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.
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