MBE Advance Access published online on February 29, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn036
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Research Article |
Evolution of the insulin receptor family and of receptor isoform expression in vertebrates
1 3D Lab (Development, Differentiation & Degeneration), Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, E-28040 Madrid, Spain
2 CIBERDEM, ISCIII
3 Departmento de Biodiversidad y Biología Evolutiva, Museo Nacional de Ciencias Naturales, José Gutiérrez Abascal, 2, E-28006 Madrid, Spain
# Author for correspondence: Catalina Hernández-Sánchez, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, E-28040 Madrid, Spain. E-mail: chernandez{at}cib.csic.es; Tel/Fax: 34 91 534 9201
Received for publication November 7, 2007. Revision received January 14, 2008. Accepted for publication January 29, 2008.
The molecular phylogeny of the vertebrate insulin receptor family was reconstructed under maximum likelihood (ML) to establish homologous relationships among its members. A sister group relationship between the orphan insulin related receptor (IRR) and the insulin-like growth factor 1 receptor (IGF1R) to the exclusion of the insulin receptor (IR) obtained maximal bootstrap support. While both IR and IGF1R were identified in all vertebrates, IRR could not be found in any teleost fish. The ancestral character states at each position of the receptor molecule were inferred for IR, IRR+IGF1R, and all three paralogous groups based on the recovered phylogeny using ML in order to determine those residues that could be important for the specific function of IR. For 18 residues, ancestral character state of IR was significantly distinct (posterior probability >0.95) with respect to the corresponding inferred ancestral character states both of IRR+IGF1R, and of all three vertebrate paralogs. Most of these IR distinct (shared-derived) residues were located on the extracellular portion of the receptor (because this portion is larger and the rate of generation of IR shared-derived sites is uniform along the receptor), suggesting that functional diversification during the evolutionary history of the family was largely generated modifying ligand affinity rather than signal transduction at the tyrosine kinase domain. In addition, two residues at positions 436 and 1095 of the human IR sequence were identified as radical cluster-specific sites in IRR+IGF1R. Both Ir and Irr have an extra exon (namely exon 11) with respect to Igf1r. We used the molecular phylogeny to infer the evolution of this additional exon. The Irr exon 11 can be traced back to amphibians whereas we show that presence and alternative splicing of Ir exon 11 seems to be restricted exclusively to mammals. The highly divergent sequence of both exons and the reconstructed phylogeny of the vertebrate insulin receptor family strongly indicate that both exons were acquired independently by each paralog.
Key Words: Insulin receptor • alternative splicing • ancestral character states