Running title: SELECTIVE PRESSURE VARIATION IN BMP15 AND GDF9

Bone Morphogenetic Protein 15 (BMP15) and Growth and Differentiation Factor 9 (GDF9) are TGFbeta-like oocyte-derived growth factors involved in ovarian folliculogenesis as critical regulators of many granulosa cell processes and ovulation rate. Ovarian phenotypic effect caused by alterations in BMP15 and GDF9 genes appears to differ between species and may be relevant to their mono- or poly-ovulating status. Through phylogenetic analysis we recently showed that these two paralogous genes are strongly divergent and in rapid evolution as compared to other members of the TGFbeta superfamily. Here, we evaluate the amino-acid substitution rates of a set of proteins implicated in the ovarian function, including BMP15 and GDF9, with special attention to the mono- or poly-ovulating status of the species. Among a panel of mono- and polyovulating mammals, we demonstrate a better conservation of some areas in BMP15 and GDF9 within mono-ovulating species. Homology modeling of BMP15 and GDF9 homodimers and heterodimers 3D structures was suggestive that these areas may be involved in dimer formation BOR Papers in Press. Published on August 6, 2014 as DOI:10.1095/biolreprod.114.119735