Genome-Wide Identification of a Regulatory Mutation in BMP15 Controlling Prolificacy in Sheep.

ABSTRACT

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. In the Noire du Velay (NV) sheep population, a recent genetic study has evidenced the segregation of such a mutation named FecL L . 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 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. A new single nucleotide polymorphism (OARX50977717T > 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). The variant allele was called FecX N and shown to segregate also in the Blanche du Massif Central (BMC) sheep population. 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. Homozygous FecX N carrier ewes were fertile with increased prolificacy in contrast to numerous mutations affecting BMP15. At the molecular level, FecX N was shown to decrease BMP15 promoter activity and supposed to impact BMP15 expression in the oocyte. This regulatory action was proposed as the causal mechanism for the FecX N mutation to control ovulation rate and prolificacy in sheep.