celebrated edict against duelling; he and the Comte
de Chapelles fought two other lords in broad daylight in the Place Royale at Paris. One of their opponents
was killed, and Richelieu determined to prove that no lord was above the law. In spite of the efforts of the
greatest families in France, Bouteville and Chapelles were executed in 1627. Eight years afterwards Louis
XIII. arranged to visit Dangu in the company of the Cardinal, but when the widowed Madame de Bouteville
heard of the intended honour, she sent this message: “The King will be received at Dangu with the honours
due to the majesty of a King of France; but as for the Cardinal, I shall place under the drawbridge twelve
barrels of powder, to which a light will be applied as he passes, in order to send him to heaven, where he
ought to have been long ago.” The King came alone. But Richelieu had his revenge, and in five years Dangu
passed into the hands of a recently ennobled favourite of the great Cardinal.’

On the left-hand side, on entering the village of L es T h ill ier s- en- Vex i n , where the route nationale to
Rouen is reached, a little distance from the road, is the Château de Bois d’Enemets, built in the time of Louis XIII.,
and attributed to Mansard.
After a short run on the straight and perfectly level main road, a turning to the left is taken, which drops at a
gentle gradient down the side of the Gambon Valley—reminiscent of the chalky valleys of Kent—through the
hamlet of Harquency, with its midget Norman church, to
LE GRAND ANDELY
Although possessing an almost cathedral-like church, the major attraction of Le Grand Andely must be its
early sixteenth-century inn—the Hôtel du Grand Cerf. It was built in 1515 by Nicholas Duval, Seigneur du
Viennois, a favourite of François I., and in the carving on the oak beams of the house one frequently comes across
the salamander and the fleur-de-lys of that monarch. The frontage on the street and the charming little courtyard
are made beautiful with the dark brown timber, in many places richly carved, which has never been hidden by
plaster.
 Going through a beautifully decorated door from a corner of the courtyard, one enters the old hall of the house
through a tambour, or lobby, of richly carved and panelled oak. The chief feature is the great fireplace, which
almost makes folk who sit at the little tables appear as figures in a romantic picture. It was only in 1749 that the
house was sold to the M. Lefèvre who turned it into an inn. Sir Walter Scott, Rosa Bonheur, Viollet-le-Duc,
Chateaubriand, and Victor Hugo, all stayed at Le Grand Cerf, but the book in which these famous guests wrote
their names was stolen a few years ago.
The church dates between the thirteenth and fifteenth centuries, but belongs chiefly to the earlier period, and
has three towers and fifty-two beautiful sixteenth-century windows worthy of careful examination. It has stalls of
the Flamboyant period and three pictures by Quentin Varin, the first master of Nicholas Poussin, the most famous
of the French painters of the seventeenth century, who was born, in 1594, in a village close to Les Andelys, and to
whom a statue has been erected in the town.
On June 2 every year there is a pilgrimage to the F o ntaine de S t e. C l ot il de , which is under the shade of
lime-trees near the church. Its waters are sacred in connection with the legend that Ste. Clotilde gave them the
strength and flavour of wine for the workmen who were building a convent for her, and had complained of having
nothing but water to drink.
LE PETIT ANDELY
A short straight road leads from Le Grand to Le Petit Andely, with its church standing in the centre of a space
where one turns either to the right to go on to Rouen or to the left for Château Gaillard, whose walls, gleaming
white in the sunshine, still frown above the picturesque main street of the town. The interesting church seems to
have been built very soon after the first siege of the castle, and therefore at the beginning of the thirteenth century.
The choir is considered to be the oldest part, but the whole building is very much of the same period, and is a very
perfect example of early French architecture. Inside and out the style is a little plain, but the beauty of its
proportions is very striking. The paintings on the walls are fifteenth century, and the copper chandeliers belong to
the eighteenth.
CHÂTEAU GAILLARD
Just before the last houses of the little town are reached an opening to the left leads to the footpath which
climbs up the steep, grassy ascent to the ruins of Richard Cœur-de-Lion’s ‘saucy’ castle.
Although, since the year 1603, when Henri IV. gave permission for the castle to be destroyed, it has been used
as a quarry for dressed stone at various times in that period, the great pile still retains its chief features, and is, in
many ways, one of the most notable castles in the world. Richard coolly determined to fortify the spot soon after
the Treaty of Louviers, in which it was expressly agreed that neither France nor England should either fortify or
have any feudal rights in Les Andelys! Only three months after the compact had been sworn he of the lion-heart
began the great fortress. It was to be no ordinary castle; it was to be impregnable; and M. Dieulafoy suggests that
Richard I. utilized his experience in the Crusades and built after the Syrian plan, Antioch and Tyre having been
found exceedingly hard to capture.
The oval inner bailey has the outer surface of its exceedingly lofty wall formed of nineteen semicircular
buttresses, which touch one another, and are practically a continuous series of half-towers, leaving no flat surface
anywhere. Inside this remarkable inner bailey stands the circular keep, whose walls are 27 feet thick, with an
angular projection towards the gateway of the bailey. The outer courtyard was defended with five great circular
towers. The weak point of the defence, however, was the high ground that overlooked the walls on the south-west
side, and to make this impregnable an exceptionally strong outer castle, with three large towers and two small
ones, was built, with a deep ditch separating it from the main works. All this and much more can be seen by
anyone who cares to climb up and down the steep grassy banks that fall away from the walls.
When the great pile was completed, Richard gazed on his ‘Dreadnought’ castle, with its frowning
 CHÂTEAU GAILLARD.
The ruins of Richard Cœur de Lion’s great castle built above the Seine to
defend the English frontier.

