Über die Autorin bzw. den Autor

Dr. Patrizia Ferretti. Developmental Biology Unit, Institute of Child Health, University College London.

Prof. Andrew Copp (Dean of Institute). Neural Development Unit, Institute of Child Health, University College London.

Prof. Cheryll Tickle. Professor of Anatomy & Physiology, The Wellcome Trust Building, University of Dundee.

Prof. Gudrun Moore. Institute of Child Health, University College London.

The editors are all distinguished developmental biologists with a broad range of expertise in human birth defects. Andrew Copp holds an endowed chair in Developmental Neurobiology at University College London and is Dean of the world-renowned Institute of Child Health.

Von der hinteren Coverseite

In the Western world, birth defects constitute the greatest single cause of infant mortality and a significant cause of infant morbidity, with a major impact on healthcare services and the affected families. Birth defects are the consequence of defective embryonic development that can be due to genetic, epigenetic or teratogenic factors.

The first edition of Embryos, Genes and Birth Defects, edited by the late Peter Thorogood, was a radical new book aimed at bridging the gap between the medical disciplines of embryology and dysmorphology, and recent advances in cellular, molecular and developmental biology. This new edition remains unique in its breadth and brings up to date our understanding of birth defects and of the strategies utilized to gain such knowledge. It features new chapters on human cytogenetics, mutagenesis and the yes and ears.

The book present key topics in developmental biology and explains how they provide the foundations of an understanding of clinical birth defects. The first six chapters introduce concepts and strategies adopted to elucidate developmental anomalies leading to birth defects. The book then focuses on specific organs and reviews the cellular and molecular mechanisms affecting their development and how disruption of these mechanisms by genetic or environmental factors may underlie certain birth defects. The chapters are concise and provide an up to date coverage of topics in a format that is easily accessible and yet at the forefront of research.

Written primarily for paediatricians, obstetricians, clinical geneticists and allied workers, this book guides the reader through the contribution of modern molecular biology to our understanding of human development. Developmental and cellular biologists will learn how errors in cellular and genetic mechanisms can lead to classical disorders, diseases and syndromes.

Aus dem Klappentext

In the Western world, birth defects constitute the greatest single cause of infant mortality and a significant cause of infant morbidity, with a major impact on healthcare services and the affected families. Birth defects are the consequence of defective embryonic development that can be due to genetic, epigenetic or teratogenic factors.

The first edition of Embryos, Genes and Birth Defects, edited by the late Peter Thorogood, was a radical new book aimed at bridging the gap between the medical disciplines of embryology and dysmorphology, and recent advances in cellular, molecular and developmental biology. This new edition remains unique in its breadth and brings up to date our understanding of birth defects and of the strategies utilized to gain such knowledge. It features new chapters on human cytogenetics, mutagenesis and the yes and ears.

The book present key topics in developmental biology and explains how they provide the foundations of an understanding of clinical birth defects. The first six chapters introduce concepts and strategies adopted to elucidate developmental anomalies leading to birth defects. The book then focuses on specific organs and reviews the cellular and molecular mechanisms affecting their development and how disruption of these mechanisms by genetic or environmental factors may underlie certain birth defects. The chapters are concise and provide an up to date coverage of topics in a format that is easily accessible and yet at the forefront of research.

Written primarily for paediatricians, obstetricians, clinical geneticists and allied workers, this book guides the reader through the contribution of modern molecular biology to our understanding of human development. Developmental and cellular biologists will learn how errors in cellular and genetic mechanisms can lead to classical disorders, diseases and syndromes.

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Embryos, Genes and Birth Defects

John Wiley & Sons

Chapter One

Philip Stanier and Gudrun Moore

Introduction

Without even considering early fetal loss, it is reported that as many as 3.5% of all live-born babies have some kind of major abnormality, referred to as a birth defect. Actual incidences may vary according to locality, culture, ethnicity and the efficiency of recognition and reporting. If minor abnormalities such as cleft lip are included, then the incidence is nearer to 5%. In the Western world, birth defects constitute the greatest single cause of infant mortality and have a major impact on national health care budgets (http://www.modimes.org/).

In this introductory chapter some basic precepts and concepts are presented and explained. For a comprehensive introduction to embryonic development per se, the reader is referred to any one of several excellent publications that already exist (e.g. Alberts et al., 2002; Gilbert, 2003; Wolpert, 2002). What this chapter attempts to provide is the information that might be necessary for a clinician or advanced student specializing in paediatric medicine to understand and appreciate in context what follows. In that sense, an element of unorthodoxy might be discerned by some readers. However, we hope that this rationale will be justified as the reader progresses through the book.

