Ingenious Genes: How Gene Regulation Networks Evolve to Control Development

Preface

Preface You are a collection of more than 10 trillion (1013 ) cells, busy performing many tasks on which your continued existence depends. That is impressive enough, but consider too your history. You began as a single cell that repeatedly divided and differentiated to produce about a hundred cell types, as different as bone and neuron, arranged together in just the right way. This complex and delicate process may be commonplace, but it should be no less awe-inspiring for that. What is it that allows cells to pull off a trick as difficult as development? Your genes are involved in the production of proteins that perform many cellular tasks. Most catalyze chemical reactions; some provide the building blocks for the rest of you; others work together to turn on and off the production of proteins made with other genes. These genes are called transcription factors. Their regulation of gene expression is crucial to overcoming the difficulty of development. Your gene regulation network is contained in each cell, and the same network had to produce the right gene activity in the great variety of situations that the great variety of cells in your body have faced, all the way back to that first cell. Genes working together make up a truly ingenious system. How does the system work? How did it come about? This book proposes answers to those questions. The first question is about how gene regulation occurs during development . How can a fundamentally simple system of genes turning each other on and off result in the right outcomes to such a variety of challenges? I propose that the key lies in how multiple transcription factors combine to regulate a simple gene. They act in a qualitatively consistent way. This means that each transcription factor is either always promoting the expression of a gene or always inhibiting that expression. This way of acting x Preface together is similar to the way neurons act in the brain to allow good outcomes to a variety of situations you face. Multiple transcription factors acting together in this way allow the expression of genes to be finely tuned to the variable microenvironments of cells. How did you come to have such a refined simple system? Darwin’s theory of evolution by natural selection is half of the answer to that question . Your ancestors’ gene regulation networks accrued many adaptive mutations. Those mutations were unguided but lucky. The majority of unguided mutations to any system will do more harm than good, but some systems are virtually impossible to be improved in this way. I argue that gene regulation networks are quite the opposite. They are highly evolvable, with an impressively high chance of improvement by unguided mutation. The reason for this also boils down to the qualitative consistency of gene regulation networks, which allows mutations that add or remove transcription factors to have only small effects on the regulation of specific genes. Mutations that have small effects are more likely to be adaptive than mutations that have large effects. Therefore, the qualitative consistency of gene regulation networks allows them to be highly evolvable. This book begins with some history of evolutionary theory, with a particular emphasis on explanations of organisms’ adaptive complexity and evolvability. Much of the book concerns models or frameworks for thinking about gene regulation networks. Two frameworks for gene regulation networks are described in detail. The first was developed by Stuart Kauffman, who has argued that gene regulation networks are fundamentally systems that repeat patterns of gene expression. I criticize Kauffman’s framework as inadequate to explain how gene regulation networks overcome the difficulty of development. I propose a second framework, which I call the connectionist framework. In so doing, I borrow work done in the fields of artificial intelligence and philosophy of mind and apply it to gene regulation. Finally, I try to bring this work to bear on how we should understand the developmental process that produced each of us. I propose that we gain insight when we identify gene regulation networks as the controller of development. This is due to both the nature and the evolution of development. The ingenuity of genes is explained by how gene regulation networks evolve to control development. ...