However, several studies have reported an aberrant expression of BMP15 and GDF9 in the ovary of PCOS patients ( Teixeira Filho et al., 2002 Wei et al., 2014). Here, again, several missense variants were discovered in both genes, but the pathogenic role of these mutations remains controversial in the etiology of this syndrome. Alterations of BMP15 and GDF9 were also searched in association with polycystic ovary syndrome (PCOS). Particularly, the 10-fold higher prevalence of BMP15 variants among patients with POI compared with the control population supports the causative role of these mutations ( Persani et al., 2014). Indeed, numerous heterozygous missense mutations have been identified in both genes associated with primary or secondary amenorrhea in different cohorts of women affected by primary ovarian insufficiency (POI) all over the world. In humans also, a focus was done on BMP15 and GDF9 about their implication in various ovarian dysfunctions. Knockout mice models gave the first evidence of the importance of these two oocyte-derived factors acting individually as homodimers and/or through a synergistic cooperation to control the ovarian function ( Elvin et al., 1999 Yan et al., 2001). Among them, the most important are surely BMP15 and GDF9. Among the local factors produced by the oocyte itself, members of the bone morphogenetic protein/growth and differentiation factor (BMP/GDF) family play an integral role in this control ( Persani et al., 2014). There is now an accumulation of evidence that the oocyte plays a central role in controlling the ovarian folliculogenesis from the early stages up to ovulation. This regulatory action was proposed as the causal mechanism for the FecX N mutation to control ovulation rate and prolificacy in sheep. At the molecular level, FecX N was shown to decrease BMP15 promoter activity and supposed to impact BMP15 expression in the oocyte. Homozygous FecX N carrier ewes were fertile with increased prolificacy in contrast to numerous mutations affecting BMP15. In both NV and BMC, the FecX N allele frequency was estimated close to 0.10, and its effect on LS was estimated at +0.20 lamb per lambing at the heterozygous state. The variant allele was called FecX N and shown to segregate also in the Blanche du Massif Central (BMC) sheep population. A new single nucleotide polymorphism (OARX:50977717T > A, NC_019484) located on the X chromosome upstream of the BMP15 gene was evidenced to be highly associated with the prolificacy variability ( P = 1.93E-11). In order to identify this mutation, we have combined a case/control genome-wide association study with ovine 50k SNP chip genotyping, whole genome sequencing, and functional analyses. However, based on litter size (LS) records of FecL L non-carrier ewes, the segregation of a second prolificacy major mutation was suspected in this population. In the Noire du Velay (NV) sheep population, a recent genetic study has evidenced the segregation of such a mutation named FecL L. The search for the genetic determinism of prolificacy variability in sheep has evidenced several major mutations in genes playing a crucial role in the control of ovulation rate.