Genetic Mutations in Sheep Influencing Ovarian Follicular Growth and Ovulation-Rate

Kenneth P McNatty *,


Studies of the genetics of ovulation-rate have proven helpful for understanding the physiology of ovarian follicular function in mammals. Since 2000 studies of the inherited patterns of ovulation-rate in sheep have revealed at least 6 different point mutations in either the pro- or mature protein regions of bone morphogenetic protein (BMP)-15 and at least two different point mutations in the mature protein region of growth and differentiation factor (GDF)-9. Animals homozygous for any of the X-chromosome derived BMP-15 mutations (e.g. FecXB) and one of the GDF-9 mutations (FecGH) on sheep chromosome 5 are sterile with streak ovaries whereas those heterozygous have ovulation-rates approximately one higher than those of the wild-types. Animals heterozygous for both FecGH and FecXB have ovulation-rates that are additive for each mutation separately indicating that these growth factors can co-operate with one another. Within the sheep ovary both BMP15 and GDF9 are expressed exclusively by oocytes. These findings together with those from other studies in cattle and humans show that the oocyte has a major role to play in regulating ovulation-rate in mammals. In addition to BMP15 and GDF9 a point mutation in a BMP type I receptor known as activin-like kinase (ALK)-6 on sheep chromosome 6 also has a profound influence on ovulation-rate. Animals heterozygous and homozygous for the ALK-6 mutation have ovulation-rates that are 1.5- and 3.5-fold higher respectively than their wild-types. As with BMP-15 and GDF-9 the ALK-6 gene is expressed in oocytes but also in granulosa cells of developing ovarian follicles. Other mutations in sheep known to effect ovarian follicular development and/or ovulation-rate have been localised to chromosomes 5 (Thoka ewes) 11 (Lacaune) and X (Woodlands) but these genes remain to be identified. In the case of the Woodlands mutation (FecX2W) it seems that this also affects ovulation-rate at the level of the ovary as the patterns of expression of the BMP-15 ALK-6 and ALK-5 genes in oocytes or granulosa cells differ between those carrying the FecX2W mutation and the wild-type. In summary a remarkable range of naturally-occurring ovulation-rates varying between 0 and 15 have been identified in domesticated sheep. All the genes identified as responsible for this diversity are expressed in oocytes and/or adjacent follicular cells. An understanding of how these factors influence follicular development ovulation rate and fecundity are currently the subject of intense research.