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Please use this identifier to cite or link to this item: http://hdl.handle.net/2262/41243

Title: Mutational dynamics of murine angiogenin duplicates
Author: FARES, MARIO ALI
Sponsor: 
Name Grant Number
238885
04/YI1/M518

Author's Homepage: http://people.tcd.ie/faresm
Keywords: AMYOTROPHIC-LATERAL-SCLEROSIS
SITE-DIRECTED MUTAGENESIS
DETECT SELECTIVE CONSTRAINTS
RIBONUCLEASE-A SUPERFAMILY
FUNCTIONAL DIVERGENCE
STRUCTURAL FEATURES
MONOCLONAL-ANTIBODY
TUMOR-GROWTH
Issue Date: 2010
Citation: Codoner, FM, Alfonso-Loeches, S, Fares, MA, Mutational dynamics of murine angiogenin duplicates, BMC Evolutionary Biology, 10, 1, 2010, 310
Series/Report no.: BMC Evolutionary Biology
10
1
Abstract: Background: Angiogenin (Ang) is a protein involved in angiogenesis by inducing the formation of blood vessels. The biomedical importance of this protein has come from findings linking mutations in Ang to cancer progression and neurodegenerative diseases. These findings highlight the evolutionary constrain on Ang amino acid sequence. However, previous studies comparing human Angiogenin with homologs from other phylogenetically related organisms have led to the conclusion that Ang presents a striking variability. Whether this variability has an adaptive value per se remains elusive. Understanding why many functional Ang paralogs have been preserved in mouse and rat and identifying functional divergence mutations at these copies may explain the relationship between mutations and function. In spite of the importance of testing this hypothesis from the evolutionarily and biomedical perspectives, this remains yet unaccomplished. Here we test the main mutational dynamics driving the evolution and function of Ang paralogs in mammals. Results: We analysed the phylogenetic asymmetries between the different Ang gene copies in mouse and rat in the context of vertebrate Ang phylogeny. This analysis shows strong evidence in support of accelerated evolution in some Ang murine copies (mAng). This acceleration is not due to non-functionalisation because constraints on amino acid replacements remain strong. We identify many of the amino acid sites involved in signal localization and nucleotide binding by Ang to have evolved under diversifying selection. Compensatory effects of many of the mutations at these paralogs and their key structural location in or nearby important functional regions support a possible functional shift (functional divergence) in many Ang copies. Similarities between 3D-structural models for mAng copies suggest that their divergence is mainly functional. Conclusions: We identify the main evolutionary dynamics shaping the variability of Angiogenin in vertebrates and highlight the plasticity of this protein after gene duplication. Our results suggest functional divergence among mAng paralogs. This puts forward mAng as a good system candidate for testing functional plasticity of such an important protein while stresses caution when using mouse as a model to infer the consequences of mutations in the single Ang copy of humans.
Description: PUBLISHED
URI: http://hdl.handle.net/2262/41243
Access: OpenAccess
info:eu-repo/semantics/openAccess
Appears in Collections:Genetics (Scholarly Publications)

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