3 Model Organisms in the Study of Development and Disease

T past two decades have brought major breakthroughs in our understanding of the molecular and genetic circuits that control a myriad of developmental events in vertebrates and invertebrates. These detailed studies have revealed surprisingly deep similarities in the mechanisms underlying developmental processes across a wide range of bilaterally symmetric metazoans (bilateralia). Such phylogenetic comparisons have defined a common core of genetic pathways guiding development and have made it possible to reconstruct many features of the most recent common ancestor of all bilateral animals, which most likely lived 600–800 million years ago (Shubin et al., 1997; Knoll and Carroll, 1999). As flushed out in more detail below and reiterated as a major unifying theme throughout the book, the common metazoan ancestor already had in place many of the genetic pathways that are present in modern-day vertebrates and invertebrates. This ancestor can be imagined as an advanced worm-like or primitive shrimp-like creature which had a few distinct body specializations along the nose-to-tail axis and was subdivided into three distinct germ layers (ectoderm, mesoderm, and endoderm). It also had evolved an inductive signaling system to partition the ectoderm into neural versus nonneural components and is likely to have possessed appendages or outgrowths from its body wall with defined anterior–posterior, dorsal–ventral, and proximo–distal axes, as well as light-sensitive organs, a sensory system for detecting vibrations, a rudimentary heart, a molecular guidance system for initiating axon outgrowth to the midline of the nervous system, ion channels for conducting electrical impulses, synaptic machinery required for neural transmission, trachea, germ cells, and an innate immune system. The fact that the ancestor of vertebrate and invertebrate model organisms was a highly evolved creature which had already invented complex interacting systems controlling development, physiology, and behavior has profound implications for medical genetics. The central points that we explore in this chapter can be broadly put into two categories: (1) the great advantages of model organisms for identifying and understanding genes that are altered in heritable human diseases and (2) the functions of many of those genes and the evidence that they were present in the ancestral bilateral organisms and have remained largely intact in both vertebrate and invertebrate lineages during the ensuing course of evolution. In the course of discussing these points, we review the compelling evidence that developmentally important genes have been phylogenetically conserved and the likelihood that developmental disorders in humans will often involve genes controlling similar morphogenetic processes in vertebrates and invertebrates. A systematic analysis of human disease gene homologs in Drosophilasupports this view since 75% of human disease genes are structurally related to genes present in Drosophila and more than a third of these human genes are highly related to their fruit fly counterparts (Bernards and Hariharan, 2001; Reiter et al., 2001; Chien et al., 2002). Since its inception, the field of human genetics has focused on the identification of genes that, as single entities, can cause disease when mutated. The discovery of such new disease genes has advanced at an accelerating pace in the last decade, and the rate is now over 175 genes per year (Peltonen and McKusick, 2001). This rate is likely to accelerate even further in the near term because of the sequencing of human genome. Most of the 4000–5000 estimated human disease genes should be identified before long. In anticipation of this asymptotic discovery process, the emphasis in human genetics is shifting to understanding the function of these disease genes. An obvious avenue for functional analysis of disease genes is to study them in the closely related mouse using gene knockout techniques to assess the effects of either eliminating the gene’s function or inducing specific disease-causing mutations. In some cases, this type of analysis has resulted in excellent mouse models for diseases that have phenotypes very similar to human diseases. In other cases, mouse knockout mutations have been less informative than hoped, either because the greater genetic redundancy in vertebrates masks the effect of mutations in single genes or because the mutations of interest are lethal at an early embryonic stage. Since there are limitations to the mouse system and there are deep ancestrally derived commonalities in the body plan organization and physiology of vertebrate and invertebrate model organisms, particularly flies and nematodes for which there are well-developed and powerful molecular genetic tools, these organisms are likely to play an increasingly important role in the functional analysis of human disease genes. This chapter also compares the strengths and weaknesses of several well-developed model systems, ranging from single-cell eukaryotes to primates, as tools for dissecting the function of human disease genes. We propose that multiple model systems can be employed in cross-genomic analysis of human disease genes to address different kinds of issues, such as basic eukaryotic cellular functions (e.g., yeast and slime molds), assembly of genes into various types of molecular machines and pathways (e.g., flies and nematodes), and accurate models of human disease processes (e.g., vertebrates such as zebrafish and mice).