Model Organisms in Drug Discovery

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FORWARD GENETICS IN THE DISCOVERY OF NEW PATHWAYS 239 Figure 9.5 Schematic representation of a typical breeding protocol. In a recessive screen, mutant alleles are propagated in a heterozygous state from G1 to G2 (A, B), and homozygote animals (C) derived from G2 inter- or backcrosses are screened for variant phenotypes. Note that each G1 animal generates a separate micro-pedigree, in which mutations m1–m4 segregate
240 CHEMICAL MUTAGENESIS IN THE MOUSE In theory, a recessive screen would require 1000 G3 pedigrees for onefold genome coverage, i.e. analysis of 30–35 000 mutations. Because the analysis of 10–15 animals per pedigree will only allow the recovery of about 50% of the segregating phenotypes, and a larger number of animals per pedigree would provide diminishing returns, the observation of 2000 pedigrees is required in practice. Although the phenotyping of 20–30 000 animals is a substantial effort, this scale can be achieved readily in an industrial setting. A typical physiological pathway can be estimated to have 5–10 components, so a recessive screen of only 0.3–0.5-fold coverage has a high likelihood to provide at least one hit in each pathway. Although only preliminary data have been reported from recessive screens investigating postnatal phenotypes, a number of results from screens for recessive mutations affecting development (Kasarskis et al., 1998; Hentges et al., 1999; Zoltewicz et al., 1999; Anderson, 2000; Herron et al., 2002) have been published. Examples include the identification of a mutation in the FRAP/mTOR gene as the cause of the flat-top phenotype (Hentges et al., 2001), and alterations of Rab23 (Eggenschwiler et al., 2001) in the open brain mutation (Sporle et al., 1996; Gunther et al., 1997; Sporle and Schughart, 1998). Screens for specific chromosomal regions Region-specific screens use large deletions or inversions to facilitate the recovery of recessive mutations. By breeding ENU-treated males with females carrying specific chromosomal deletions, recessive mutations induced in the hemizygous region are uncovered and can be identified in G1 animals (Rinchik et al., 1990; Rinchik and Carpenter, 1999). The advantages are the simple breeding scheme and the fact that mutations are immediately mapped by failing to complement the deletion. The application of this strategy is limited by the availability of chromosomal deletions. A very elegant improvement of the region-specific screen design is the use of genetically engineered balancer chromosomes carrying large inversions. This scheme also requires a three-generation breeding scheme and has been reviewed in detail by Justice (Justice, 2000). The role of mutagenesis in the analysis of quantitative traits Substantial effort has been put into analysis of the molecular basis of quantitative trait loci (QTL) occurring spontaneously as differences between inbred strains of mice and rats (Stoll et al., 2001). Analyzing a QTL in a model organism requires three major steps: genetic mapping of the chromosomal
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Model Organisms in Drug Discovery M
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Copyright u 2003 John Wiley & Sons
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Contents List of contributors .....
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CONTENTS ix 7 Genetics and Genomics
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List of Contributors Hector Beltran
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LIST OF CONTRIBUTORS xiii Stefan Sc
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1 Introduction to Model Systems in
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Organism INTEGRATING MODEL ORGANISM
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INTEGRATING MODEL ORGANISM RESEARCH
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INTEGRATING MODEL ORGANISM RESEARCH
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10 GROWING YEAST FOR FUN AND PROFIT
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3 Caenorhabditis elegans Functional
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THE DRUG DISCOVERY PROCESS 43 thoug
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multivulva phenotype of Ras gain-of
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disease. These molecular targets ar
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FROM DISEASE TO TARGET 49 Figure 3.
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FROM DISEASE TO TARGET 51 Figure 3.
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signaling pathway. The third catego
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FROM DISEASE TO TARGET 55 resistant
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phenomenon was first observed in C.
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profiles. The C. elegans gene expre
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emerging technologies. Forward gene
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The compound library LEAD DISCOVERY
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LEAD DISCOVERY 65 previous section,
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LEAD DISCOVERY 67 Figure 3.5 Distri
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Compound learning set for assay val
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10 000-15 000 human drug targets ar
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transporter itself. The SSRIs that
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REFERENCES 75 de Montigny, C., Blie
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REFERENCES 77 Lewis, J. A., Wu, C.
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REFERENCES 79 Tissenbaum, H. A. and
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82 DROSOPHILA AS A TOOL FOR DRUG DI
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100 DROSOPHILA AS A TOOL FOR DRUG D
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5 Drosophila - a Model System for T
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EVOLUTIONARY CONSERVATION OF DISEAS
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TARGET IDENTIFICATION/TARGET VALIDA
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CHEMICAL GENETICS 143 acid identity
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3. A hit identifies a biologically
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about their function in a multicell
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REFERENCES 149 Han, Z. S., Enslen,
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REFERENCES 151 Rintelen, F., Stocke
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
Page 193 and 194: 186 GENETICS AND GENOMICS IN THE ZE
Page 209 and 210: 8 Lipid Metabolism and Signaling in
Page 211 and 212: FISH AS A MODEL ORGANISM 205 genes
Page 213 and 214: LIPID METABOLISM SCREEN 207 transpo
Page 215 and 216: LIPID METABOLISM SCREEN 209 Figure
Page 217 and 218: the embryo media containing radioac
Page 219 and 220: ZEBRAFISH AS A MODEL SYSTEM 213 Fig
Page 221 and 222: ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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Page 225 and 226: REFERENCES 219 Chau, I. and Cunning
Page 227 and 228: REFERENCES 221 Patrono, C., Patrign
Page 229 and 230: 224 CHEMICAL MUTAGENESIS IN THE MOU
Page 243: 238 CHEMICAL MUTAGENESIS IN THE MOU
Page 257 and 258: 252 SATURATION SCREENING OF DRUGGAB
Page 285 and 286: 280 INDEX bupropion 92 busulfan 143
Page 287 and 288: 282 INDEX Dscam 171 dual-energy X-r
Page 289 and 290: 284 INDEX L-685,818 16 lead discove
Page 291 and 292: 286 INDEX protein function 19-22 pr
Page 293: 288 INDEX yeast (continued) functio
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