Abstract
Bone Morphogenetic Protein 15 (BMP15) is a TGFβ-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. Alterations of the BMP15 gene have been found associated with different ovarian phenotypic effects depending on the species, from sterility to increased prolificacy in sheep, slight subfertility in mouse or associated with primary ovarian insufficiency (POI) in women. To investigate the evolving role of BMP15, a phylogenetic analysis of this particular TGFβ family member was performed. A maximum likelihood phylogenetic tree of several TGFβ/BMP family members expressed by the ovary showed that BMP15 has a very strong divergence and a rapid evolution compared to others. Moreover, among 24 mammalian species, we detected signals of positive selection in the hominidae clade corresponding to F146, L189 and Y235 residues in human BMP15. The biological importance of these residues was tested functionally after site directed-mutagenesis in a COV434 cells luciferase assay. By replacing the positively selected amino acid either by alanine or the most represented residue in other studied species, only L189A, Y235A and Y235C mutants showed a significant increase of BMP15 signaling when compared to wild type. Additionally, the Y235C mutant was more potent than wild type in inhibiting progesterone secretion of ovine granulosa cells in primary culture. Interestingly, the Y235C mutation was previously identified in association with POI in women. In conclusion, this study evidences that the BMP15 gene has evolved faster than other members of the TGFß family and was submitted to a positive selection pressure in the hominidae clade. Some residues under positive selection are of great importance for the normal function of the protein and thus for female fertility. Y235 represents a critical residue in the determination of BMP15 biological activity, thus indirectly confirming its role in the onset of POI in women.
Highlights
Bone Morphogenetic Protein 15 (BMP15) is an oocyte-derived growth factor belonging to the transforming growth factor-beta (TGFβ) superfamily, which is involved in ovarian follicular development as a critical regulator of many granulosa cell (GC) processes such as proliferation and steroidogenesis [1,2,3,4]
Given that positive selection is often associated with branch length and fast gene evolution [23], and that genes involved in reproduction evolve faster and often evidenced positive selection [24,25,26], we carried out positive selection analyses on BMP15
We used the BMP15 sequences from 24 mammals (Figure 2 and Table S2) analyzed by branch-site models from PAML packages [27] within the PhyleasProg web server [28], in order to determine whether the different species of the phylogenetic tree underwent selective pressures and to detect signals of local episodic positive selection
Summary
BMP15 is an oocyte-derived growth factor belonging to the transforming growth factor-beta (TGFβ) superfamily, which is involved in ovarian follicular development as a critical regulator of many granulosa cell (GC) processes such as proliferation and steroidogenesis [1,2,3,4]. We performed a phylogenetic analysis of sereval TGFβ/BMP family members expressed within the ovary throughout selected species: human, mouse and rat (Figure 1 and Table S1).
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