MEPE evolution in mammals reveals regions and residues of prime functional importance

Abstract

In mammals, the matrix extracellular phosphoglycoprotein (MEPE) is known to activate osteogenesis and mineralization via a particular region called dentonin, and to inhibit mineralization via its ASARM (acidic serine-aspartate rich MEPE-associated motif) peptide that also plays a role in phosphatemia regulation. In order to understand MEPE evolution in mammals, and particularly that of its functional regions, we conducted an evolutionary analysis based on the study of selective pressures. Using 37 mammalian sequences we: (1) confirmed the presence of an additional coding exon in most placentals; (2) highlighted several conserved residues and regions that could have important functions; (3) found that dentonin function was recruited in a placental ancestor; and (4) revealed that ASARM function was present earlier, pushing the recruitment of MEPE deep into amniote origins. Our data indicate that MEPE was involved in various functions (bone and eggshell mineralization) prior to acquiring those currently known in placental mammals.

What Makes an Egg Unique? Clues from Evolutionary Scenarios of Egg-Specific Genes1

“…S2A). This hypothesis is widely supported by several studies [11,41,42] and by our synteny analysis showing that in the G. gallus (also for M. gallopavo and T. guttata), OC-116 is localized in a mineralization-specific gene cluster (including bone sialoproteins and dentin matrix acidic phosphoprotein 1) on chromosome 4 and that this gene cluster is conserved between birds and mammals (Supplemental Fig. S2B).…”

“…The structure of OC-116 clearly shows that this gene belongs to the secretory calcium-binding phosphoprotein (SCPP) gene family, which is associated with the tissue mineralization in vertebrates [41]. In spite of the sequences of SCPP protein family being highly divergent, thanks to multiple sequence alignment based on exon conservation presented in Bardet's study [42], we were able to rebuild a phylogenetic tree. It seems to indicate a homology relationship between OC-116 and other SCPP proteins (Supplemental Fig.…”

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

“…To validate the potential role of these mutations, hence to predict sensitive positions in MMP20, we analyzed a large set of representative mammalian lineages sequences, covering over 150 million years of evolution. This type of evolutionary analysis has been shown to be an efficient method to validate and predict disease-associated missense mutations (Delgado et al, 2007; Al Hashimi et al, 2009; Bardet et al, 2010; Silvent et al, 2014). This method is termed phylomedicine (Kumar et al, 2011), which is complementary to existing genetic diagnosis.…”

Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

“…Recently, our group successfully used this approach for predicting sensitive positions in various proteins of the secretory calcium-binding phosphoprotein family (26), and showed that missense mutations lead to genetic diseases. This approach was demonstrated on the following proteins: amelogenin (27), enamelin (28), matrix extracellular phospho-glycoprotein (29), amelotin (30), dentin matrix protein 1 (31), and ameloblastin. 6 Here, we perform the evolutionary molecular analysis of mammalian TNSALP to (i) highlight the functional or structural importance of various positions and domains; (ii) predict sensitive positions that should be responsible for a genetic disorder when substituted; and (iii) validate our predictions by using missense mutations reported in humans.…”