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GENOMES 4
GENOMES 4
T. A. BROWN
Garland Science About the Author
Vice President: Denise Schanck I became fascinated with the natural world when I was very
Senior Editor: Elizabeth Owen young. I began my research career studying the effects of metal
Assistant Editor: David Borrowdale pollution on microorganisms and the tolerance that some plants
Senior Production Editor: Georgina Lucas display to high concentrations of toxic metals. I then became
Production Editor: Deepa Divakaran excited by DNA and worked on mitochondrial genes in fungi
Illustrator: Matthew McClements, Blink Studio Ltd in order to learn the new (in those days) techniques for gene
Layout: Georgina Lucas cloning and DNA sequencing. I contributed to the discovery of
Cover Designer: Matthew McClements, Blink Studio Ltd mitochondrial introns and to work that described the base-paired
Copyeditor: Heather Whirlow Cammarn structure of these introns. I then became interested in ancient
Proofreader: Jo Clayton DNA and was one of the first people to carry out DNA extractions
Indexer: Bill Johncocks with bones and preserved plant remains. This work has required
close collaboration with archaeologists, and has led to my current
The cover image shows a circo plot showing the similarities interests in paleogenomics, the origins of agriculture, and the
between the genomes of four species: human, chimpanzee, evolution of domesticated plants.
mouse, and zebrafish. Courtesy of Martin Krzywinski, BC Cancer
I obtained my PhD from University College London in 1977 and
Research Centre.
then worked in New York, Oxford, Colchester, and Manchester
before beginning in 1984 as a Lecturer in Biotechnology at the
© 2018 by Garland Science, Taylor & Francis Group, LLC
University of Manchester Institute of Science and Technology
This book contains information obtained from authentic and (UMIST). I was appointed Professor of Biomolecular Archaeology
highly regarded sources. Every effort has been made to trace in 2000 and was Head of Biomolecular Sciences at UMIST from
copyright holders and to obtain their permission for the use of 2002–2004. I was then Associate Dean in the Faculty of Life
copyright material. Reprinted material is quoted with permission, Sciences of the University of Manchester until 2006, before taking
and sources are indicated. A wide variety of references are a break from administration in order to have more time to do
listed. Reasonable efforts have been made to publish reliable research.
data and information, but the author and the publisher cannot My other undergraduate textbooks include Introduction to
assume responsibility for the validity of all materials or for the Genetics, A Molecular Approach (Garland Science).
consequences of their use.
All rights reserved. No part of this publication may be reproduced,

stored in a retrieval system or transmitted in any form or by
any means—graphic, electronic, or mechanical, including
photocopying, recording, taping, or information storage and
retrieval systems—without permission of the copyright holder.
The publisher makes no representation, express or implied, that

the drug doses in this book are correct. Readers must check
up-to-date product information and clinical procedures with
the manufacturers, current codes of conduct, and current safety
regulations.
ISBN 9780815345084
Library of Congress Cataloging-in-Publication Data

Names: Brown, T. A. (Terence A.), author.
Title: Genomes 4 / Terry Brown.
Other titles: Genomes | Genomes four
Description: 4th. | New York, NY : Garland Science, [2017] | Preceded by:
Genomes 3 / T. A. Brown. 3rd ed. New York : Garland Science, c2007. |
Includes bibliographical references and index.
Identifiers: LCCN 2017013507 | ISBN 9780815345084 (alk. paper)
Subjects: | MESH: Genome
Classification: LCC QH447 | NLM QU 470 | DDC 572.8/6--dc23
LC record available at https://lccn.loc.gov/2017013507
Published by Garland Science, Taylor & Francis Group, LLC, an informa business,
711 Third Avenue, New York, NY 10017, USA, and 2 Park Square, Milton Park, Abingdon, OX14 4RN, UK.
Printed in the United States of America
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
Visit our web site at http://www.garlandscience.com

PREFACE
There have been remarkable advances in our knowledge of genomes since

the previous edition of this book was published ten years ago. Back in 2007,
next-generation sequencing was in its infancy and high-throughput meth-
ods for transcriptomics and proteomics were only beginning to be exploited.
The application of these methods over the last ten years has resulted in an
exponential increase in the number of species for which genome sequences
and annotations are now available, and has enabled multiple versions of the
genome of a single species to be examined. The profusion of new sequences
has had a particularly dramatic impact on bacterial genomics, with introduc-
tion of the pan-genome concept and the discovery of extensive lateral transfer
of genes between species. Our knowledge of eukaryotic genomes has under-
gone equally dramatic change, with the discovery of new types of noncoding
RNA, including the vast numbers of long RNAs that are transcribed from the
supposedly intergenic regions of many genomes.
Genomes 4 retains the overall structure of the previous editions, with the book
divided in four parts, on genome sequencing and annotation, genome
anatomies, genome expression, and genome replication and evolution. With
some small changes, the order of chapters remains unchanged. However,
the text throughout has been completely updated and, in many chapters,
substantially revised. In particular, the development of transcriptomics
and proteomics has reached the point where in Genomes 4 it is possible to
describe the processes of transcription and translation from a genomewide
perspective, rather than simply through an examination of the expression of
individual genes. This was my aim when I wrote the first edition of Genomes
way back in 1999, but the information available at that time meant that these
core chapters were fairly orthodox treatments of gene rather than genome
expression. We are still some way from being able to describe the entire
expression of a genome as a single integrated process, but we are getting there
and I hope that in Genomes 4 I have been able to convey to the reader at least
some aspects of the joined-up nature of genome expression.
Genomes 4 has been a long time in the making and I would like to thank Liz
Owen of Garland Science for her continued enthusiasm for the book and her
gentle reminders about approaching deadlines. I also wish to thank David
Borrowdale and Georgina Lucas at Garland for managing the production of
the book, and Matthew McClements for his splendid artwork. As with the pre-
vious editions, Genomes 4 would not have been finished without the support
of my wife, Keri. The acknowledgment in the first edition that “if you find this
book useful then you should thank Keri, not me, because she is the one who
ensured that it was written” is equally true for the fourth edition.
vi PREfAcE
A NOTE TO ThE REAdER

I have tried to make the fourth edition of Genomes as user friendly as possible.
The book therefore includes a number of devices intended to help the reader
and to make the book an effective teaching and learning aid.
Organization of the Book

Genomes 4 is divided into four parts:
Part I – Studying Genomes begins with an orientation chapter that introduces

the reader to genomes, transcriptomes, and proteomes, and then in Chapter 2
moves on to the methods, centered on PCR and cloning, that were used in the
pre-genome era to examine individual genes. The techniques that are used
for constructing genetic and physical maps, which are still important in many
genome projects, are then described in Chapter 3, followed in Chapter 4 by the
methodology for obtaining DNA sequences and assembling reads into draft
and finished genomes sequences. Two chapters are then devoted to analysis
of genome sequences: Chapter 5 on the annotation of a genome by identifica-
tion of genes and other features, and Chapter 6 on functional analysis of the
genes that are discovered.
Part II – Genome Anatomies surveys the anatomies of the various types of

genome that are found on our planet. Chapter 7 covers eukaryotic nuclear
genomes, with emphasis on the human genome, partly because of the import-
ance of the human genome in so many areas of research, but also because
our genome is the best studied of all those for which sequences are available.
Chapter 8 deals with the genomes of prokaryotes and of eukaryotic organelles,
the latter included here because of their prokaryotic origins, and Chapter 9
describes viral genomes and mobile genetic elements, these being grouped
together because some types of mobile element are related to viral genomes.
Part III – How Genomes are Expressed describes how the biological inform-
ation contained in a genome is utilized by the cell within which that genome
resides. Chapter 10 addresses the important issue of how the packaging of
DNA into chromatin affects expression of different parts of the genome, and
Chapter 11 then describes the central role that DNA-binding proteins play
in expressing those parts of the genome that are active at a particular time.
Chapter 12 moves on to the transcriptome, describing how transcriptomes
are studied, their compositions, and how a cell’s transcriptome is synthesized
and maintained. Chapter 13 gives an equivalent description of proteomics
and the proteome, and Chapter 14 concludes this part of the book by explor-
ing how the genome acts within the context of the cell and organism, respond-
ing to extracellular signals and driving the biochemical changes that underlie
differentiation and development.
Part IV – How Genomes Replicate and Evolve links DNA replication, muta-
tion, and recombination with the gradual evolution of genomes over time. In
Chapters 15–17 the molecular processes responsible for replication, mutation,
repair, and recombination are described, and in Chapter 18 the ways in which
these processes are thought to have shaped the structures and genetic con-
tents of genomes over evolutionary time are considered. Chapter 18 then ends
with a small number of case studies to illustrate how molecular phylogenom-
ics and population genomics are being used in research and biotechnology.
PREfAcE vii
LEARNiNG AidS
Each chapter has a set of Short Answer Questions and In-Depth Problems, as
well as an annotated Further Reading list. At the end of the book there is an
extensive Glossary.
Short answer questions require 50- to 500-word answers. The questions

cover the entire content of each chapter in a fairly straightforward manner,
and most can be marked simply by checking each answer against the relevant
part of the text. A student can use the short answer questions to work system-
atically through a chapter, or can select individual ones in order to evaluate
their ability to answer questions on specific topics. The short answer ques-
tions could also be used in closed-book tests.
In-depth problems require a more detailed answer. They vary in nature and
in difficulty, the simplest requiring little more than a literature survey, the
intention of these particular problems being that the student advances his or
her learning a few stages from where Genomes 4 leaves off. Other problems
require that the student evaluates a statement or a hypothesis, based on their
understanding of the material in the book, possibly supplemented by read-
ing around the subject. These problems will, hopefully, engender a certain
amount of thought and critical awareness. A few problems are difficult, in
some cases to the extent that there is no solid answer to the question posed.
These are designed to stimulate debate and speculation, which stretches the
knowledge of each student and forces them to think carefully about their
statements. The in-depth problems can be tackled by students working indi-
vidually, or alternatively can form the starting point for a group discussion.
Further Reading lists at the end of each chapter include those research
papers, reviews, and books that I look on as the most useful sources of addi-
tional material. My intention throughout Genomes 4 has been that students
should be able to use the reading lists to obtain further information when
writing extended essays or dissertations on particular topics. Research papers
are therefore included, but only if their content is likely to be understand-
able to the average reader of the book. Emphasis is also placed on accessible
reviews, one strength of these general articles being the context and relevance
that they provide to a piece of work. The reading lists are divided into sections
reflecting the organization of information in the chapter, and in some cases I
have appended a few words summarizing the particular value of each item to
help the reader decide which ones he or she wishes to seek out. In some cases,
Further Reading also includes URLs for databases and other online resources
relevant to the material covered in a chapter.
The Glossary defines every term that is highlighted in bold in the text, along
with a number of additional terms that the reader might come across when
referring to books or articles in the reading lists. The glossary therefore pro-
vides a quick and convenient means by which the reader can remind them-
selves of the technical terms relevant to the study of genomes, and also acts
as a revision aid to make sure those definitions are clearly understood during
the minutes of uncertainty that many students experience immediately before
an exam.
viii PREfAcE
iNSTRucTOR RESOuRcES
The images from the book are available through www.garlandscience.com in
two convenient formats: PowerPoint® and JPEG. They have been optimized
for display on a computer. Figures are searchable by figure number, by fig-
ure name, or by keywords used in the figure legend from the book. Help on
answering the In-Depth Problems, found at the end of each chapter, is also
available.
AcKNOWLEdGMENTS
The Author and Publisher of Genomes 4 gratefully acknowledge the contribu-
tion of the following reviewers in the development of this edition.
David Baillie, Simon Fraser University; Linda Bonen, University of Ottawa;

Hugh Cam, Boston College; Yuri Dubrova, University of Leicester; Bart Eggen,
University of Groningen; Robert Fowler, San José State University; Sidney
Fu, George Washington University; Adrian Hall, Sheffield Hallam University;
Lee Hwei Huih, Universiti Tunku Abdul Rahman; Glyn Jenkins, Aberystwyth
University; Julian M. Ketley, University of Leicester; Torsten Kristensen,
University of Aarhus; Gerhard May, University of Dundee; Mike McPherson,
University of Leeds; Isidoro Metón, Universitat de Barcelona; Gary Ogden,
St. Mary’s University; Paul Overvoorde, Macalester College; John Rafferty,
University of Sheffield; Andrew Read, University of Manchester; Joaquin
Cañizares Sales, Universitat Politècnica de València; Michael Schweizer,
Heriot-Watt University; Eric Spana, Duke University; David Studholme, Exeter
University; John Taylor, University of Newcastle; Gavin Thomas, University
of York; Matthew Upton, Plymouth University; Guido van den Ackerveken,
Utrecht University; Vassie Ware, Lehigh University; Wei Zhang, Illinois
Institute of Technology.
CONTENTS IN BRIEF
CHAPTER 1 Genomes, TranscripTomes, and proTeomes 1

