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Originally published as Genetics Published Articles Ahead of Print on February 1, 2008.
Genetics, Vol. 178, 931-946, February 2008, Copyright © 2008
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
3 Corresponding author: Department of Biology, University College London, Gower St., London WC1E 6BT, United Kingdom.
E-mail: david.gems{at}ucl.ac.uk
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.
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