The origin story and emergence of molecular biology is muddled. The early triumphs in bacterial genetics and the complexity of animal and plant genomes complicate an intricate history. This book documents the many advances, as well as the prejudices and founder fallacies. It highlights the premature relegation of RNA to simply an intermediate between gene and protein, the underestimation of the amount of information required to program the development of multicellular organisms, and the dawning realization that RNA is the cornerstone of cell biology, development, brain function and probably evolution itself. Key personalities, their hubris as well as prescient predictions are richly illustrated with quotes, archival material, photographs, diagrams and references to bring the people, ideas and discoveries to life, from the conceptual cradles of molecular biology to the current revolution in the understanding of genetic information.
Key Features
- Documents the confused early history of DNA, RNA and proteins - a transformative history of molecular biology like no other.
- Integrates the influences of biochemistry and genetics on the landscape of molecular biology.
- Chronicles the important discoveries, preconceptions and misconceptions that retarded or misdirected progress.
- Highlights major pioneers and contributors to molecular biology, with a focus on RNA and noncoding DNA.
- Summarizes the mounting evidence for the central roles of non-protein-coding RNA in cell and developmental biology.
- Provides a thought-provoking retrospective and forward-looking perspective for advanced students and professional researchers.
The Open Access version of this book, available at www.taylorfrancis.com, has been made available under a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 license.
Preface
Chapter 1 Overview
• The genetic material?
• Halcyon days
• Worlds apart
• Huge genomes, strange genetics
• The age of Aquarius
• All that junk
• The expanding repertoire of RNA
• Glimpses of a modern RNA world
• Genome sequencing and transposable elements
• The human genome
• Small RNAs with mighty functions
• Large RNAs with many functions
• The epigenome
• The programming of development
• RNA and repeats rule
• Plasticity
• Beyond the jungle of dogmas
Chapter 2 The genetic material?
• The nature of matter
• Sugars and fats
• Proteins: ‘the locus of life’
• Nucleic acids and chromosomes
• Chromosomes as the mediators of genetic inheritance
• The ‘Modern Synthesis’
• Distinguishing DNA and RNA
• One gene-one protein and the ‘nature of mutations’
• DNA is the genetic material
• The double helix – icon of the coming age
Chapter 3 Halcyon days
• The big question
• Discovery of the ribosome
• The messenger and the adaptor
• The ‘genetic code’
• The lac operon and gene regulation
• Protein structure
• The Central Dogma
• It’s all over now
Chapter 4 Worlds apart
• The origin of cells
• Genetic recombination
• The emergence of complex organisms
• Chromatin
• Chromatin-associated RNA
• Early models of RNAs in nuclear architecture
• Heterogenous nuclear RNA
• Heroes or fools?
Chapter 5 Strange genomes, strange genetics
• Repetitive DNA
• Controlling elements
• Paramutation, imprinting and transinduction
• The bithorax ‘complex locus'
• Transvection
• Epigenetic modifiers
• The Britten and Davidson model
• Boolean models of combinatorial control
• Processed RNAs as global regulators
• Out on a limb
Chapter 6 The Age of Aquarius
• Recombinant DNA and ‘gene cloning’
• Enabling technologies
• DNA sequencing
• The gold rushes
• Hox genes
• Oncogenes and tumor suppressors
• Immunology and monoclonal antibodies
• Biotechnological exploitation
• Cell-free DNA amplification and shotgun cloning
• A world of proteins
Chapter 7 All that junk
• The C-value enigma
• Duplication and transposition
• Mutational load, nonsense DNA, nonsense RNA
• Neutral evolution
• Conservation and selection
• Junk DNA
• Selfish DNA
• Genes-in-pieces!
• Not junk?
Chapter 8 The expanding repertoire of RNA
• Spliceosomal RNAs
• Small nucleolar RNAs
• Other small guide, scaffolding and regulatory RNAs
• Catalytic RNAs and the ancient RNA World hypothesis
• The catalytic heart of splicing and translation
• The digital and analog faces of RNA
• Candles in the dark
Chapter 9 Glimpses of a modern RNA world
• Riboregulators
• Riboswitches
• Antisense RNAs and complex transcription in eukaryotes
• Long untranslated RNAs
• UTR derived RNAs
• First glimpses of small regulatory RNAs in animals
• Curiosities or emissaries?