CHAPTER 2 sTudyinG dna 27
CHAPTER 3 mappinG Genomes 55
CHAPTER 4 sequencinG Genomes 87
CHAPTER 5 Genome annoTaTion 119
CHAPTER 6 idenTifyinG Gene funcTions 135
CHAPTER 7 eukaryoTic nuclear Genomes 155
CHAPTER 8 Genomes of prokaryoTes and eukaryoTic orGanelles 181
CHAPTER 9 Viral Genomes and mobile GeneTic elemenTs 203
CHAPTER 10 accessinG The Genome 219
CHAPTER 11 The role of dna-bindinG proTeins in
Genome expression 241
CHAPTER 12 TranscripTomes 257
CHAPTER 13 proTeomes 293
CHAPTER 14 Genome expression in The conTexT of cell
and orGanism 329
CHAPTER 15 Genome replicaTion 357
CHAPTER 16 muTaTions and dna repair 389
CHAPTER 17 recombinaTion and TransposiTion 411
CHAPTER 18 how Genomes eVolVe 429
GLOssARY 463
INDEX 491
CONTENTS
CHAPTER 1 Ligases join DNA fragments together 37

End-modification enzymes 38
GENOmEs, TRANsCRIPTOmEs,
AND PROTEOmEs 1 2.2 the polymeRAse chAiN ReActioN 38
Carrying out a PCR 39
1.1 DNA 2 The rate of product formation can be followed
Genes are made of DNA 3 during a PCR 40
DNA is a polymer of nucleotides 4 PCR has many and diverse applications 41
The double helix is stabilized by base pairing
and base stacking 8 2.3 DNA cloNiNg 41
The double helix has structural flexibility 9 Why is gene cloning important? 41
The simplest cloning vectors are based on E. coli
1.2 RNA AND the tRANscRiptome 11 plasmids 43
RNA is a second type of polynucleotide 12 Bacteriophages can also be used as cloning
The RNA content of the cell 12 vectors 44
Many RNAs are synthesized as precursor molecules 13 Vectors for longer pieces of DNA 47
There are different definitions of the transcriptome 15 DNA can be cloned in organisms other
than E. coli 48
1.3 pRoteiNs AND the pRoteome 16
There are four hierarchical levels of protein structure 16 summARy 50
Amino acid diversity underlies protein diversity 17
shoRt ANsweR QuestioNs 51
The link between the transcriptome and the
proteome 19 iN-Depth pRoblems 51
The genetic code is not universal 20
FuRtheR ReADiNg 52
The link between the proteome and the
biochemistry of the cell 22
summARy 23 CHAPTER 3
shoRt ANsweR QuestioNs 24 mAPPING GENOmEs 55
iN-Depth pRoblems 24 3.1 why A geNome mAp is
impoRtANt 55
FuRtheR ReADiNg 25 Genome maps are needed in order to sequence
the more complex genomes 55
Genome maps are not just sequencing aids 57
CHAPTER 2
sTuDYING DNA 27 3.2 mARkeRs FoR geNetic mAppiNg 58
Genes were the first markers to be used 58
2.1 eNzymes FoR DNA mANipulAtioN 28 RFLPs and SSLPs are examples of DNA markers 59
The mode of action of a template-dependent DNA Single-nucleotide polymorphisms are the most
polymerase 28 useful type of DNA marker 61
The types of DNA polymerase used in research 30
Restriction endonucleases enable DNA molecules 3.3 the bAsis to geNetic mAppiNg 63
to be cut at defined positions 32 The principles of inheritance and the discovery
Gel electrophoresis is used to examine the results of linkage 63
of a restriction digest 34 Partial linkage is explained by the behavior of
Interesting DNA fragments can be identified by chromosomes during meiosis 65
Southern hybridization 35 From partial linkage to genetic mapping 68
cONTENTS xi
3.4 liNkAge ANAlysis with DiFFeReNt Shotgun sequencing of eukaryotic genomes

types oF oRgANisms 69 requires sophisticated assembly programs 102
Linkage analysis when planned breeding More complex genomes can be sequenced by a
experiments are possible 69 hierarchical shotgun approach 104
Gene mapping by human pedigree analysis 71 What is a genome sequence and do we always
Genetic mapping in bacteria 73 need one? 107
The limitations of linkage analysis 74
4.4 A suRvey oF eukARyotic geNome
3.5 physicAl mAppiNg by DiRect seQueNciNg pRojects 109
exAmiNAtioN oF DNA molecules 75 The Human Genome Project: genome sequencing
Conventional restriction mapping is applicable in the heroic age 109
only to small DNA molecules 75 The Neanderthal genome: assembly of an extinct
Optical mapping can locate restriction sites in genome by use of the human sequence as a
longer DNA molecules 77 reference 110
Optical mapping can be used to map other The giant panda genome: shotgun sequencing
features in a DNA molecule 79 based entirely on next-generation data 111
The barley genome: the concept of gene space 113
3.6 physicAl mAppiNg by AssigNiNg
mARkeRs to DNA FRAgmeNts 81 summARy 115
Any unique sequence can be used as an STS 81 shoRt ANsweR QuestioNs 115
DNA fragments for STS mapping can be obtained as
radiation hybrids 82 iN-Depth pRoblems 116
A clone library can be used as the mapping reagent 83 FuRtheR ReADiNg 117
summARy 84
shoRt ANsweR QuestioNs 85 CHAPTER 5
iN-Depth pRoblems 85 GENOmE ANNOTATION 119
FuRtheR ReADiNg 86 5.1 geNome ANNotAtioN by computeR
ANAlysis oF the DNA seQueNce 119
The coding regions of genes are open reading
CHAPTER 4 frames 119
sEquENCING GENOmEs 87 Simple ORF scans are less effective with genomes
of higher eukaryotes 120
4.1 chAiN-teRmiNAtioN seQueNciNg 87 Locating genes for noncoding RNA 122
Chain-termination sequencing in outline 87 Homology searches and comparative genomics
Not all DNA polymerases can be used for give an extra dimension to gene prediction 123
sequencing 89
Chain-termination sequencing with Taq polymerase 90 5.2 geNome ANNotAtioN by ANAlysis
Strengths and limitations of chain-termination oF geNe tRANscRipts 124
sequencing 91 Hybridization tests can determine if a fragment
contains transcribed sequences 125
4.2 Next-geNeRAtioN seQueNciNg 92 Methods are available for precise mapping of the
Preparation of a sequencing library is the common ends of transcripts 126
feature of next-generation methods 93 Exon–intron boundaries can also be located with
Various next-generation sequencing methods have precision 126
been devised 95
Third- and fourth-generation methods enable 5.3 ANNotAtioN by geNomewiDe RNA
sequencing in real time 97 mAppiNg 127
Tiling arrays enable transcripts to be mapped onto
4.3 how to seQueNce A geNome 98 chromosomes or entire genomes 128
The potential of the shotgun method was proven Transcript sequences can be directly mapped
by the Haemophilus influenzae sequence 99 onto a genome 129
Many prokaryotic genomes have been sequenced
by the shotgun method 100 5.4 geNome bRowseRs 131
xii cONTENTS
summARy 132 CHAPTER 7

shoRt ANsweR QuestioNs 132 EukARYOTIC NuCLEAR
iN-Depth pRoblems 133 GENOmEs 155
FuRtheR ReADiNg 133 7.1 NucleAR geNomes ARe coNtAiNeD
iN chRomosomes 155
Chromosomes are much shorter than the DNA
CHAPTER 6 molecules they contain 155
IDENTIfYING GENE fuNCTIONs 135 Special features of metaphase chromosomes 157
DNA–protein interactions in centromeres
6.1 computeR ANAlysis oF geNe and telomeres 159
FuNctioN 135
Homology reflects evolutionary relationships 135 7.2 how ARe the geNes ARRANgeD iN A
Homology analysis can provide information on NucleAR geNome? 161
the function of a gene 136 Genes are not evenly distributed within a genome 161
Identification of protein domains can help to A segment of the human genome 162
assign function to an unknown gene 137 The yeast genome is very compact 164
Annotation of gene function requires a common Gene organization in other eukaryotes 165
terminology 138
7.3 how mANy geNes ARe theRe AND
6.2 AssigNiNg FuNctioN by whAt ARe theiR FuNctioNs? 167
geNe iNActivAtioN AND Gene numbers can be misleading 168
oveRexpRessioN 139 Gene catalogs reveal the distinctive features of
Functional analysis by gene inactivation 140 different organisms 169
Individual genes can be inactivated by Families of genes 172
homologous recombination 140 Pseudogenes and other evolutionary relics 174
Gene inactivation without homologous
recombination 142 7.4 the Repetitive DNA coNteNt oF
Gene overexpression can also be used to eukARyotic NucleAR geNomes 176
assess function 144 Tandemly repeated DNA is found at centromeres
The phenotypic effect of gene inactivation or and elsewhere in eukaryotic chromosomes 176
overexpression may be difficult to discern 145 Minisatellites and microsatellites 176
Interspersed repeats 177
6.3 uNDeRstANDiNg geNe FuNctioN
by stuDies oF expRessioN pAtteRN summARy 178
AND pRoteiN pRoDuct 146
Reporter genes and immunocytochemistry shoRt ANsweR QuestioNs 178
can be used to locate where and when genes iN-Depth pRoblems 179
are expressed 146
Directed mutagenesis can be used to probe gene FuRtheR ReADiNg 179
function in detail 147
6.4 usiNg coNveNtioNAl geNetic CHAPTER 8

ANAlysis to iDeNtiFy geNe GENOmEs Of PROkARYOTEs
FuNctioN 149
Identification of human genes responsible for AND EukARYOTIC ORGANELLEs 181
inherited diseases 150
8.1 physicAl FeAtuRes oF pRokARyotic
Genomewide association studies can also
identify genes for diseases and other traits 151 geNomes 181
The traditional view of the prokaryotic
summARy 152 chromosome 181
Some bacteria have linear or multipartite genomes 183
iN-Depth pRoblems 153
8.2 geNetic FeAtuRes oF pRokARyotic
geNomes 186
FuRtheR ReADiNg 154 Gene organization in the E. coli K12 genome 186
cONTENTS xiii
Operons are characteristic features of prokaryotic

genomes 188
CHAPTER 10
Prokaryotic genome sizes and numbers of genes ACCEssING THE GENOmE 219
vary according to biological complexity 189
10.1 iNsiDe the Nucleus 219
Genome sizes and numbers of genes vary within The nucleus has an ordered internal
individual species 190 structure 220
Distinctions between prokaryotic species are The DNA content of a nondividing nucleus
further blurred by lateral gene transfer 192 displays different degrees of packaging 221
Metagenomes describe the members of a The nuclear matrix is thought to provide
community 194 attachment points for chromosomal DNA 222
Each chromosome has its own territory
8.3 eukARyotic oRgANellAR within the nucleus 223
geNomes 195 Each chromosome comprises a series of
The endosymbiont theory explains the origin of topologically associated domains 224
organellar genomes 195
Insulators mark the boundaries of topologically
Most organellar genomes are circular 196 associated domains 226
The gene catalogs of organellar genomes 197
10.2 Nucleosome moDiFicAtioNs AND
summARy 198 geNome expRessioN 228
shoRt ANsweR QuestioNs 200 Acetylation of histones influences many nuclear
activities including genome expression 228
iN-Depth pRoblems 201 Histone deacetylation represses active regions
of the genome 229
FuRtheR ReADiNg 201
Acetylation is not the only type of histone
modification 230
Nucleosome repositioning also influences gene
CHAPTER 9 expression 231
VIRAL GENOmEs AND
10.3 DNA moDiFicAtioN AND geNome
mOBILE GENETIC ELEmENTs 203 expRessioN 234
9.1 the geNomes oF bActeRiophAges Genome silencing by DNA methylation 234
AND eukARyotic viRuses 203 Methylation is involved in genomic imprinting
Bacteriophage genomes have diverse structures and X inactivation 235
and organizations 203
summARy 236
Replication strategies for bacteriophage
genomes 205 shoRt ANsweR QuestioNs 237
Structures and replication strategies for iN-Depth pRoblems 238
eukaryotic viral genomes 206
Some retroviruses cause cancer 207 FuRtheR ReADiNg 238
Genomes at the edge of life 209
9.2 mobile geNetic elemeNts 210 CHAPTER 11

