Clustering of Genetically Defined Allele Classes in the Caenorhabditis elegans DAF-2 Insulin/IGF-1 Receptor

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Clustering of Genetically Defined Allele Classes in the Caenorhabditis elegans DAF-2 Insulin/IGF-1 Receptor Powered By Docstoc
					Copyright Ó 2008 by the Genetics Society of America
DOI: 10.1534/genetics.107.070813



       Clustering of Genetically Defined Allele Classes in the Caenorhabditis
                      elegans DAF-2 Insulin/IGF-1 Receptor

              Dhaval S. Patel,*,1 Acely Garza-Garcia,†,‡ Manoj Nanji,* Joshua J. McElwee,*,2
                        Daniel Ackerman,* Paul C. Driscoll†,‡ and David Gems*,3
 *Department of Biology, and †Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United
      Kingdom and ‡Division of Molecular Structure, National Institute for Medical Research, London NW7 1AA, United Kingdom
                                                     Manuscript received January 11, 2007
                                                 Accepted for publication November 27, 2007


                                                              ABSTRACT
                The DAF-2 insulin/IGF-1 receptor regulates development, metabolism, and aging in the nematode
             Caenorhabditis elegans. However, complex differe
				
DOCUMENT INFO
Description: The DAF-2 insulin/IGF-1 receptor regulates development, metabolism, and aging in the nematode Caenorhabditis elegans. However, complex differences among daf-2 alleles complicate analysis of this gene. We have employed epistasis analysis, transcript profile analysis, mutant sequence analysis, and homology modeling of mutant receptors to understand this complexity. We define an allelic series of nonconditional daf-2 mutants, including nonsense and deletion alleles, and a putative null allele, m65. The most severe daf-2 alleles show incomplete suppression by daf-18(0) and daf-16(0) and have a range of effects on early development. Among weaker daf-2 alleles there exist distinct mutant classes that differ in epistatic interactions with mutations in other genes. Mutant sequence analysis (including 11 newly sequenced alleles) reveals that class 1 mutant lesions lie only in certain extracellular regions of the receptor, while class 2 (pleiotropic) and nonconditional missense mutants have lesions only in the ligand-binding pocket of the receptor ectodomain or the tyrosine kinase domain. Effects of equivalent mutations on the human insulin receptor suggest an altered balance of intracellular signaling in class 2 alleles. These studies consolidate and extend our understanding of the complex genetics of daf-2 and its underlying molecular biology. [PUBLICATION ABSTRACT]
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