Genetic mutations influencing ovulation rate in sheep.

Ovulation rate in mammals is determined by a complex exchange of endocrine signals between the pituitary gland and the ovary, and by paracrine signals within ovarian follicles between the oocyte and its adjacent somatic cells. One approach to identifying factors regulating ovulation rate is to find mutations that influence the target phenotype and, in this context, sheep are proving to be remarkable experimental models. Recently, in three sheep families, namely Inverdale, Hanna and Booroola, the inherited mutation was mapped to a specific region of the sheep X chromosome (Inverdale, Hanna) or sheep chromosome 6 (Booroola) and in each, a point mutation was identified in genes from the bone morphogenetic protein (BMP) relatives of the transforming growth factor beta superfamily or their receptors. In Inverdale (I) and Hanna (H) sheep, separate point mutations were identified in the BMP15 gene corresponding to sites in the mature peptide coding region of the BMP15 growth factor (also known as growth differentiation factor 9B; GDF9B). Expression of the BMP15 gene was located exclusively in oocytes from the primary stage of follicular growth. There is a complete block of normal follicular development in females carrying two copies of the Inverdale mutation (II), two copies of the Hanna mutation (HH), or one copy of each mutation (HI). Increased ovulation rates are found in females with only one copy of either mutation (I+ or H+). In Booroola sheep, a point mutation was identified in the highly conserved intracellular serine threonine kinase signalling domain of the BMP-1B receptor. Within the ovary, this gene is expressed in oocytes in primordial and pre-antral follicles and in granulosa cells from the primary stage of growth as well as in corpora lutea. The effect of the Booroola mutation is additive for ovulation rate: animals with one copy of the mutation have an ovulation rate of 3 or 4, whereas those with two copies have an ovulation rate of between 5 and 14. Physiological studies of the above mutations demonstrate that the oocyte plays an active role with respect to its adjacent somatic cells during follicular development and support the hypothesis that the oocyte has a significant influence on the number of follicles that proceed to ovulation.