RNA transposons with long terminal repeats are THE ROLE Of DNA-BINDING
related to viral retroelements 210
Some RNA transposons lack long terminal repeats 212 PROTEINs IN GENOmE
DNA transposons are common in prokaryotic EXPREssION 241
genomes 213
11.1 methoDs FoR stuDyiNg
DNA transposons are less common in eukaryotic
genomes 214 DNA-biNDiNg pRoteiNs AND theiR
AttAchmeNt sites 241
summARy 216 X-ray crystallography provides structural data for
any protein that can be crystallized 241
shoRt ANsweR QuestioNs 216 NMR spectroscopy is used to study the structures
of small proteins 243
Gel retardation identifies DNA fragments that
FuRtheR ReADiNg 217 bind to proteins 244
xiv cONTENTS
Protection assays pinpoint binding sites with RNA silencing was first identified as a means of
greater accuracy 244 destroying invading viral RNA 276
Modification interference identifies nucleotides MicroRNAs regulate genome expression by
central to protein binding 246 causing specific target mRNAs to be degraded 278
Genomewide scans for protein attachment sites 247
12.4 iNFlueNce oF RNA pRocessiNg
11.2 the speciAl FeAtuRes oF oN the compositioN oF A
DNA-biNDiNg pRoteiNs 249 tRANscRiptome 278
The helix–turn–helix motif is present in The splicing pathway for eukaryotic pre-mRNA
prokaryotic and eukaryotic proteins 249 introns 279
Zinc fingers are common in eukaryotic proteins 250 The splicing process must have a high degree of
Other nucleic acid-binding motifs 251 precision 280
Enhancer and silencer elements specify alternative
11.3 iNteRActioN betweeN DNA AND its splicing pathways 282
biNDiNg pRoteiNs 252
Direct readout of the nucleotide sequence 252 12.5 tRANscRiptomes iN ReseARch 284
The nucleotide sequence has a number of indirect Transcriptome analysis as an aid to genome
effects on helix structure 253 annotation 284
Contacts between DNA and proteins 253 Cancer transcriptomes 286
Transcriptomes and the responses of plants
summARy 254 to stress 287
shoRt ANsweR QuestioNs 255 summARy 289
iN-Depth pRoblems 256 shoRt ANsweR QuestioNs 289
FuRtheR ReADiNg 256 iN-Depth pRoblems 290
FuRtheR ReADiNg 290
CHAPTER 12
TRANsCRIPTOmEs 257 CHAPTER 13
12.1 compoNeNts oF the PROTEOmEs 293
tRANscRiptome 257
The mRNA fraction of a transcriptome is small 13.1 stuDyiNg the compositioN oF
but complex 257 A pRoteome 293
Short noncoding RNAs have diverse functions 259 The separation stage of a protein profiling
Long noncoding RNAs are enigmatic transcripts 260 project 294
Microarray analysis and RNA sequencing are The identification stage of a protein profiling
used to study the contents of transcriptomes 262 project 297
Comparing the compositions of two proteomes 299
12.2 syNthesis oF the compoNeNts Analytical protein arrays offer an alternative
oF the tRANscRiptome 263 approach to protein profiling 300
RNA polymerases are molecular machines
for making RNA 264 13.2 iDeNtiFyiNg pRoteiNs thAt
Transcription start points are indicated by iNteRAct with oNe ANotheR 301
promoter sequences 266 Identifying pairs of interacting proteins 301
Synthesis of bacterial RNA is regulated by Identifying the components of multiprotein
repressor and activator proteins 268 complexes 304
Synthesis of bacterial RNA is also regulated by Identifying proteins with functional interactions 305
control over transcription termination 271 Protein interaction maps display the interactions
Synthesis of eukaryotic RNA is regulated within a proteome 306
primarily by activator proteins 272
13.3 syNthesis AND DegRADAtioN
12.3 DegRADAtioN oF the oF the compoNeNts oF the
compoNeNts oF the tRANscRiptome 275 pRoteome 308
Several processes are known for nonspecific Ribosomes are molecular machines for making
RNA turnover 275 proteins 308
cONTENTS xv
During stress, bacteria inactivate their ribosomes Yeast mating types are determined by
in order to downsize the proteome 311 gene conversion events 338
Initiation factors mediate large-scale Genome rearrangements are responsible
remodeling of eukaryotic proteomes 312 for immunoglobulin and T-cell receptor
The translation of individual mRNAs can also diversity 339
be regulated 313
Degradation of the components of the 14.3 chANges iN geNome Activity
proteome 314 uNDeRlyiNg DevelopmeNt 341
Bacteriophage λ: a genetic switch enables a
13.4 iNFlueNce oF pRoteiN choice to be made between alternative
pRocessiNg oN the compositioN developmental pathways 342
oF the pRoteome 315 Bacillus sporulation: coordination of activities in
The amino acid sequence contains instructions two distinct cell types 343
for protein folding 315 Caenorhabditis elegans: the genetic basis of
Some proteins are activated by proteolytic positional information and the determination
cleavage 318 of cell fate 346
Important changes in protein activity can be Fruit flies: conversion of positional information
brought about by chemical modification 320 into a segmented body plan 348
Homeotic selector genes are universal features
13.5 beyoND the pRoteome 322 of higher eukaryotic development 350
The metabolome is the complete set of Homeotic genes also underlie plant
metabolites present in a cell 322 development 352
Systems biology provides an integrated
description of cellular activity 323 summARy 352
summARy 326
FuRtheR ReADiNg 354
FuRtheR ReADiNg 327
CHAPTER 15
GENOmE REPLICATION 357
CHAPTER 14
GENOmE EXPREssION 15.1 the topology oF geNome
ReplicAtioN 357
IN THE CONTEXT Of CELL The double-helical structure complicates the
AND ORGANIsm 329 replication process 358
The Meselson–Stahl experiment proved that
14.1 the RespoNse oF the geNome replication is semiconservative 359
to exteRNAl sigNAls 330 DNA topoisomerases provide a solution to the
Signal transmission by import of the topological problem 361
extracellular signaling compound 330 Variations on the semiconservative theme 363
Receptor proteins transmit signals across cell
membranes 332 15.2 the iNitiAtioN phAse oF geNome
Some signal transduction pathways have few ReplicAtioN 364
steps between receptor and genome 333 Initiation at the E. coli origin of replication 364
Some signal transduction pathways have many Origins of replication have been clearly defined
steps between receptor and genome 334 in yeast 365
Some signal transduction pathways operate Origins in higher eukaryotes have been less easy
via second messengers 336 to identify 366
14.2 chANges iN geNome Activity 15.3 eveNts At the ReplicAtioN FoRk 367
ResultiNg iN cellulAR DNA polymerases are molecular machines for
DiFFeReNtiAtioN 336 making (and degrading) DNA 367
Some differentiation processes involve changes to DNA polymerases have limitations that
chromatin structure 336 complicate genome replication 369
xvi cONTENTS
Okazaki fragments must be joined together to Defects in DNA repair underlie human diseases,
complete lagging-strand replication 370 including cancers 406
15.4 teRmiNAtioN oF geNome summARy 406

ReplicAtioN 372 shoRt ANsweR QuestioNs 407
Replication of the E. coli genome terminates
within a defined region 373 iN-Depth pRoblems 407
Little is known about termination of replication in FuRtheR ReADiNg 408
eukaryotes 374
Telomerase completes replication of chromosomal
DNA molecules, at least in some cells 375
Telomere length is implicated in cell senescence
CHAPTER 17
and cancer 378 RECOmBINATION AND
Drosophila has a unique solution to the TRANsPOsITION 411
end-shortening problem 379
17.1 homologous RecombiNAtioN 412
15.5 RegulAtioN oF eukARyotic The Holliday and Meselson–Radding models for
geNome ReplicAtioN 380 homologous recombination 412
Genome replication must be synchronized The double-strand break model for homologous
with the cell cycle 380 recombination 414
Origin licensing is the prerequisite for passing RecBCD is the most important pathway for
the G1–S checkpoint 380 homologous recombination in bacteria 415
Replication origins do not all fire at the same time 382 E. coli can also carry out homologous
The cell has various options if the genome is recombination by the RecFOR pathway 417
damaged 383 Homologous recombination pathways in
eukaryotes 417
summARy 384 The primary role of homologous recombination
is thought to be DNA repair 418
iN-Depth pRoblems 385 17.2 site-speciFic RecombiNAtioN 419
Bacteriophage λ uses site-specific recombination
FuRtheR ReADiNg 386 during the lysogenic infection cycle 419
Site-specific recombination is an aid in
construction of genetically modified plants 421
CHAPTER 16
17.3 tRANspositioN 421
muTATIONs AND DNA REPAIR 389 Replicative and conservative transposition of
DNA transposons 422
16.1 the cAuses oF mutAtioNs 389
Errors in replication are a source of point Retroelements transpose replicatively via an
mutations 390 RNA intermediate 423
Replication errors can also lead to insertion and summARy 425
deletion mutations 391
Mutations are also caused by chemical and shoRt ANsweR QuestioNs 426
physical mutagens 394 iN-Depth pRoblems 427
16.2 RepAiR oF mutAtioNs AND otheR FuRtheR ReADiNg 427
types oF DNA DAmAge 398
Direct repair systems fill in nicks and correct
some types of nucleotide modification 398 CHAPTER 18
Base excision repairs many types of damaged
nucleotide 399 HOw GENOmEs EVOLVE 429
Nucleotide excision repair is used to correct more 18.1 geNomes: the FiRst 10 billioN
extensive types of damage 401 yeARs 429
Mismatch repair corrects replication errors 402 The first biochemical systems were centered
Single- and double-strand breaks can be repaired 403 on RNA 429
If necessary, DNA damage can be bypassed during The first DNA genomes 432
genome replication 405 How unique is life? 433
cONTENTS xvii
18.2 evolutioN oF iNcReAsiNgly

complex geNomes 434
Genome sequences provide extensive evidence
of past gene duplications 434
A variety of processes could result in gene
duplication 438
Whole-genome duplication is also possible 439
Smaller duplications can also be identified in
the human genome and other genomes 442
Both prokaryotes and eukaryotes acquire
genes from other species 444
Genome evolution also involves rearrangement of
existing genes 445
There are competing hypotheses for the origins of
introns 448
The evolution of the epigenome 449
18.3 geNomes: the lAst 6 millioN

yeARs 450
The human genome is very similar to that of the
chimpanzee 451
Paleogenomics is helping us understand the
recent evolution of the human genome 452
18.4 geNomes toDAy: DiveRsity iN

populAtioNs 453
The origins of HIV/AIDS 454
The first migrations of humans out of Africa 455
The diversity of plant genomes is an aid in crop
breeding 457
summARy 458
FuRtheR ReADiNg 460
GLOssARY 463
INDEX 491
T A
A T
T A
pARt i
G C
A T
C G
C G
T A
G C
G C
A T
T A
G C
C G
A T
T A
T A
stuDyiNg geNomes
cHapTer
1
Genomes, TranscripTomes,
and proTeomes
Life as we know it is specified by the genomes of the myriad organisms with 1.1 DNA
which we share the planet. Every organism possesses a genome that contains the
biological information needed to construct and maintain a living example of that 1.2 RNA AND the tRANscRiptome
organism. Most genomes, including the human genome and those of all other
cellular life forms, are made of DNA (deoxyribonucleic acid), but a few viruses 1.3 pRoteiNs AND the pRoteome
have RNA (ribonucleic acid) genomes. DNA and RNA are polymeric molecules
made up of chains of monomeric subunits called nucleotides. Each molecule
of DNA comprises two polynucleotides wound around one another to form the
famous double helix, in which the two strands are held together by chemical
bonds that link adjacent nucleotides into structures called base pairs.
The human genome, which is typical of the genomes of all multicellular ani-
mals, consists of two distinct parts (Figure 1.1):
• The nuclear genome comprises approximately 3,235,000,000 base pairs of
DNA, divided into 24 linear molecules, the shortest 48,000,000 base pairs in
length and the longest 250,000,000 base pairs, each contained in a different
chromosome. These 24 chromosomes consist of 22 autosomes and the
two sex chromosomes, X and Y. Altogether, some 45,500 genes are present
in the human nuclear genome.
• The mitochondrial genome is a circular DNA molecule of 16,569 base

pairs, up to 10 copies of which are present in each of the energy-generating
organelles called mitochondria. The human mitochondrial genome con-
tains just 37 genes.
Each of the approximately 1013 cells in the adult human body has its own copy
or copies of the nuclear genome, the only exceptions being those few cell types,
such as red blood cells, that lack a nucleus in their fully differentiated state. The
vast majority of cells are diploid and so have two copies of each autosome, plus
two sex chromosomes, XX for females or XY for males—46 chromosomes in all.
These are called somatic cells, in contrast to sex cells, or gametes, which are
haploid and have just 23 chromosomes, one of each autosome and one sex chro-
mosome. Each cell also has multiple copies of the mitochondrial genome: 2000–
7000 copies in somatic cells, such as those in the liver and heart tissue, and over
100,000 copies in each female oocyte.
2 chapter 1: Genomes, Transcriptomes, and Proteomes
Figure 1.1 Nuclear and mitochondrial Human cell

components of the human genome.
Human family Nuclear genome Mitochondrial genome
Genomes | chapter 01 | figure 01