machicolations crowning the unassailable white walls, and exclaimed: ‘Comme elle est belle, ma fillette d’un an!’
Philippe Auguste, however, with justifiable indignation at the broken treaty, began hostilities, assuring Richard that
he would take his saucy castle if it were made of iron, to which came the prompt reply, ‘I will hold it were it made
of butter’; and Richard soon afterwards defeated the French army on the Plains of Gamaches. But in 1199 Richard
died, and in his successor’s feeble hands Château Gaillard was soon in peril, for, in 1203, Philippe began a siege
which lasted for five months.
The English Governor was Roger de Lacy, Constable of Chester, who was left to look after himself, when
John with his army had made one half-hearted effort to relieve him. The fort on the island opposite Le Petit Andely
was taken, and the little town soon afterwards fell into the hands of the French, the people fleeing to the castle for
safety. But the Governor had no pleasure in seeing his food-supplies consumed by non-combatants, and the hapless
creatures were soon turned out to shift for themselves. Some were at first allowed to pass through the French lines,
but many were stopped, and lay in the grassy hollows, starving between friends and foes. The French King finally
took pity on them and fed them, and allowed them to go before all were dead.
Meanwhile the siege proceeded with vigour; a wooden tower was built, and the outer castle was sapped and
an entrance gained. The outer bailey was surprised by an entry being made through an unprotected window which
may be seen to-day. Finally, the inner bailey was entered through a breach in the gateway, which the besiegers
succeeded in making with a mangonel, and they rushed in with such impetuosity that the English had no time to
reach the keep, and its enormous strength was therefore useless. There were only 180 Englishmen left when
Philippe gained possession; the Governor was given his liberty, and the garrison marched out as the French flag
was unfurled above the towers.
In 1314 Marguerite of Burgundy, wife of Louis X., was imprisoned in the castle and strangled with her own
hair by order of her husband, who wished for another consort, and later on Blanche, wife of Charles le Bel, also
accused of adultery, was kept there until removed to the Abbey of Maubisson for imprisonment for the remainder
of her life.
In 1334 David Bruce, the son of Robert the Bruce, spent the seven years of his exile in France in Château
Gaillard, while Edward Balliol had made himself King in Scotland.
Charles the Bad, King of Navarre, was another famous prisoner, in 1355. He was sent to the castle by King
Jean of France for having had designs on the throne, and escaped when the King was captured by the English at
Poitiers, in 1356.
The vivid story of the castle told in full, with a detailed account of its defences, would keep one at Château
Gaillard much longer, and it is with the keenest regret that one leaves the steep hill, with its strange ruins standing
out in front of the widespread view over a great horseshoe bend of the Seine.
The road by the river is followed for two kilometres, with the white, castle-like chalk cliffs on the right, to a
few houses called L a Vacher i e , where one goes to the right and zigzags up the steep ascent that leads to the
villages of Heuquevill e and Am f r ev i lle les Ch am p s .
From Amfreville the road winds steeply down to the charming valley of the Andelle, and crosses the river at
the village of S t. Nicho las- d e- P on t- S t . P ier r e , where there is a fine fifteenth-century château, approached
by an avenue of evergreen trees. There is an imposing façade flanked by two towers, and close by are the ruins of
an older castle.
After a steep, winding ascent through the forest of Longboël the plateau of Caux is reached, the River Andelle
dividing it from that of Vexin.
At Boos the route nationale is joined, and one may stop to see the remarkable ruins of a thirteenth-century
manor-house of the Abbesses of St. Armand de Rouen. The beautiful octagonal pigeon-house of the sixteenth
century is decorated with inlaid tiles.
Just before descending the steep hill down to Rouen, from whence there is a remarkable panorama of the city,
the village of Bl ossevi lle Bon secou r s is passed through. An important Benedictine abbey was founded there
in 1030. It was fortified in the fourteenth century, but in 1597, after the wars of the League, it was destroyed at the
demand of the people of Rouen, who had always been apprehensive that the cannons would be turned upon them.
* * * * * *
The routes from Rouen to Havre, Dieppe, Boulogne and Calais, are described in Section I.
 SECTION XXVIII

