Evolutionary analysis of selective constraints identifies ameloblastin AMBN as a potential candidate for amelogenesis imperfectaReportar como inadecuado

Evolutionary analysis of selective constraints identifies ameloblastin AMBN as a potential candidate for amelogenesis imperfecta - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 Institut des Sciences de l-Evolution, UMR 5554-CNRS 2 Evolution Paris Seine

Abstract : Background: Ameloblastin AMBN is a phosphorylated, proline-glutamine-rich protein secreted during enamel formation. Previous studies have revealed that this enamel matrix protein was present early in vertebrate evolution and certainly plays important roles during enamel formation although its precise functions remain unclear. We performed evolutionary analyses of AMBN in order to i identify residues and motifs important for the protein function, ii predict mutations responsible for genetic diseases, and iii understand its molecular evolution in mammals. Results: In silico searches retrieved 56 complete sequences in public databases that were aligned and analyzed computationally. We showed that AMBN is globally evolving under moderate purifying selection in mammals and contains a strong phylogenetic signal. In addition, our analyses revealed codons evolving under significant positive selection. Evidence for positive selection acting on AMBN was observed in catarrhine primates and the aye-aye. We also found that i an additional translation initiation site was recruited in the ancestral placental AMBN, ii a short exon was duplicated several times in various species including catarrhine primates, and iii several polyadenylation sites are present. Conclusions: AMBN possesses many positions, which have been subjected to strong selective pressure for 200 million years. These positions correspond to several cleavage sites and hydroxylated, O-glycosylated, and phosphorylated residues. We predict that these conserved positions would be potentially responsible for enamel disorder if substituted. Some motifs that were previously identified as potentially important functionally were confirmed, and we found two, highly conserved, new motifs, the function of which should be tested in the near future. This study illustrates the power of evolutionary analyses for characterizing the functional constraints acting on proteins with yet uncharacterized structure.

Keywords : Ameloblastin Evolution Enamel Mammals Purifying selection Positive selection Phylomedicine

Autor: Frédéric Delsuc - Barbara Gasse - Jean-Yves Sire -

Fuente: https://hal.archives-ouvertes.fr/


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