Terry The
Brown genome
| Fourth Editionis a store of
biological information, but on its own it is unable
© garlandscience design by blink studio ltd
to release that information to the cell. Utilization of the biological information
contained in the genome requires the coordinated activity of enzymes and other
proteins, which participate in a complex series of biochemical reactions referred
to as genome expression (Figure 1.2). The initial product of genome expression
is the transcriptome, a collection of RNA molecules derived from those genes
that are active in the cell at a particular time. The transcriptome is maintained by
the process called transcription, in which individual genes are copied into RNA
molecules. The second product of genome expression is the proteome, the cell’s
repertoire of proteins, which specifies the nature of the biochemical reactions
that the cell is able to carry out. The proteins that make up the proteome are syn-
thesized by translation of some of the individual RNA molecules present in the
transcriptome.
This book is about genomes and genome expression. It explains how genomes
are studied (Part I), how they are organized (Part II), how they function (Part III),
and how they replicate and evolve (Part IV). It was not possible to write this book
until quite recently. Since the 1950s, molecular biologists have studied individ-
ual genes or small groups of genes, and from these studies they have built up a
wealth of knowledge about how genes work. But only during the last few years
have techniques been available that make it possible to examine entire genomes.
Individual genes are still intensively studied, but information about individual
genes is now interpreted within the context of the genome as a whole. This new,
broader emphasis applies not just to genomes but to all of biochemistry and cell
biology. No longer is it sufficient simply to understand individual biochemical
GENOME
pathways or subcellular processes. The challenge now is provided by systems
biology, which attempts to link together these pathways and processes into net-
Transcription
works that describe the overall functioning of living cells and living organisms.
This book will lead you through our knowledge of genomes and show you how
TRANSCRIPTOME this exciting area of research is underpinning our developing understanding of
RNA copies of the active protein-coding genes biological systems. First, however, we must pay attention to the basic principles
Translation
of molecular biology by reviewing the key features of the three types of biological
molecule involved in genomes and genome expression: DNA, RNA, and protein.
PROTEOME
The cell's repertoire of proteins 1.1 DNA
DNA was discovered in 1869 by Friedrich Miescher, a Swiss biochemist work-
Genomes | chapter 01 | figure 02 ing in Tübingen, Germany. The first extracts that Miescher made from human
Figure
Terry 1.2
Brown genome
| Fourth Edition expression. The
genome
© specifies
garlandscience designthe transcriptome,
by blink studio ltd and white blood cells were crude mixtures of DNA and chromosomal proteins, but
the transcriptome specifies the proteome. the following year he moved to Basel, Switzerland (where the research institute
1. 1 DNA 3
named after him is now located), and prepared a pure sample of nucleic acid
from salmon sperm. Miescher’s chemical tests showed that DNA is acidic and rich
in phosphorus and also suggested that the individual molecules are very large,
although it was not until the 1930s, when biophysical techniques were applied to
DNA, that the huge lengths of the polymeric chains were fully appreciated.
Genes are made of DNA

The fact that genes are made of DNA is so well known today that it can be diffi-
cult to appreciate that for the first 75 years after its discovery the true role of DNA
was unsuspected. As early as 1903, W. S. Sutton had realized that the inheritance
patterns of genes parallel the behavior of chromosomes during cell division, an
observation that led to the chromosome theory, the proposal that genes are
located in chromosomes. Examination of cells by cytochemistry, which makes
use of stains that bind specifically to just one type of biochemical, showed that
chromosomes are made of DNA and protein, in roughly equal amounts. Biologists
at that time recognized that billions of different genes must exist and the genetic
material must therefore be able to take many different forms. But this requirement
appeared not to be satisfied by DNA, because in the early part of the twentieth
century it was thought that all DNA molecules were the same. On the other hand,
it was known, correctly, that proteins are highly variable, polymeric molecules,
each one made up of a different combination of 20 chemically distinct amino acid
monomers (Section 1.3). Genes simply had to be made of protein, not DNA.
The errors in understanding DNA structure lingered on, but by the late 1930s it
had become accepted that DNA, like protein, has immense variability. The notion
that protein was the genetic material initially remained strong but was eventually
overturned by the results of two important experiments:
• Oswald Avery, Colin MacLeod, and Maclyn McCarty showed that DNA
is the active component of the transforming principle, a bacterial
cell extract that, when mixed with a harmless strain of Streptococcus
pneumoniae, converts these bacteria into a virulent form capable of
causing pneumonia when injected into mice (Figure 1.3A). In 1944, when
the results of this experiment were published, only a few microbiologists
appreciated that transformation involves transfer of genes from the
cell extract into the living bacteria. However, once this point had been
accepted, the true meaning of the Avery experiment became clear:
bacterial genes must be made of DNA.
• Alfred Hershey and Martha Chase used radiolabeling to show that when
a bacterial culture is infected with bacteriophages (also called phages,
a type of virus), DNA is the major component of the bacteriophages that
enters the cells (Figure 1.3B). This was a vital observation because it was
known that, during the infection cycle, the genes of the infecting bac-
teriophages are used to direct synthesis of new bacteriophages, and this
synthesis occurs within the bacteria. If only the DNA of the infecting bac-
teriophages enters the cells, then it follows that the genes of these bacterio-
phages must be made of DNA.
Although from our perspective these two experiments provide the key results
that tell us that genes are made of DNA, biologists at the time were not so easily
convinced. Both experiments have limitations that leave room for skeptics to
argue that protein could still be the genetic material. For example, there were
worries about the specificity of the deoxyribonuclease enzyme that Avery and
colleagues used to inactivate the transforming principle. This result, a central
part of the evidence for the transforming principle being DNA, would be invalid
if, as seemed possible, the enzyme contained trace amounts of a contaminating
protease and hence was also able to degrade protein. Neither is the bacteriophage
experiment conclusive, as Hershey and Chase stressed when they published their
results: “Our experiments show clearly that a physical separation of phage T2
into genetic and nongenetic parts is possible ... The chemical identification of the
(A) The transforming principle (B) The Hershey–Chase experiment
DNA
Protein capsid
Harmless bacteria Mouse survives
Phage attached
to bacteria
Harmless bacteria + Mouse dies Virulent bacteria Agitate in blender

transforming principle
Phage now
detached
Harmless bacteria + Mouse dies Virulent bacteria

treated with protease or ribonuclease Centrifuge
70% 32P
Harmless bacteria + Mouse survives 20% 35S
Pellet of bacteria
treated with deoxyribonuclease
Genomes1.3
Figure | chapter
the01two
| figure 03
experiments that suggested that genes are to a body and legs that enable the bacteriophage to attach to the
Terry Brown | Fourth Edition
made of DNA.
© garlandscience design by blinkand
(A) Avery colleagues
studio ltd showed that the transforming surface of a bacterium and inject its genes into the cell. The DNA of
principle is made of DNA. The top two panels show what happens when the bacteriophages was labeled with 32P, and the protein was labeled
mice are injected with harmless Streptococcus pneumoniae bacteria with with 35S. A few minutes after infection, the culture was agitated to
or without addition of the transforming principle, a cell extract obtained detach the empty phage particles from the cell surface. The culture
from a virulent strain of S. pneumoniae. When the transforming principle was then centrifuged, which collects the bacteria plus phage genes
is present, the mouse dies, because the genes in the transforming as a pellet at the bottom of the tube but leaves the lighter phage
principle convert the harmless bacteria into the virulent form; these particles in suspension. Hershey and Chase found that the bacterial
virulent bacteria subsequently were recovered from the lungs of the pellet contained 70% of the 32P-labeled component of the phages (the
dead mouse. The lower two panels show that treatment with protease DNA) but only 20% of the 35S-labeled material (the phage protein). In a
or ribonuclease has no effect on the transforming principle but that second experiment, not depicted here, Hershey and Chase showed that
the transforming principle is inactivated by deoxyribonuclease. new phages produced at the end of the infection cycle contained less
(B) The Hershey–Chase experiment used T2 bacteriophages, each of than 1% of the protein from the parent phages. For more details of the
which comprises a DNA molecule contained in a protein capsid attached bacteriophage infection cycle, see Figure 2.27.
genetic part must wait, however, until some questions ... have been answered.”
In retrospect, these two experiments are important not because of what they tell
us but because they alerted biologists to the fact that DNA might be the genetic
material and was therefore worth studying. This is what influenced Watson and
Crick to work on DNA, and as we will see, it was their discovery of the double-
helix structure, which solved the puzzling question of how genes can replicate,
that really convinced the scientific world that genes are made of DNA.
DNA is a polymer of nucleotides

The names of James Watson and Francis Crick are so closely linked with DNA that
it is easy to forget that when they began their collaboration in October 1951, the
detailed structure of the DNA polymer was already known. Their contribution was
1. 1 DNA 5
(A) A nucleotide O- O- O-
γ β α 5‘
-
O P O P O P O CH2 BASE
O
O O O 4‘C H H C1‘
Phosphate 3‘ 2‘
H H
OH H
Sugar
(B) The four bases in DNA

NH2 NH2 O O
N C C N C C CH3
C5 6 4
7 1N N3 5CH C NH HN C
HC 8 HC
9 4 2 2 6 9
N C N CH C CH N C N C NH C CH
3 1 1
O N 2 O N
Adenine (A) Cytosine (C) Guanine (G) Thymine (T)