GISORS TO DIEPPE VIA BEAUVAIS,

86¼ MILES
(138½ KILOMETRES)
DISTANCES ALONG THE ROUTE

Kil. Miles.
Gisors to Trie-Château 4 2½
Trie-Château to La Houssoye 12 7½
La Houssoye to St. Martin-le-Nœud 11½ 7¼
St. Martin-le-Nœud to Beauvais 6 3¾
Beauvais to Le Pont-qui-Penche 11 7
Le Pont-qui-Penche to Gournay-en-Bray 20 12¼
Gournay-en-Bray to Le Pont-Rouge 10 6¼
Le Pont-Rouge to Forges-les-Eaux 11 7
Forges-les-Eaux to Les Hayons 18 11¼
Les Hayons to Les Grandes-Ventes 16 10
Les Grandes-Ventes to Dieppe 19 11¾

NOTES FOR DRIVERS

Gisors to Beauvais.—Level as far as the steep, winding descent near Auneuil.

Beauvais to Dieppe.—The two hills of any consequence are at (1) Torcy; (2) Valley of the Varenne.

PLACES OF INTEREST ON THE ROUTE

[This is an alternative route to that described through Rouen, and the information is therefore restricted to the
smallest space.]

La Houssoye.—Church partly fourteenth century, with stalls and sculptured wainscot of sixteenth century.
Beauvais.—A considerable town, famous for its carpets and tapestries. Cathedral consists of choir and transepts
only; commenced in 1227, after a great fire. Had the nave been completed, it would have been the most
stupendous Gothic building in the world. Palais de Justice, fourteenth and fifteenth centuries, formerly an
episcopal palace. Church of St. Étienne, twelfth century; nave dates from 1545.
Gournay-en-Bray.—Great butter-making town; Church of St. Hildebert, eleventh to thirteenth century, with
massive walls and Romanesque pillars and arches.
Forges-les-Eaux.—Has mineral springs, containing carbonate of iron, manganese, etc.; the Établissement, where
the waters are taken, stands in a beautiful park; casino, hotels, and concert-rooms.
Pommeréval.—Village, with ruined château; sixteenth-century church, altar-screen with bas-reliefs.
Les Grandes-Ventes.—Village, with Classic church, dating from 1545.
Torcy-le-Grand.—Church of sixteenth century; ruins of fourteenth-century castle on island in the Varenne;
Fontaine de St. Ribert pilgrimage.
Arques-la-Bataille.—Famous for its castle, which the English held as late as 1449; the great keep was built by
William of Arques in the eleventh century. The Battle of Arques was fought in 1589 between Henri IV., with
about 5,000 men, and Mayenne, with an army of 30,000 defenders of the League. Owing to the marshy
ground, the guns of the castle, and his own personal courage, Henri won a great victory.
No. 28. GISORS TO DIEPPE.
 HINTS ON TOURING IN FRANCE
BY JOHN L. KIRK, B.A.
I. THE QUESTION OF EXPENSE
The main route described in this book was taken from Havre to Mentone by the author and four other persons,
one of whom drove and acted as mechanic. From Mentone to Havre four only were carried.
A rough summary of the expenses is given below:

£ s. d.
Hotel and incidental expenses,
including sight-seeing and tips Fr. 1782.80
Motor expenses Fr. 446.15
Total Fr. 2228.95 = 48 10 0

Add to this the amounts shown in the motor

‘In Addition’ list 13 13 0
Grand total for all, except wear and tear
of tyres and machinery, for the twenty-eight
days taken to cover the route 62 3 0

Details of the Above

Expenses connected with the 15-20 H.-P. Car, running 2,347 Miles in 28 Days

Petrol (590 litres) Fr. 259.35

Oil (44 litres) 53.40
Harbour dues at Havre (landing and embarking) 15.00
Number-plates for French numbers 5.00
Spanish customs and formalities 23.80
French formalities 16.20
Repair to luggage-carrier 4.50
Tyres (carriage of spare tyres and repairs) 22.80
Garage, cleaning, etc. 43.10
Italian stamp duty 3.00
Total Fr. 446.15

In Addition

Sea transit— £ s. d.
Southampton to Havre 3 00
Havre to Southampton 3 00
Insurance for one month 415 0
French driving licence (Fr. 20)[[L] 016 0
Subscription to Touring Club de France, including two guide-books 0 80
Name-plates 0 40
Maps and road-books 110 0
Wear and tear and depreciation in tyres, etc. x y z
£1313 0
+x y z
Fr. 446.15 = 17 17 0
£3110 0
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