Chapter 10 Genome sequences and transposable elements
• Genome mapping
• Genetics at genome scale
• Whole genome sequencing of bacteria and archaea
• Genome sequencing of unicellular eukaryotes
• Genome sequencing of model plants and animals
• The G-value enigma
• Comparative genomics at nucleotide resolution
• Pseudogenes and retrogenes
• Transposable elements as functional modules
• Transposable elements as drivers of phenotypic innovation
• The great exploration – the diversity of life
• From genome sequence to genome biology
Chapter 11 The human genome
• The project
• Assessment of functionality
• The majority of the genome is active
• Damaged genes
• A plethora of ‘rare’ diseases
• Complex traits and disorders
• The transformation of medical research and healthcare
Chapter 12 Small RNAs with mighty functions
• Unusual genetic phenomena involving RNA
• The RNA interference pathway
• Transcriptional gene silencing: RNA-directed DNA methylation
• Research and biotechnology applications
• MicroRNAs
• Piwi-associated RNAs (piRNAs)
• Other classes of small RNAs
• RNA communication between species
• CRISPR
• RNA-directed genome editing
Chapter 13 Large RNAs with many functions
• Pervasive transcription
• The amazing complexity of the transcriptome
• Protein-coding or noise?
• The restricted expression of long noncoding RNAs
• Other indices of functionality of long noncoding RNAs
• The genetic signatures of long noncoding RNAs
• An avalanche of long noncoding RNAs
• A plethora of functions
• The Wild West
Chapter 14 The epigenome
• Chromatin structure
• Topological domains
• Enhancers
• Nucleosomes and histones
• Nucleosome remodeling
• Histone modifications
• The histone code
• DNA methylation
• The regulation of development
Chapter 15 The programming of development
• Autopoiesis
• The overarching question
• Tissue architecture and cell identity
• Programmed ontogeny
• Lineage specification
• How much information is required?
• Constraints imposed by the superlinear scaling of regulatory information
• How much information is there in the human genome?
• Genomes as .zip files of transcriptomes
Chapter 16 RNA and repeats rule
• RNA is a core component of chromatin
• Regulation of chromosome structure
• RNA guidance of chromatin remodeling
• Guidance of transcription factors
• Guidance of DNA methylation
• Guidance of histone modifications
• Xist as the exemplar
• Enhancer RNAs and chromatin structure
• RNA scaffolding of phase-separated domains
• An addition to the ancient RNA world hypothesis
• Structure-function relationships in lncRNAs
• A new view of the genome of complex organisms
Chapter 17 Plasticity
• RNA modifications and the unknown epitranscriptome
• The expansion of RNA editing in cognitive evolution
• A>I editing
• C>U editing
• The brain
• RNA-directed transgenerational epigenetic inheritance
Chapter 18 Beyond the jungle of dogmas
• The misunderstanding of molecular biology
• The evolution of evolvability
References
Biography
John Mattick is the Professor of RNA Biology at UNSW Sydney. He obtained his PhD in Biochemistry at Monash University in Melbourne and undertook his postdoctoral training at Baylor College of Medicine in Houston. Most recently he was the Chief Executive of Genomics England, Executive Director of the Garvan Institute of Medical Research in Sydney, and Director of the Institute for Molecular Bioscience, the Australian Genome Research Facility, the ARC Special Research Centre for Molecular and Cell Biology, and the ARC Special Research Centre for Functional and Applied Genomics at the University of Queensland.
His research interests have been focused for the past three decades on the role of regulatory RNAs in the evolution and development of complex organisms. He pioneered the thesis that the majority of the genome of humans and other complex organisms, previously considered to be ‘junk’, is devoted to regulatory RNAs that direct the epigenetic trajectories of differentiation and development. He has published over 300 research articles and reviews, which have been cited over 83,000 times. His work has received editorial coverage in Nature, Science, Scientific American, New Scientist and the New York Times. It has also been highlighted in two books: The Deeper Genome by John Parrington and Promoting the Planck Club by Don Braben.
He has received numerous awards including the International Union of Biochemistry and Molecular Biology Medal, the University of Texas MD Anderson Cancer Center Bertner Award for Distinguished Contributions to Cancer Research, and the Human Genome Organization Chen Medal for Distinguished Achievement in Human Genetics and Genomic Research. He is a Fellow of the Australian Academy of Science, the Royal Society of New South Wales, the Australian Academy of Technology and Engineering and the Australian Academy of Health and Medical Sciences. He is also an Associate Member of the European Molecular Biology Organization.