Terry Brown
Figure | Fourth
1.4 Edition of a nucleotide. (A) General structure of a deoxyribonucleotide, which is the
structure
type of nucleotide found in DNA. (B) The four bases that occur in deoxyribonucleotides.
not to determine the structure of DNA per se but to show that in living cells two
DNA chains are intertwined to form the double helix. First, therefore, we should
examine what Watson and Crick knew before they began their work.
DNA is a linear, unbranched polymer in which the monomeric subunits are
four chemically distinct nucleotides that can be linked together in any order in
chains that are hundreds, thousands, or even millions of units in length. Each
nucleotide in a DNA polymer is made up of three components (Figure 1.4):
• 2ʹ-Deoxyribose, which is a pentose, a type of sugar composed of five car-
bon atoms. These five carbons are numbered 1ʹ (spoken as one-prime), 2ʹ,
and so on. The name 2ʹ-deoxyribose indicates that this particular sugar is
a derivative of ribose, in which the hydroxyl (-OH) group attached to the
2ʹ-carbon of ribose has been replaced by a hydrogen (-H) group.
• A nitrogenous base, one of cytosine or thymine (single-ring pyrimidines)

or adenine or guanine (double-ring purines). The base is attached to the
1ʹ-carbon of the sugar by a β-N-glycosidic bond attached to nitrogen num-
ber one of the pyrimidine or number nine of the purine.
• A phosphate group, comprising one, two, or three linked phosphate units

attached to the 5ʹ-carbon of the sugar. The phosphates are designated α, β,
and γ, with the α-phosphate being the one directly attached to the sugar.
A molecule made up of just the sugar and base is called a nucleoside; addition
of the phosphates converts this to a nucleotide. Although cells contain nucleo-
tides with one, two, or three phosphate groups, only the nucleoside triphosphates
act as substrates for DNA synthesis. The full chemical names of the four nucleo-
tides that polymerize to make DNA are
• 2ʹ-deoxyadenosine 5ʹ-triphosphate
• 2ʹ-deoxycytidine 5ʹ-triphosphate
• 2ʹ-deoxyguanosine 5ʹ-triphosphate
• 2ʹ-deoxythymidine 5ʹ-triphosphate
The abbreviations of these four nucleotides are dATP, dCTP, dGTP, and dTTP,
respectively, or when referring to a DNA sequence, A, C, G, and T, respectively.
In a polynucleotide, individual nucleotides are linked together by phospho-
diester bonds between their 5ʹ- and 3ʹ-carbons (Figure 1.5). From the structure
Figure 1.5 A short DNA polynucleotide 5‘-P terminus

showing the structure of the O- O- O-
5‘
phosphodiester bond. Note that the two -
ends of the polynucleotide are chemically O
distinct. O O O
3‘
O
5‘
A phosphodiester bond O P O CH2 BASE
O
O-
3‘
O
5‘
BASE
O P O CH2
O
O-
3‘
OH
3‘-OH terminus

of this linkage, we can see that the polymerization reaction (Figure 1.6) involves
removal of the two outer phosphates (the β- and γ-phosphates) from one nucleo-
tide and replacement of the hydroxyl group attached to the 3ʹ-carbon of the sec-
ond nucleotide. Note that the two ends of the polynucleotide are chemically dis-
tinct, one having an unreacted triphosphate group attached to the 5ʹ-carbon (the
5ʹ- or 5ʹ-P terminus) and the other having an unreacted hydroxyl attached to the
3ʹ-carbon (the 3ʹ- or 3ʹ-OH terminus). This means that the polynucleotide has a
chemical direction, expressed as either 5ʹ → 3ʹ (down in Figure 1.5) or 3ʹ → 5ʹ (up
in Figure 1.5). An important consequence of the polarity of the phosphodiester
bond is that the chemical reaction needed to extend a DNA polymer in the 5ʹ → 3ʹ
direction is different from that needed to make a 3ʹ → 5ʹ extension. The DNA poly-
merase enzymes present in living organisms are only able to carry out 5ʹ → 3ʹ
synthesis, which adds significant complications to the process by which double-
stranded DNA is replicated (Section 15.3).
In the years before 1950, various lines of evidence had shown that cellu-
lar DNA molecules are composed of two or more polynucleotides assembled
together in some way. The possibility that unraveling the nature of this assembly
might provide insights into how genes work prompted Watson and Crick, among
others, to try to solve the structure. According to Watson in his book The Double
Helix, their work was a desperate race against the famous American biochem-
ist Linus Pauling, who initially proposed an incorrect triple-helix model, giving
Watson and Crick the time they needed to complete the double-helix structure. It
is now difficult to separate fact from fiction, especially regarding the part played
by Rosalind Franklin, whose X-ray diffraction studies provided the bulk of the
experimental data in support of the double helix and who was herself very close
to solving the structure. The one thing that is clear is that the double helix, discov-
ered by Watson and Crick on Saturday, March 7, 1953, was the single most impor-
tant breakthrough in biology during the twentieth century.
The discovery of the double helix can be looked on as one of the first multidis-
ciplinary biological research projects. Watson and Crick used four quite different
types of information to deduce the double-helix structure:
• Biophysical data of various kinds were used to infer some of the key features
of the structure. The water content of DNA fibers was particularly important
because it enabled the density of the DNA in a fiber to be estimated. The
number of strands in the helix and the spacing between the nucleotides
had to be compatible with the fiber density. Pauling’s triple-helix model
was based on an incorrect density measurement that suggested that the
DNA molecule was more closely packed than is actually the case.
1. 1 DNA 7
5‘-P terminus Figure 1.6 the polymerization reaction

O- O- O- that results in synthesis of a DNA
-
5‘
BASE
polynucleotide. Synthesis occurs in the
O P O P O P O CH2 5ʹ → 3ʹ direction, with the new nucleotide
O
O O O being added to the 3ʹ-carbon at the end
of the existing polynucleotide. The β-
3‘ and γ-phosphates of the nucleotide are
O
removed as a pyrophosphate molecule.
5‘
BASE
O P O CH2
O
O-
- -
O O 3‘
O-
- OH
O P O P O P
O 3‘-OH terminus
O O O
5‘ BASE
CH2
O
3‘
OH O O
-
O P O P O-
O- O-
Pyrophosphate
O- O- O-
5‘
-
O
O O O
3‘
O
5‘
O P O CH2 BASE
-
O
O
3‘
O
5‘
BASE
O P O CH2
O
O-
3‘
OH
X-ray diffraction
• © garlandscience patterns
design by blink studio ltd (Section 11.1), most of which were produced by
Rosalind Franklin, revealed the detailed helical structure (Figure 1.7).
• The base ratios, which had been discovered by Erwin Chargaff of Columbia
University in New York, enabled the pairing between the polynucleotides
in the helix to be deduced. Chargaff had carried out a lengthy series of chro-
matographic studies of DNA samples from various sources and showed
Figure 1.7 Franklin’s photo 51 showing the X-ray diffraction pattern

obtained with a fiber of DNA. The cross shape indicates that DNA has a helical
structure, and the extent of the shadowing within the diamond spaces above,
below, and to either side of the cross show that the sugar–phosphate backbone
is on the outside of the helix (see Figure 1.9). The positions of the various smears
that make up the arms of the cross enable dimensions such as the diameter,
rise per base pair, and pitch (see Table 1.1) of the molecule to be calculated. The
missing smears (the gap in each arm of the cross, marked by the arrows) indicate
the relative positioning of the two polynucleotides. These missing smears enabled
Watson and Crick to recognize that there are two grooves of different depths on
the outer surface of the helix (see Figure 1.9). (From Franklin R & Gosling RG [1953]
Nature 171:740–741. With permission from Macmillan Publishers Ltd.)
Human cells Escherichia coli Figure 1.8 the base ratio experiments performed by chargaff. DNA
bacteria was extracted from various organisms and treated with acid to hydrolyze the
phosphodiester bonds and release the individual nucleotides. Each nucleotide
was then quantified by chromatography. The data show some of the actual results
obtained by Chargaff. These indicate that, within experimental error, the amount
of adenine is the same as that of thymine and the amount of guanine is the same
as that of cytosine.
Purify the DNA

that although the values are different in different organisms, the amount
of adenine is always the same as the amount of thymine and the amount
of guanine equals the amount of cytosine (Figure 1.8). These base ratios
led to the base-pairing rules, which were the key to the discovery of the
double-helix structure.
• The construction of scale models of possible DNA structures, which was

Mild acid treatment the only major technique that Watson and Crick performed themselves,
breaks phosphodiester bonds enabled the relative positioning of the various atoms to be checked, to
ensure that pairs that formed bonds were not too far apart and that other
atoms were not so close together as to interfere with one another.
The double helix is stabilized by base pairing and base stacking

Chromatography to
quantify each nucleotide The double helix is right-handed, which means that if it were a spiral staircase and
you were climbing upward, then the rail on the outside of the staircase would be
on your right-hand side. The two strands run in opposite directions (Figure 1.9A).
Base ratio Base ratio The helix is stabilized by two types of chemical interaction:
A:T 1.00 A:T 1.09 • Base pairing between the two strands involves the formation of hydrogen
G:C 1.00 G:C 0.99 bonds between an adenine on one strand and a thymine on the other
strand, or between a cytosine and a guanine (Figure 1.9B). Hydrogen
bonds are weak electrostatic interactions between an electronegative
© garlandscience design by blink studio ltd atom (such as oxygen or nitrogen) and a hydrogen atom attached to a
second electronegative atom. Hydrogen bonds are longer than covalent
bonds and are much weaker; typical bond energies are 8–29 kJ mol–1 at
25°C, compared with up to 348 kJ mol–1 for a single covalent bond between
a pair of carbon atoms. As well as their role in the DNA double helix,
hydrogen bonds stabilize protein secondary structures. The two base-pair
combinations—A base-paired with T and G base-paired with C—explain
the base ratios discovered by Chargaff. These are the only pairs that are
permissible, partly because of the geometries of the nucleotide bases and
the relative positions of the atoms that are able to participate in hydrogen
bonds, and partly because the pair must be between a purine and a
pyrimidine: a purine–purine pair would be too big to fit within the helix,
and a pyrimidine–pyrimidine pair would be too small.
• Base stacking involves attractive forces between adjacent base pairs and
adds stability to the double helix once the strands have been brought
together by base pairing. Base stacking is sometimes called π–π inter-
actions, because it is thought to involve the p electrons associated with
the double bonds of the purine and pyrimidine structures. However, this
hypothesis is now being questioned, and the possibility that base stacking
involves a type of electrostatic interaction is being explored.
Both base pairing and base stacking are important in holding the two poly-
nucleotides together, but base pairing has added significance because of its bio-
logical implications. The limitation that A can only base-pair with T and G can
only base-pair with C means that DNA replication can result in perfect copies
of a parent molecule through the simple expedient of using the sequences of the
preexisting strands to dictate the sequences of the new strands. This is template-
dependent DNA synthesis, the system used by all cellular DNA polymerases
1. 1 DNA 9
(A) Base pair 5‘ end 3‘ end Figure 1.9 Double-helix structure of

O H O
5‘ 3‘
H H DNA. (A) Two representations of the double
A T O P O- C C helix. On the left, the structure is shown
CH HC with the sugar–phosphate backbone
G C O O of each polynucleotide drawn as a gray
T A C G CH2
CH2 ribbon with the base pairs in green. On the
C G O O right, the chemical structure for three base
G C CH HC pairs is given. (B) A base-pairs with T, and
C C -
T A O P O G base-pairs with C. The bases are drawn
H H
O H H O in outline, with the hydrogen bonding
A T
Minor Sugar–phosphate H H indicated by dotted lines. Note that a
T A backbone
O P O- C C
groove
CH HC G-C base pair has three hydrogen bonds
C G O O whereas an A-T base pair has just two.
G C G G
C CH2
CH2
T A O O
A T CH HC
Major C C -
O P O
groove T A H H
O H H O
G C H H
O P O- C C
A T
CH HC
C G O O
T A T T
A CH2
CH2
A T O O
CH HC
G C
C C -
O P O
H H
3‘ 5‘ 3‘ end O H 5‘ end
Hydrogen O
bonds
(B)
Thymine (T) Adenine (A) Cytosine (C) Guanine (G)
H H
+ + -
- N O
CH3 O H N N H N
+ +
N H -
N N N- H N N
N N SUGAR N N SUGAR
+
SUGAR
O SUGAR
O H N
H
(Section
Terry 2.1).Edition
Brown | Fourth Base pairing therefore enables
DNA molecules to be replicated by
a garlandscience
© system that designisby so
blinksimple
studio ltd and elegant that
as soon as the double-helix struc-
ture was publicized by Watson and Crick, every biologist became convinced that
genes really are made of DNA.
The double helix has structural flexibility

The double helix described by Watson and Crick, and shown in Figure 1.9A, is
called the B-form of DNA or B-DNA. Its characteristic features lie in its dimen-
sions: a helical diameter of 2.37 nm, a rise of 0.34 nm per base pair, and a pitch
(the distance taken up by a complete turn of the helix) of 3.4 nm, corresponding to
10 base pairs (bp)per turn. The DNA in living cells is thought to be predominantly
in this B-form, but it is now clear that genomic DNA molecules are not entirely
uniform in structure. This is mainly because each nucleotide in the helix has the
flexibility to take up a slightly different molecular shape. To adopt these different
conformations, the relative positions of the atoms in the nucleotide must change
slightly. There are a number of possibilities but the most important conforma-
tional changes are as follows:
• Rotation around the β-N-glycosidic bond changes the orientation of the
base relative to the sugar: the two possibilities are called the anti- and syn-
conformations (Figure 1.10A). Base rotation influences the positioning of
the two polynucleotides.
Figure 1.10 changes in nucleotide (A) Rotation around the β-N-glycosidic bond (B) Sugar pucker
configuration that can affect 5' BASE
the conformation of the double NH2 NH2 2'
helix. (A) Structures of anti- and syn- N N
N N O 1'
deoxyadenosine. The two structures differ 4'
3'
in the orientation of the base relative to
the sugar component of the nucleoside; N N N N
C2'-endo
rotation around the β-N-glycosidic bond HOCH2 HOCH2
O O
converts one form into the other. The 5' BASE
three other nucleosides also have anti- H H H H 3'
and syn-conformations. (B) Sugar pucker, H H H H O 1'

