Evolutionary Analysis of Mammalian Enamelin, The Largest Enamel Protein, Supports a Crucial Role for the 32-kDa Peptide and Reveals Selective Adaptation in Rodents and Primates

  • Nawfal Al-Hashimi
  • Jean-Yves Sire
  • Sidney Delgado


Enamelin (ENAM) plays an important role in the mineralization of the forming enamel matrix. We have performed an evolutionary analysis of mammalian ENAM to identify highly conserved residues or regions that could have important function (selective pressure), to predict mutations that could be associated with amelogenesis imperfecta in humans, and to identify possible adaptive evolution of ENAM during 200 million years ago of mammalian evolution. In order to fulfil these objectives, we obtained 36-ENAM sequences that are representative of the mammalian lineages. Our results show a remarkably high conservation pattern in the region of the 32-kDa fragment of ENAM, especially its phosphorylation, glycosylation, and proteolytic sites. In primates and rodents we also identified several sites under positive selection, which could indicate recent evolutionary changes in ENAM function. Furthermore, the analysis of the unusual signal peptide provided new insights on the possible regulation of ENAM secretion, a hypothesis that should be tested in the near future. Taken together, these findings improve our understanding of ENAM evolution and provide new information that would be useful for further investigation of ENAM function as well as for the validation of mutations leading to amelogenesis imperfecta.


Enamelin Evolution Teeth Mammals Purifying selection Positive selection 



We thank Mehboob Chilwan (Erasmus, University of Keele, UK) for English corrections. This work was supported by CNRS and UPMC (UMR 7138) Grants.

Supplementary material

239_2009_9302_MOESM1_ESM.doc (120 kb)
Amino acid alignment of the 36 mammalian ENAMs analyzed. The sequences were aligned against the human sequence and are ordered following the mammalian relationships shown in Fig. 3. The 24 complete sequences are indicated in bold characters. This alignment leads to 1,550 positions (including all gaps). The signal peptide (exons 3 and 4) is underlined. Remarkably conserved residues and motifs are on gray background.][: exon limits; (.): residue identical to human ENAM residue; (−): indel; (=): unknown amino acid; (#): the 77 residues identical in all sequences; (+): the 10 site-specific positive selection in human ENAM (see also Figs. 5 and 7).(DOC 120 kb)
239_2009_9302_MOESM2_ESM.doc (78 kb)
Comparison of the 20 nucleotides located at the 5′ and 3′ UTR, and at both splice sites of introns 3–9 in ten ENAM sequences of species representative of the main mammalian lineages. Conserved positions are indicated in bold characters. Three mutations at the splicing sites (boxed bp) are known to lead to AIH2 (see Fig. 1).(DOC 78 kb)
239_2009_9302_MOESM3_ESM.doc (70 kb)
Substitution rates calculated for 22 mammalian ENAMs taken two by two using the HyPhy program.(DOC 69 kb)


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Nawfal Al-Hashimi
    • 1
  • Jean-Yves Sire
    • 1
  • Sidney Delgado
    • 1
  1. 1.Université Pierre et Marie Curie, UMR 7138—Systématique, Adaptation, EvolutionParisFrance

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