Paulo Amaral is an Assistant Professor of Bioengineering at Insper in São Paulo, Brazil. He obtained his MSc in Biochemistry at the Institute of Chemistry, University of São Paulo, and PhD in Molecular Genetics at the Institute for Molecular Bioscience, University of Queensland, in Brisbane. He undertook his postdoctoral training at the CRUK/Wellcome Trust Gurdon Institute and Milner Therapeutics Institute, University of Cambridge, supported by a Royal Society and British Academy Newton International Fellowship, Corpus Christi College Research Fellowship and Borysiewicz Biomedical Sciences Fellowship.
He has also taught at different institutions as visiting lecturer at both undergraduate and graduate levels, including at the Karolinska Institutet and Uppsala University in Sweden, and Humanitas University and Università Campus Bio-Medico di Roma in Italy. Since 2004, his research has explored the roles of noncoding DNA, regulatory RNAs and RNA modifications in a variety of biological systems, in both academia and industry. He was one of the first to show that noncoding RNAs associate with chromatin and guide chromatin modifications for gene activation, and has been a longstanding student of the history of molecular biology, especially of the overlooked middleman, but almost certainly the key player, RNA.
“Thrilling and provocative ... There is a need for such a book... There’s nothing quite like this out there.
An epic tale of biology’s central molecule, RNA.
DNA does only one thing, store information. RNA has a thrilling plethora of functions, including telling DNA what to do.
This book takes the reader on an odyssey through the wonders of RNA and its central role in biology.
DNA science dominated the second half of the 20th Century, but it’s clear that the 21st Century belongs to RNA. This long-overdue book reveals the diverse wonders of RNA in a series of thrilling and provocative stories.”
Tom Cech, Nobel laureate, University of Colorado Boulder
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“The book is truly monumental and will be treasured by RNA scientists and others, as well. It beautifully captures the excitement and wonder that I have been lucky to experience working in the RNA field since the early 1960s.”
Joan Steitz, Yale University
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“This book is really disruptive and presents a coherent view of our understanding of biology in terms of the genetic molecules, the nucleic acids, DNA and RNA. It covers an immense territory of molecular biology and its history of discoveries, all presented with a clear-cut intellectual thread.
... It is very timely by its breadth and emphasis on the role of RNA in biology. It makes a strong case for RNA and its late acceptance... the fight uphill, like that of Sisyphus, was tough and demanded a lot of perseverance. It is really rather complete.”
Eric Westhof, University of Strasbourg
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“The book is unique. It provides the long-overdue correction of the still widespread static views on evolution, development and genome organization and function. It has the potential to induce radical changes in widely held views and attitudes.”
Peter Vogt, Scripps Research Institute, La Jolla
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"History is the key to our modern understanding of RNA. This magnum opus describes how science, scientific thought and landmark discoveries revealed the central role of RNA in molecular biology and evolution. The authors are not only modern pioneers of RNA science, but also the best histo-RNA-ians of our time.”
John Rinn, University of Colorado, Boulder
_____________________________________"RNA, the Epicenter of Genetic Information is much more than what its title might suggest. This epic book by Mattick and Amaral superbly reflects the continuing excitement about RNA research. It is not only a description of our current understanding of the role of RNA in cell and developmental biology but is also a useful history of molecular biology. Each of the eighteen chapters is a brilliantly written semi-autonomous essay on a particular segment of the RNA odyssey. I wholeheartedly recommend this book to anybody interested in the biology of RNA, in evolution, and in the organization and function of complex genomes."
Witold Filipowicz, Friedrich Miescher Institute for Biomedical Research, Basel
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"Those who might think that this book is only for the scientists, think again. It is not. It will appeal in equal measure to the thinking generalist and culturally curious interested in the thrilling history of molecular biology, the wonders of the long-overlooked central molecule RNA and its pivotal role in human development and evolution.
An epic, provocative, and highly original book that highlights the way science is so often sidetracked by preconceptions and hubris, and explores the struggle to understand all that junk DNA we were told we had. The junk is not junk! The answers are all there. A story and a journey not to be missed!"Gabriel Farago (USA TODAY Bestselling author of the Jack Rogan Mysteries Series)