4'
illustrating the positioning of the sugar OH H OH H 2'
carbons in the C2ʹ-endo- and C3ʹ-endo-
configurations. anti-deoxyadenosine syn-deoxyadenosine C3'-endo

• Sugar
© garlandscience pucker
design by blink studio
refers ltd to the three-dimensional shape of the sugar. The ribose
component of the nucleotide does not have a planar structure: when it is

viewed from the side, one or two of the carbon atoms are either above or
below the plane of the sugar (Figure 1.10B). In the C2ʹ-endo-configuration,
the 2ʹ-carbon is above the plane and the 3ʹ-carbon is slightly below, and
in the C3ʹ-endo-configuration, the 3ʹ-carbon is above the plane and the
2ʹ-carbon is below. Because the 3ʹ-carbon participates in the phosphodies-
ter bond with the adjacent nucleotide, the two pucker configurations have
different effects on the conformation of the sugar–phosphate backbone.
Conformation changes resulting from rotation around the β-N-glycosidic
bond and sugar pucker can give rise to major changes in the overall structure of
the helix. It has been recognized since the 1950s that changes in the dimensions
of the double helix occur when fibers containing DNA molecules are exposed to
different relative humidities. For example, the modified version of the double
helix called A-DNA has a diameter of 2.55 nm, a rise of 0.23 nm per base pair, and
a pitch of 2.5 nm, corresponding to 11 base pairs per turn (Table 1.1). Like the
B-form, A-DNA is a right-handed helix and the bases are in the anti-conformation
relative to the sugar. The main difference lies with the sugar pucker: the sugars in
the B-form are in the C2ʹ-endo-configuration, and those in A-DNA are in the C3ʹ-
endo-configuration. Other right-handed variations of the double helix include Bʹ-,
C-, Cʹ-, Cʹʹ-, D-, E-, and T-DNAs.
A more drastic reorganization is also possible, leading to the left-handed
Z-DNA, in which the sugar–phosphate backbone adopts an irregular zigzag con-
formation. Z-DNA is a more tightly wound version of the double helix with 12 bp
per turn and a diameter of only 1.84 nm (Table 1.1). It is known to occur in regions
of a double helix that contain repeats of the motif GC (that is, the sequence of each
strand is ...GCGCGCGC...). In these regions, each G nucleotide has the syn- and
C3ʹ-endo-conformations and each C has the anti- and C2ʹ-endo-conformations.
tAble 1.1 FeAtuRes oF DiFFeReNt coNFoRmAtioNs oF the DNA

Double heliX
Feature A-DNA B-DNA Z-DNA
Type of helix Right-handed Right-handed Left-handed
Helical diameter (nm) 2.55 2.37 1.84
Distance between base pairs (nm) 0.23 0.34 0.38
Distance per complete turn (nm) 2.5 3.4 4.6
Number of base pairs per turn 11 10 12
Base orientation anti anti mixture
Sugar pucker C3ʹ-endo C2ʹ-endo mixture
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Plate IV
The modern reproduction of the Tomb of St. Martin. To face p. 213.
When Martin died, the people of Poitiers flocked to Condate to
claim the body of their former abbat. But the people of Tours
asserted their better claim, and carried him off in a ship to Tours. The
body of the saint was landed from the ship on the south bank of the
Loire, and deposited in a small oratory; the spot was called the
Station of the Body of St. Martin. It was moved thence to a more
central spot, and miracles began to be wrought at its new abode.
Briccius, his successor in the bishopric, built a church over it in the
eleventh year after the Saint’s death. Perpetuus removed this church
and built a more magnificent structure. The rich gifts of kings and
others made the church of Perpetuus very beautiful. St. Odo, in a
sermon on its destruction by fire, described it as lined with various
coloured marbles; in one place the walls were red with Protonis
marble, in another white with Parian, in another green with Prasine.
This church was burned by Willicharius. Chlotaire I rebuilt it. The
Normans burned it again in 853 and 903, and soon after the year
1000 it was rebuilt by Hervey the Treasurer in the form in which it
existed to the time of the Revolution. The Calvinists pillaged it, as
has been said above. At the destruction in the time of the Revolution
the various parts of the church were sold to speculators, and under
the First Empire all disappeared except the two towers which now
remain. The Cathedral church in the old Roman city, the eastern part
of the present city, was burned in the wars between Louis VII of
France and our Henry II, who was Lord of Tours and Count of Anjou.
In 1861 a rock-hewn tomb was found under a house which was
known to stand on the site of the high altar of the Abbey church. A
subterranean chapel was built over the tomb, and adorned with red
granite. This is now the Confessio of the new basilica of St. Martin.
There had only been two bishops of Tours before Martin. The first,
Gatian, died in 301. He had officiated secretly[203] in the remarkable
cave, across the front of which the ancient church of St. Radegonde
now stands, with its inscriptions.
Sca Radegundis Gemma Galliæ Pretiosissima, Ora pro

nobis. S. R. Regina Galliæ. Scus Gatianus Turonum Primus
Episcopus huius Parochiæ Fundator Primo Sæculo.
Lidorius succeeded Gatian after a lapse of thirty-seven years, and

built a small basilica for his bishop’s stool.
Martin had, during his bishopric, brought from St. Maurice, in the
valley of the Rhone, some relics of that saint, which he deposited in
a chapel built by Lidorius, to which also he removed from the
cemetery the remains of Gatian. This was the origin of the Cathedral
church of Tours, and we are thus enabled to see why its primary
dedication was to St. Maurice, and its second and permanent
dedication is to St. Gatian.
The public library at Tours, which is now on the quay facing the
Loire, and not at the place, as indicated by the guide-books, where
the Mairie stands, has a remarkably interesting collection of
manuscripts. Two of the finest of them are undoubtedly of
Charlemagne’s time. One of these, Tours No. 22 (St. Martin No. 247)
is a beautiful Book of the Gospels, written all in gold on very white
parchment, in remarkably perfect condition. The gold employed must
have been singularly pure. There are 277 leaves each with double
columns of 25 lines, and in all 289 leaves; the size is 12 ⅖ by 9⅕
inches. The initial letters are quite simple, and in exceedingly good
taste. The other, Tours No. 23 (St. Martin No. 174), is also a Book of
the Gospels, with 193 leaves, 11 ⅗ by 9⅕ inches. It has so-called
Hibernian initial letters, purple, with interlacements, and birds’ heads
with the characteristic eyes and beaks. It is much more probably
Anglian than Hibernian, and we may attribute it to the scriptorium of
the school of York, or to that of St. Martin of Tours as a copy from a
York manuscript. The present librarian assigns it to the writing school
of Marmoutier, across the Loire, which he thinks was the chief writing
school of Tours in Alcuin’s time. That opinion is founded on a remark
in connexion with the first establishment of Marmoutier, to which
reference will be made below;[204] the English student may well
attribute the MS. to St. Martin’s itself, produced, as a copy, under
Alcuin’s own eye, especially as it has always appeared in the
catalogue of St. Martin’s and not in that of Marmoutier, and is now
classed as a St. Martin’s MS.
The Evangeliarium first mentioned, in gold letters on white
parchment, is a book of historic fame. It is the book on which the
kings of France down to Louis XIV, in 1650, took their oath of fidelity
and protection to St. Martin of Tours, when admitted as abbat and
first canon of the collegiate church. The book was bound with great
magnificence of gold and gems; and when the Huguenots, under the
Prince of Condé, sacked the place, they carried off the rich binding,
but fortunately left the manuscript itself quite uninjured. The oath of
the kings is written on the reverse of folio 277, in a style closely
copied from the manuscript itself, probably in the eleventh or twelfth
century, all in small gold capital letters, with a point after every word.
The entry runs as follows;—
Hoc est iuramentum regis Francie quod facere tenetur dum

primo recipitur in abbatem et canonicum huius ecclesie beati
Martini Turonensis.
Ego N. annuente Domino Francorum rex Abbas et
canonicus huius ecclesie Beati Martini Turonensis iuro Deo et
Beato Martino me de cetero protectorem et defensorem fore
huius Ecclesie in omnibus necessitatibus et utilitatibus suis
custodiendo et conservando possessiones honores iura
privilegia libertates franchisias et immunitates eiusdem
Ecclesie quantum divino fultus adiutorio secundum posse
meum recta et pura fide sic me Deus adiuvet et hec sancta
verba.
The first king who held the secular abbacy of St. Martin of Tours
was Charles the Bald, Charlemagne’s grandson, who became king
of France (Neustria) in 843, about thirty years after Charlemagne’s
death. There were ecclesiastical abbats till the year 845, when the
Count Vivian became the first lay abbat. After Charles the Bald it is
probable that the kings held the abbacy. Hugh Capet (987-996)
united the title of Abbat of St. Martin to that of King of France. The
fifteen kings from Louis VII in 1137 to Louis XIV in 1630 took the
oath on this book on admission to the abbacy.
The status of the abbat and of the brethren of St. Martin was long
in uncertainty. Charlemagne refers to the vague status of the
brethren in his letter of rebuke to them, which is given on p. 237;
they called themselves canons, or monks, as best suited the
necessities of an occasion. Probably there had been a time when the
monastery included both secular and regular inmates. It is uncertain
also whether the brethren elected the bishop (or archbishop) of
Tours, and, indeed, whether they had not a bishop of their own.
Hadrian I, addressing the abbat Itherius, who was the first founder of
Cormery as a place of residence for regular monks of St. Benedict,
writes thus[205] of St. Martin’s—“we decree that it be lawful to have a
bishop there as has been from ancient times up to now, by whose
preaching the people who come from various parts with devoted
mind to the holy thresholds of the said confessor of Christ may
receive remedial help from the Creator of souls.” Urban II, in 1096, at
the Council of Tours, recognized this, and “united the Martinensian
bishopric to the Apostolic See”, a very honourable extinction. We
have the names of eight abbats before Itherius. The seventh of
them, Wicterbus, was bishop and abbat; the eighth, the immediate
predecessor of Itherius, Wulfhard I, was abbat only. It is supposed
that the appointment of Alcuin, one of the secular clergy and in
deacon’s orders, was a decided step in the secularization of the
Abbey, and that his policy was in the same direction. It may be
suggested that already in the time of Itherius that abbat was
conscious of a secularizing tendency, and on that account founded
Cormery; and that Alcuin found the existence of the regular abbey at
Cormery a convenient outlet for the remnant of regular brethren at
St. Martin’s, and handed St. Martin’s over to his successor, Wulfhard
II, as a purely secular foundation. The step to a lay abbacy was then
not a long one.
CHAPTER XIII
Further details of the Public Library of Tours.—Marmoutier.—The Royal Abbey
of Cormery.—Licence of Hadrian I to St. Martin’s to elect bishops.—Details of the
Chapter of the Cathedral Church of Tours.
The Public Library of Tours, as we have seen, has a very large