The relationship between genotype and phenotype

The term 'genotype' is generally used to refer to the genetic make-up or constitution of an individual organism, be it virus, fruit fly or human. In contrast, we use the word 'phenotype' to cover the form and functioning of an individual, to the extent that it may encompass metabolism and behaviour (and thus we can refer to 'behavioural phenotypes'). The word 'genotype' is subtly but distinctly different from the term 'genome', which refers not to the totality of genes in an individual cell but to the array of genes in a complete haploid set of genes characteristic for that species. In this sense, a genome is a species-specific concept, whereas genotype is a concept applying to an individual of the species in question.

The complexity of the phenotype reflects largely but not entirely the complexity of the genotype. However, there is not necessarily a simple and direct relationship, since genome size and genome complexity are rather different entities. Overall genome size, in terms of DNA, is to some extent determined by the relative proportion of non-protein coding sequences contained within it. Thus, some plant, insect and amphibian species contain far more total DNA in their genomes than does Homo sapiens, even though they are phenotypically simpler and contain fewer genes (indeed, some amphibian species contain up to 9 x [10.sup.11] nucleotide bases per haploid genome, as opposed to the 2:85 x [10.sup.9] nucleotides recently sequenced in humans; International Human Genome Sequencing Consortium, 2004). Much of this increase in DNA content is thought to represent a greater than normal proportion of non-coding, repetitive sequences. If we consider genome complexity in terms of the number of genes present, then a more systematic relationship emerges. In simple organisms, such as viruses, the limited number of genes in the genome can be accurately determined. However, for more complex multicellular organisms, total gene number is an estimate based on confirmed genes and potential coding regions identified by predictive methods. Therefore, the size of these estimates has changed as our ability to visualize the DNA sequence and our understanding of genomic organization has evolved. Currently, Drosophila melanogaster, the fruit fly, is estimated to contain some 14 000 genes in its genome, whereas the genome of Homo sapiens is thought to comprise between 20 000 and 25 000. However, this latter set of figures is still subject to revision and does not take into account the considerable protein variation that can accrue from alternate usage and splicing of exons or the existence of functional non-coding RNAs.

Whereas gene mapping refers to identification of the chromosomal location of an individual gene, genome mapping is a programme of research designed to identify the chromosomal location of all genes in the genome of a particular species. Although it is the international Human Genome Project that has received wide media attention, it should be noted that genome mapping projects for other species are also under way or recently completed. These include a number of model organisms, such as the mouse, fruitfly, toad and nematode worm, as well as those of economically important food species, such as cow, pig and chicken (http://www.ncbi.nlm.nih.gov/Genomes/ index.html). The mapping of individual genes, or of candidate gene loci, means that chromosomal 'maps' of congenital abnormality can be drawn up (see Chapters 2, 3 and 4; also OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM), whereby the location of genes, in which mutation produces a particular dysmorphology or inherited metabolic disease, can be displayed (Figure 1.1).

At this point we should ask ourselves what kind of information is encoded within the genes. Are the genes really the 'blueprint' to which they are often analogized? A blueprint implies some kind of descriptive specification. Is that indeed how the genome is organized? In fact, the information content of genes is one-dimensionally complex, since it is specified by the nature of the linear sequence of nucleotide bases along the DNA molecule. In dramatic contrast, the phenotype is three-dimensionally complex (and four-dimensionally complex if we include dynamic phenomena, such as metabolism and homeostasis, rather than just morphology); yet the linear nucleotide sequence itself conveys no sense of what the phenotype might look like. To appreciate just how phenotypic complexity might be generated we have to move away from the rather dated analogy of a descriptive specification and think of the genome and its implementation as a generative programme. The more appropriate and meaningful analogy of origami has been proposed to illustrate the characteristics of a generative programme (Wolpert, 1991). Here, the instructions for creating a topologically complex shape from a sheet of paper contain within them no description of the final outcome. The complexity is generated progressively by implementing those instructions, which may in themselves be very simple, even though the outcome is complex. In this way, the genome, or at least the developmentally significant parts of it, can be seen as assembly rules for building an embryo.

In one sense, genes 'simply' encode proteins. Transcription of a gene produces a message that is translated from the four-letter alphabet (nucleotides) of the nucleic acids to the approximately 20-letter alphabet (amino acids) of the proteins, by virtue of the genetic code. The primary structure of a protein, i.e. the linear sequence of amino acids, together with any post-translational modifications, determines its secondary and tertiary structure. Proteins endow cells with properties such as characteristic metabolisms, behaviour, polarity, adhesiveness and receptivity to signals (Figure 1.2) and it is this functional level that marks the implementation of those assembly rules. Within the increasingly multicellular embryo, cell interactions and inductions are initiated, cell lineages are established, and morphogenesis, growth and...