Genome-Wide Association Studies Identify Two Novel BMP15 Mutations Responsible for an Atypical Hyperprolificacy Phenotype in Sheep
Figure 6
Hypothesized overview of ovulation quota control by the various Fecundity mutations.
(A) The mono ovulation quota is tightly controlled by the integrative action of i) BMP15 homodimer through BMPR1B, BMPR2 and SMAD1/5/8, ii) BMP15/GDF9 heterodimer through SMAD2/3 and iii) GDF9 homodimer through TBR1, BMPR2 and SMAD2/3. (B) Increased of ovulation rate due to FecX mutations. This drawing represents an overview of hyperprolificacy dependent of BMP15 variants. Heterozygous or homozygous FecX mutations leading to an increased OR affect either the signaling pathways of BMP15 homodimer, BMP15/GDF9 heterodimer or both whereas the GDF9 homodimer signaling pathway remains stable. (C) Increased of ovulation rate due to FecG mutations. This drawing represents an overview of hyperprolificacy dependent of GDF9 variants. Heterozygous or homozygous FecG mutations leading to an increased OR impair either the signaling pathways of GDF9 homodimer, BMP15/GDF9 heterodimer or both whereas the BMP15 homodimer signaling pathway remains stable. (D) Dose sensitive effect of each FecX and FecG mutations on the BMP15, GDF9 homodimers and BMP15/GDF9 heterodimer signaling pathways. Based on the various in vitro tests performed, we assigned a dose (n = 0, 1 or 2) to each signaling pathway in an attempt to explain the prolificacy phenotype observed for all the FecX and FecG mutations. When the ovulation rate is normal ( = 1), i.e. the WT situation, 2 doses of BMP15 homodimer (blue), GDF9 homodimer (purple) and BMP15/GDF9 heterodimer (pink) were considered. As example, in the case of the FecXGr mutation where the BMP15 homodimer signaling pathway seemed clearly affected at homozygous and heterozygous status (as shown on Figure 5), we assumed that the BMP15/GDF9 heterodimer signaling pathway remained totally active.