and interesting collection of manuscripts, which have come mainly
from three sources, the libraries, namely, of (1) the Cathedral church
of Tours, (2) the Monastery known as Marmoutier, and (3) the
Collegiate church of St. Martin. Twenty-one other churches and
foundations in the neighbourhood contributed manuscripts, besides
such collections as the expelled nobles possessed. In 1791 the
libraries of the old churches were collected into one depot, the
French Church having been organized as a civil institution in that
year and monastic vows made illegal. In 1793 the Conseil Général of
the Indre-et-Loire ordered that “les livres et manuscrits provenant
des maisons religieuses et des émigrés seront placés au ci-devant
Évêché, à l’effet de quoi le citoyen Suzor sera averti de l’évacuer au
plus tard le 15 mars prochain”. The third floor of the Évêché was
used for housing the manuscripts, &c., and by a most fortunate
appointment a true lover of the old things was made librarian. This
was Dom Jean Joseph Abrassart, ex-religious of Marmoutier. He
succeeded in saving a very large proportion of the ancient
manuscripts known to be in existence in the neighbourhood,
especially those at Marmoutier.
The library of the Cathedral church at Tours dated from the time of
St. Perpetuus, the sixth bishop, who left to his Cathedral church all
his manuscripts except the copy of the Gospels written by the hand
of St. Hilary of Poitiers (353-68) whom St. Martin had visited.[206]
Perpetuus was Bishop of Tours from 460 to 494. Ruinart, whose
edition of Gregory of Tours Migne took as the original of his edition,
notes that he had seen in the Cathedral library at Tours a book in
Saxon characters which had been supposed to be the work of
Hilary’s own hand; but he found that it contained matter much later
than Hilary’s time, and that the author had appended an inscription
stating himself to be Holaindus by name. A catalogue of the
Cathedral library was made in 1706 by the Chanoine Victor
d’Avanne, at which time the library contained 461 manuscripts. The
Chanoine complained that many other manuscripts had been
borrowed by savants and not returned; he names as culprits Auguste
de Thou, André Duchesne, Maan, and Michel de Marolls. Of the 461
manuscripts catalogued, the Public Library now has 309.
The library of Marmoutier was founded by St. Martin himself with
the abbey: so at least the phrase is understood to mean, “except
writing (or scripture) no art was exercised there.” Dom Gérou,
librarian of Marmoutier, made a catalogue of the manuscripts in his
charge, and Chalmel’s copy of that catalogue is now in the library of
Tours. There were, in 1754, 360 manuscripts, and there are now 263
of them in the library. Many of these are of value. Marmoutier was
always rich in Latin manuscripts. In 1716 a great collection made by
the Lesdiguières family was bought at Toulouse; these were chiefly
French, and thus it comes about that the library of Tours now
possesses some of the very first rank of the most ancient
monuments of French literature.
Sulpicius Severus, who made a special visit to St. Martin at Tours,
gives us an exact description of the site of this monastery, founded
by Martin in or about 372, at a distance of two miles from the city, on
its north-east side. He describes it as bounded on the north by a
range of precipitous rock, and on the south by a portion of the
stream of the river Loire, here divided. In those times it was only
accessible by one narrow way. Martin’s own cell was of wood, but
many of the eighty brethren excavated cells for themselves in the
rock, the nature of which lends itself to such excavation. The range
of cliff is honeycombed to this day for stables, wagon-sheds, &c.;
indeed, excavations of this character are a feature of the district,
observable from Poitiers to many miles on the Orleans side of Tours.
This abbey, like that of St. Martin, gradually became secularized, and
it, like St. Martin’s, was ruled by Count Vivian forty years after
Alcuin’s death. The names of many of its abbats before Alcuin’s time
are known, but it is only from the year 814 that a continuous series is
recorded. A photograph of some remains of the abbey is given in
Plate V.
The library of the Collegiate church of St. Martin was founded by
Alcuin, who borrowed books from England, mainly from York, and
had them copied; probably some of the borrowed books remained at
Tours, for Northumbria was in too disturbed a state to look after
manuscripts lent to France. In 1739 Bernard de Montfaucon
published an inventory of this library, which then contained 272
manuscripts. Of these the library of Tours now possesses 140. The
twenty-one other sources referred to above have provided 96
manuscripts, and the library has, besides, 159 which cannot be
traced to their source. This makes nearly 1,000 manuscripts in all
from these sources. The twenty-one sources referred to, and the
number of manuscripts each has provided, are as follows: The
Augustins of Tours 16; les Carmes 11; les Capucins 1; les Dames du
Calvaire 3: l’Oratoire 19; les Récollets 1; le Grand Séminaire St.
Julien 3; St. Pierre le Puellier 2; l’Union Chrétienne 3; la Visitation 2;
Aigues Vives 1; Amboise 3; St. Florentin d’Amboise 1; l’Abbaye de
Beaumont 4; Bois-Rayer 1; Cormery 5; Notre-Dame de Loches 2; la
Chartreuse du Liget 5; les Augustines de Beaulieu-lès-Loches 1; les
Religieuses Hospitalières de Loches 1; les Minimes du Plessis-lès-
Tours 11. What endless treasures England would now have
possessed if municipal authorities had taken such care as this of the
monastic libraries in the time of Henry VIII.
Plate V
Some remains of Marmoutier. To face p. 222.
In translating the life of Alcuin, we omitted one of the examples of
Alcuin’s insight into the ways of men which the anonymous author
gives. It relates to Cormery, some miles up the river Indre, one of the
places from which manuscripts were brought into the library of Tours.
The trick played was as clever in itself as the detection of it was. It
got over the difficulty of the vessels being found to be partly empty,
and the difficulty that, if they were filled up with water, the taster of
the monastery would detect the fraud at once.
This is the passage in the Life:—
“To the brothers of Cormery, whom he greatly loved, the father had
ordered a hundred measures of wine to be given. When the wine
was to be taken to the monastery, he ordered the stewards of the
monastery, through Sigulf, a monk of Abbat Benedict, that they
should detain the conveyors of the wine, until in their presence the
wine should be poured from the vessels in which they had brought it
into others; because some of them had stealthily taken out some of
the wine, and, in order that the vessels might be full when they
reached the monastery, had put into them river-sand. That this had
been done, the fathers proved most conclusively.”
The monastery of St. Paul at Cormery has a special interest for
students of Alcuin. William of Malmesbury makes mention of it in the
famous passage in which he so highly praises Alcuin.[207] After
quoting Alcuin’s request[208] to Karl that he may have sent over from
his library of York some of the manuscripts which he describes as
the flowers of Britain, “that the garden of paradise may not be
confined to York, but some of its scions may be transplanted to
Tours,” William proceeds thus: “This is that same Alcuin who, as I
have said, was sent into France to treat of peace, and during his
abode with Charles, captivated either by the pleasantness of the
country or the kindness of the king, settled there; and being held in
high estimation, he taught the king, during his leisure from the cares
of state, a thorough knowledge of logic, rhetoric, and astronomy.
Alcuin was, of all the Angles of whom I have read, next to St.
Aldhelm and Bede, certainly the most learned, and has given proof
of his talents in a variety of compositions. He lies buried in France, at
the church of St. Paul of Cormery[209], which monastery Charles the
Great built at his suggestion; on which account, even at the present
day (about 1130 a.d.), the subsistence of four monks is distributed in
alms for the soul of our Alcuin in that church.”
We have the documents which relate to the foundation of St. Paul
of Cormery, and they do not quite carry out William’s statement.
Itherius, the predecessor of Alcuin at St. Martin’s of Tours, had
acquired land at Cormery for the residence of monks, and in 791 had
issued a precept for the construction of a monastery. Much
discussion has centred round this fact, to which further reference is
made in another part of this book.[210] In the year 800, Karl issued
two interesting documents[211], both dated from St. Martin’s at Tours,
one signed by the king himself, the other certified by Genesius,
acting as deputy for the chancellor Hercambold. The first of these
documents has interesting features, and in it we find the reason for
the abbey being called, down to the Revolution, l’Abbaye Royale de
Cormery, and having as its armorial bearings the crowned eagle of
the empire impaling the lilies of France ancient. It is addressed to “all
the faithful men of St. Martin at that time serving in the holy place
where that precious confessor of Christ rests in the body, and to all
who shall follow them. Our beloved master Albinus has with pious
devotion begged of us that he may be allowed to settle monks in the
cell of St. Paul, which in rustic speech is called Cormery, there to live
the regular life according to the statutes of the holy Benedict. This
place his predecessor Abbat Itherius had acquired; he had built it,
and handed it over to St. Martin. We have thought it right to give our
assent to his pious devotion, and have caused it to be confirmed by
our letters under the seal of our authority, in order that no severance
may ever take place. For if divine piety has given to our parents and
to us the power over the whole monastery of St. Martin, and the right
to give it to whom we will, how much more have we the power of
assigning to God the aforesaid place. It is not lawful for any one to
contemn the donation or confirmation of royal benignity, especially in
an order so pious and wholesome as this. Therefore we entirely
order that this our donation stand to all time fixed and inviolate, and
that this place be never taken away from the possession of St.
Martin, but that there monks shall live under the full rule of St.
Benedict and have protection and help from the abbats of the
monastery of St. Martin. If any abbat in time to come should
disregard this our precept, let him know that he shall render an
account of his presumption to our Lord Jesus Christ in the day of His
great advent. So also shall any who diminishes aught of the things
which Abbat Itherius of blessed memory acquired, of the property of
St. Martin which he gave to the church of St. Paul, or of the things
which the said Abbat Albinus has given, at whose request we have
caused write these letters, or anything which any one may have
given in alms for his soul. That this may stand the more firm, we
have determined to subscribe it with our own hand and have caused
it to be sealed with our ring.”
The other document, addressed to all bishops, counts, officers,
&c., grants licence to the monks, “at the request of our most beloved
and faithful the venerable Abbat Albinus”, to have two ships coming
and going with necessary things on the rivers Loire, Sarthe, and
Vienne, free from toll. This was ordered to be sealed with Karl’s ring.
The navigation of the Indre, being their own river, was no doubt free
to them without grant.
Plate VI
Capital found at Cormery. To face p. 227.
Ithier governed St. Martin’s at Tours from 770 to 791. Soon after
791 he died, and was buried in a grave at the entrance of the nave of
the abbatial church of Cormery, on the north side. The place can still
be pointed out. Fridugisus, the Nathanael of Alcuin’s letters, who
was designated by Alcuin as his immediate successor, became
abbat of St. Martin’s after Wulfhard II. He built a stone church, the
west front of which still stands in considerable part, with the
eleventh-century Romanesque tower, most of which still stands,
applied to it, the east wall of the tower being the west front of
Fridugisus. Plate VI shows a capital which has recently been found,
evidently of the time of Fridugisus. Considerable parts of the later
Gothic walls still stand. They are carefully tended by M. Octave
Bobeau, the local correspondent of the Minister of Public Education,
whose apartments are in the refectory of the abbey. The curé of
Cormery, M. l’abbé Jaillet, is a most obliging guide to the ruins, as
also to his own very fine cruciform parish church. In these most
recent days “his own” is a misdescription. The inventories have been
taken, and Monsieur le Maire is the master of the parish church and
its services. The large house of the abbats of Cormery is now a
dwelling-house in connexion with the communal school. An early
engraving in a French account of Touraine shows that the western
tower was crowned with a gallery and spire, not unlike that shown in
the illustration of Marmoutier, Plate V.
Some commentators suppose that the “other monastery”, which
Alcuin informs Arno he has built some eight miles from the city, was
this monastery of Cormery. But the distance named is not easily
reconciled with the geographical facts, and Alcuin could not properly
have stated that he was the founder of Cormery.
Cormery provided a home for the severer side of the monastic life,
St. Martin’s and Marmoutier remaining secular. Cormery being a
considerable distance away, a Benedictine abbey, of St. Julien, was
established in the eastern part of Tours, in the tenth century, by
Archbishop Théotolon, and a Romanesque abbey-church was built,
the square tower of which still remains; the church in its present
state has some ancient paintings, and deserves a visit. Being within
the limits of the ancient Roman town, it would naturally be under the
jurisdiction of the archbishop.
This will be a convenient point at which to give further details[212]
of the remarkable licence of Hadrian for a permanent bishopric of the
western part of the present city, at that time a district separate from
the ancient city, in which latter was the stool of the archbishop of
Tours.
The licence of Hadrian I, allowing the abbat and brethren of St.
Martin’s to elect and to have their own bishop, is printed (from Baluz)
in Gallia Christiana, vol. xiv, p. 7 of the Instrumenta relating to Tours.
The date is 786. The licence is addressed to Abbat Autherius, that is,
Itherius. It sets forth that by royal and papal privileges the Abbey of
St. Martin of Tours was in all respects independent of the episcopal
authority of the bishop of Tours;[213] whatsoever in the flock of St.
Martin needed arranging, ruling, or correcting, was a matter for the
abbat, provost, dean, and other most approved men. Hadrian
declares that they may have a bishop of their own, as had been the
custom from ancient times until most recent times, because of the
great numbers of persons who flocked from all parts to visit the
shrine and needed instruction in the faith. The person elected by the
abbat and the flock shall be ordained by the neighbouring bishops.
The metropolitan bishop—that is, the archbishop of Tours—shall not
enter the church for any exercise of his episcopal office, such as
ordinations, or making the chrism, nor shall he have power to
summon any of the priests of the monastery to appear before him.
The abbey bishop must not be impleaded without the assent of the
abbat. He is to have the pastoral care of the neighbouring districts
held by the abbey, and is to amend and correct in canonical manner
and due order with the consent of his abbat. If the abbat does not
choose to settle any matter of dispute which may arise between the
St. Martin’s bishop and the bishops of the neighbourhood, the matter
must come direct to the apostolic see.
That is a very remarkable document. We are not without
indications of other unusual customs in the province of Tours.
The Archbishop of Tours had eventually eleven suffragans, Le
Mans, Angers, Rennes, Nantes, Vannes, Cornouaille, Léon,
Tréquier, St. Brieuc, St. Malo, Dol. Some of these bishoprics trace
their origin to refugees from Britain in the middle of the sixth century.
A marked feature of the Archbishopric was the existence and
permanence of the office of Archpresbyter. The Chapter of Tours
itself, in its most complete form, consisted of Dean, Archdeacon of
Tours, Treasurer, Praecentor, Chancellor, two other Archdeacons,
the Archpresbyter of Tours, and fifty or more Canons. The Princeps
Archipresbyter preached on the greater Sundays, as the
Ecclesiastes Theologus did on other Sundays. At Le Mans, before
Alcuin’s time at Tours, there were two Archpresbyters, each in
management of half of the diocese; in the eleventh century there
were three; in 1200, eight. In 1230 Maurice replaced them by seven
Archdeacons, who had under them a number of rural deans, decani
rusticanis negotiis, an office into which the Archpresbyters, once so
important, subsided. Archdeacons of Le Mans are first named in the
will of St. Bertramn, in 623. At Angers the chief Archdeacon had
under him four Archpresbyters; the second Archdeacon had one
Archpresbyter and two Rural Deans; the third Archdeacon had three
Rural Deans. At Angers the Archbishop of Tours acted in 1334 much
as the Archbishop acted at St. Martin’s at Tours in or before Alcuin’s
time; he freed the Chapter from episcopal control and himself
confirmed the Deans[214].
CHAPTER XIV
Great dispute on right of sanctuary.—Letters of Alcuin on the subject to his
representatives at court and to a bishop.—The emperor’s severe letter to St.
Martin’s.—Alcuin’s reply.—Verses of the bishop of Orleans on Charlemagne,
Luitgard, and Alcuin.
In the year 801, or early in 802, a question of sanctuary arose on

