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American Journal of Medical Genetics 108:341±342 2002) Book Review GENOMIC REGULATORY SYSTEMS: DEVELOPMENT AND EVOLUTION. By Eric H. Davidson, Academic Press, San Diego, California 201p. The ®rst revolution in developmental genetics has settled into frenetic normalcy. Its goals have been nothing less than the identi®cation of those proteins and DNA sequences that regulate differential gene expression. The results of this revolution have been phenomenal. We now know many of the critical trans- cription factors that control the expression of devel- opmentally important genes, the DNA sequences in the enhancers and promoters to which they bind, and the signal transduction pathways that activate them. And in this brief 201 page) volume, Eric Davidson re¯ects upon what it all means. Davidson is perfectly situated to abstract the logic of developmental regulation from the enormous volume of relevant data. Davidson was one of the instigators of the revolution in developmental genetics, and this book can be read as the ful®llment of the prophecies he made in the late 1960s and early 1970s. Davidson sees the ``wiring systems'' of signaling cascade/transcription factor/cis-regulatory element as the core of animal development and evolution. The ®rst principles Davidson elaborates concern the modularity and Boolean logic of the cis-regulatory elements. These are the DNA sequences that constitute the promoter and enhancer, and which instruct the gene to become expressed only at speci®c times and places. There are different elements, each responding to a set of transcription factors. When the nucleus resides in a cell containing these transcription factors, the gene containing these regulatory elements becomes activated. These transcription factors can be the pro- duct of acquisition through cell lineage or the result of signaling between cells. By having different cis-reg- ulatory sequences, a particular gene can become activated at several places and tissues during develop- ment. In addition to this Boolean ``or'' logic, there is also ``and'' logic in these regulatory units. These ``and'' cis- regulatory sequences will activate the gene only if an entire set of transcription factors are present. Activa- tion is combinatorial, and ``master regulatory genes'' need not apply. Moreover, since there also exist silencer proteins that can act as negative transcriptional regulators, the ``and not'' logic is also present. Certain genes will become active in a particular cell if transcription factor set A, but not set B, is present. The regulatory units of the genes act as information processors, analogous to dendrites of neurons, where multiple inputs are sensed and integrated such that a single output in this case, either transcription or no transcription) is produced. Thus, Davidson shows instances where the regulation of gene expression can be seen as a logic circuit. Davidson's second set of principles concern the depth of regulatory information. The earliest organisms, as well as many of our contemporary invertebrates, have a ``shallow'' circuitry wherein the inputs are readily integrated by a few genes that regulate particular bat- teries of genes. In this way, transcription factors inherited through cell lineage or activated through induction can provide the information needed for the complete differentiation of that cell. In more complex organisms, there are intermediary stages, wherein the initial transcription factors act to parse off bodily regions. These regions can interact, thereby activating the expression or function of another set of transcrip- tion factors. These can further subdivide the domains, or they can initiate the expression of those batteries of genes that cause the differentiated proteins of the particular cell type to emerge. Here, readers of the American Journal of Medical Genetics will recognize the morphogenetic ®eld concept, and Davidson has been a long time proponent of such regionally speci®c developmental domains. Davidson's last points involve the mechanisms of evolutionary change. Whether small or large, morpho- logical evolution consists of changes in the cis-regula- tory circuitry of the genome. He analyzes several important evolutionary systems and provides thought- ful discussions of what developmental genetics has done to our concepts of homology and genetic co-option, ``The ®elds of development and evolution are conver- gent,'' he says, ``because both subjects are rooted in the genomic regulatory programs for body part formation.'' It is unfortunate that Davidson does not include teratogenesis in his account. Indeed, since the genetic circuitry of humans qua humans, not qua mammals) is still relatively unknown, the genus Homo does not make an appearance in this book. There are other frustrating problems: the ®gures might be several pages distant from their respective legends and text, there is nothing concerning the roles of environmental context in the regulatory circuits, and there is no discussion of non-transcriptional gene regulation. However, for the person fascinated by development and what all this new research means, DOI 10.1002/ajmg.10273 ß 2002 Wiley-Liss, Inc.

Genomic Regulatory Systems: Development and Evolution, by Eric H. Davidson

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