Abstract
The rapid evolution of reproductive proteins might be driven by positive Darwinian selection. The bone morphogenetic protein family is the largest within the transforming growth factor (TGF) superfamily. A little have been known about the molecular evolution of bone morphogenetic proteins exhibiting potential role in mammalian reproduction. In this study we investigated mammalian bone morphogenetic proteins using maximum likelihood approaches of codon substitutions to identify positive Darwinian selection in various species. The proportion of positively selected sites was tested by different likelihood models for individual codon, and M8 were found to be the best model. The percentage of positively elected sites under M8 are 2.20% with ω = 1.089 for BMP2, 1.6% with ω = 1.61 for BMP 4 0.53% for BMP15 with ω = 1.56 and 0.78% for GDF9 with ω = 1.93. The percentage of estimated selection sites under M8 is strong statistical confirmation that divergence of bone morphogenetic proteins is driven by Darwinian selection. For the proteins, model M8 was found significant for all proteins with ω > 1. To further test positive selection on particular amino acids, the evolutionary conservation of amino acid were measured based on phylogenetic linkage among sequences. For exploring the impact of these somatic substitution mutations in the selection region on human cancer, we identified one pathogenic mutation in human BMP4 and one in BMP15, possibly causing prostate cancer and six neutral mutations in BMPs. The comprehensive map of selection results allows the researchers to perform systematic approaches to detect the evolutionary footprints of selection on specific gene in specific species.
Highlights
The bone morphogenetic protein family is the largest within the transforming growth factor (TGF) superfamily and the distinguished structural feature of TGF superfamily is the presence of seven conserved cysteine, which are involved in folding of molecule into distinct three dimensional structure called cysteine knot [1]
The findings revealed that follicle stimulating hormone (FSH) induced progesterone synthesis is inhibited by BMP15, like BMP4, BMP6, BMP7 and GDF9, BMP15 is a part of luteinization inhibitors group [12]
BMP ligands and receptors are expressed in adult pituitary glands, BMP6, 7 and 15 mRNAs are expressed in mice pituitary [14], GDF9 mRNA in human pituitary, BMP15 and GDF9 mRNAs in brush tail opossum and BMP15 in sheep pituitaries [11]
Summary
The bone morphogenetic protein family is the largest within the transforming growth factor (TGF) superfamily and the distinguished structural feature of TGF superfamily is the presence of seven conserved cysteine, which are involved in folding of molecule into distinct three dimensional structure called cysteine knot [1]. An unequivocal evidence of positive selection in molecular evolution is remarkably higher in nonsynonymous than synonymous substitution rate and the ratio dN/dS indicated here by ω, quantifies the magnitude and direction of selection pressure on protein, with ω = 1, ω = > 1, and ω = < 1 indicate neutral evolution, positive selection and purifying selection respectively [17]. These conditions have been used to study evolution of male reproductive protein in vertebrate and invertebrate species [18]. Our results support the hypothesis that there was a rapid evolutionary pressure on mammalian bone morphogenetic proteins genes during evolution
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