which Alcuin and Charlemagne took opposite views. The Emperor
was imperious in his dealing with the matter.
Two of Alcuin’s pupils, Candidus and Nathanael, Ep. 179.
held offices in the court of the Emperor at Aachen.
Nathanael was the pupil to whom Alcuin wrote a well-known letter
about the temptations and occupations of the court, his warnings
against the temptations being conveyed under cover of figurative
language. “Let not the crowned doves come to thy windows, that flit
about in the chambers of the palace; let not wild horses break in at
the door of thy chamber; do not occupy thyself with dancing bears.”
To Candidus and Nathanael he wrote, in evident anxiety, to tell them
what had happened, and to bid them put it before the Emperor in a
favourable light. This is what he says.
“The venerable father Theudulfus the Bishop [of Ep. 180. a.d. 801-
Orleans] has a dispute with some of your brethren 2.
of St. Martin’s about a certain fugitive culprit. This
culprit, after suffering very many kinds of punishment, suddenly
escaped from confinement, fled to the church of St. Martin a chief
confessor of Christ, confessed his sins, begged for reconciliation,
appealed to Caesar, and demanded to go to his most holy presence.
We gave him up to the messengers of the said bishop. They knew, it
is said, that preparations had been made to waylay them; they
dismissed him as he stood before the doors of the church, and went
their way. Thereupon there came a large number of the men of the
said venerated bishop, in a hostile manner as we have ascertained.
Eight principal men entered the church on the Lord’s day with our
own bishop [Joseph, the Archbishop of Tours]. These were not the
‘eight principal men’ who are read of in the prophet[215] as wasting
the land of Nimrod with swords and lances; they came to carry off
the culprit, to profane the sanctity of the house of God, to belittle the
honour of the holy confessor of Christ, Martin; indeed they rushed
into the sanctuary within the gates of the altar. The brethren drove
them out before the front of the altar. If they deny this, they say what
is absolutely false. No one of them at that time bowed the head
before the altar of God.
“The report spread that a hostile force had come from Orleans [a
distance of seventy miles] to violate the rights of St. Martin, for they
were known to be Orleans men. The pensioners rushed together
from every part of the city to the defence of their own defender.
Tumult and fear grew rapidly all over. Our brethren rescued the men
of the aforesaid bishop from the hands of the crowd, lest they should
be evil intreated, and drove the people out of the church.
“Now I know that the above-named pontiff will bring many
accusations against our brethren; will exaggerate what was done;
will say that things were done which were not done; for we have it in
his letters.
“I therefore charge you, my dearest sons, that you cast yourselves
at the feet of my lord David the most just and serene emperor. Beg
of him that when the bishop comes to complain, an opportunity of
defence may be afforded, and of disputing with him whether it is just
that an accused person should be taken by force from a church and
subjected to the very punishments from which he has fled; whether it
is right that one who has appealed to Caesar should not be brought
to Caesar; whether it is lawful to spoil of all his goods, even to a
boot-lace, one who is penitent and has confessed his sins; whether
that saying of the Scripture[216] is well observed, Mercy rejoiceth
against judgment.”
Alcuin then criticises the letter of the Bishop of Orleans, which has
not been preserved. In the course of the criticism he says two rather
clever things.
“The venerable father says that an accused sinner ought not to be
received in the church. But if sinners are not to enter the church, how
are you to have a priest to say mass in the church, or who will there
be to respond except some quite newly baptised person? For does
not St. John say, If we say that we have no sin we deceive
ourselves, and the truth is not in us. Again, we find that in the
venerable bishop’s letter the accused man is called a devil, not a
man. Think what the Apostle says, Judge not before the time.”
Alcuin then proceeds to quote the canons on fugitives, and to
describe the arrangements made in all parts for men to take
sanctuary. He ends with a powerful appeal to the Emperor to bear in
mind the danger of allowing any supreme dignity to be made light of.
In another letter, written at the same time, and in Ep. 181. A
great part in the same words, to a bishop not fragment.
named, Alcuin adds something to what he has said
in the letter to his pupils. The man, he says, had certainly committed
many sins and done very impious wickedness. But he had the
evidence of two priests, Christian of St. Benedict of Tours and
Adalbert of St. Martin, that he had made confession to them before
he was seized and bound and tortured. Probably Alcuin thought that
would not appeal very forcibly to the mind of the Emperor, and that
the impiousness of the man would do more harm to his cause than
the fact of confession would do good. The man was given up by the
brethren of St. Martin not that he might be taken off to Orleans, but
that he might be taken before the Archbishop of Tours by the
messengers of the Bishop of Orleans, a matter very different from
what it appeared to be in Alcuin’s letter to his representatives at
Court. The attempt to carry off the fugitive was very unscrupulous,
for the man was within the altar rails and was actually lying prostrate
in supplication and appeal before the sepulchre of St. Martin.
Alcuin thought it best to send the fugitive far out of the way. We do
not know what he had done, or who he was; but we may gather that
his name was something like Kalb from the words which Alcuin
applies to him in sending him to Salzburg, to the safe keeping of
Arno the Archbishop.
“I have sent to you this animal, the calf of my Ep. 183. a.d. 801-
hand, that you may help him and keep him out of 2.
the hands of his enemies. Help him as much as
you can, for the venerable bishop, that is Theodulfus, is greatly
enraged against us. I have put into the mouth of this youth, the calf
being an animal unnaturally rational, what he must moo in the ears
of your holiness.”
Now let us hear the voice of the emperor, by no means the moo of
a calf. We learn from his letter what on other grounds we should
have imagined, namely, that the culprit was a cleric. Well might the
bishop of Orleans rage against the Abbat of St. Martin.
“In the name of the Father and of the Son and of Ep. 182.
the Holy Ghost. Charles &c.[217] to the Venerable
Master Albinus and the whole congregation of the monastery of St.
Martin.
“The day before your letter reached our presence, a letter was
brought to us from Bishop Theodulf [of Orleans], containing
complaint of dishonour done to his men, or rather to the bishop of
the city [of Tours], and in contempt of the order of our empire. Which
order we caused write under the authority of our name for the
rendering up of a certain cleric, escaped from the bishop’s custody,
and in hiding in the basilica of St. Martin, a copy of which you have
sent to us. In it we think that we did not decree anything unjustly, as
you have thought we did.
“We have had both letters read to us again, yours [that is, Alcuin’s]
and Theodulf’s. Your letter appears to us to be much harsher than
Theodulf’s, and to have been written in anger, without any seasoning
of charity towards him; in defence of the fugitive, and in accusation
against the bishop. Under cover of a concealed name it maintains
that the accused person could and should be allowed to bring an
accusation, whereas both divine and human law forbids to allow a
criminous person to accuse another. For this he was defended and
protected by you, under pretext of the authority of our name; as
though one who had been accused and judged in sight of the people
of his own city of Orleans should have an opportunity of bringing an

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There have been remarkable advances in our knowledge of genomes since

A NOTE TO ThE REAdER

Organization of the Book

Part I – Studying Genomes begins with an orientation chapter that introduces

Part II – Genome Anatomies surveys the anatomies of the various types of

Short answer questions require 50- to 500-word answers. The questions

David Baillie, Simon Fraser University; Linda Bonen, University of Ottawa;

CHAPTER 1 Genomes, TranscripTomes, and proTeomes 1

CHAPTER 1 Ligases join DNA fragments together 37

3.4 liNkAge ANAlysis with DiFFeReNt Shotgun sequencing of eukaryotic genomes

summARy 132 CHAPTER 7

6.4 usiNg coNveNtioNAl geNetic CHAPTER 8

Operons are characteristic features of prokaryotic

9.2 mobile geNetic elemeNts 210 CHAPTER 11

15.4 teRmiNAtioN oF geNome summARy 406

18.2 evolutioN oF iNcReAsiNgly

18.3 geNomes: the lAst 6 millioN

18.4 geNomes toDAy: DiveRsity iN

• The mitochondrial genome is a circular DNA molecule of 16,569 base

Figure 1.1 Nuclear and mitochondrial Human cell

Human family Nuclear genome Mitochondrial genome

Genomes | chapter 01 | figure 01

Genes are made of DNA

(A) The transforming principle (B) The Hershey–Chase experiment

Harmless bacteria Mouse survives

Harmless bacteria + Mouse dies Virulent bacteria Agitate in blender

Harmless bacteria + Mouse dies Virulent bacteria

DNA is a polymer of nucleotides

(B) The four bases in DNA

Adenine (A) Cytosine (C) Guanine (G) Thymine (T)

Genomes | chapter 01 | figure 04

• A nitrogenous base, one of cytosine or thymine (single-ring pyrimidines)

• A phosphate group, comprising one, two, or three linked phosphate units

Figure 1.5 A short DNA polynucleotide 5‘-P terminus

Genomes | chapter 01 | figure 05

5‘-P terminus Figure 1.6 the polymerization reaction

Figure 1.7 Franklin’s photo 51 showing the X-ray diffraction pattern

Purify the DNA

• The construction of scale models of possible DNA structures, which was

The double helix is stabilized by base pairing and base stacking

(A) Base pair 5‘ end 3‘ end Figure 1.9 Double-helix structure of

The double helix has structural flexibility

and syn-conformations. (B) Sugar pucker, H H H H O 1'

Genomes | chapter 01 | figure 10

component of the nucleotide does not have a planar structure: when it is

tAble 1.1 FeAtuRes oF DiFFeReNt coNFoRmAtioNs oF the DNA

Sca Radegundis Gemma Galliæ Pretiosissima, Ora pro

Lidorius succeeded Gatian after a lapse of thirty-seven years, and

Hoc est iuramentum regis Francie quod facere tenetur dum

The Public Library of Tours, as we have seen, has a very large

In the year 801, or early in 802, a question of sanctuary arose on