**6. Studies on ovulation rate in small ruminants as a model organism**

Detection of the specific major genes that control reproduction traits provides the opportunity to improve genetic gain in livestock species. However, fertility traits generally have low heritability, and reproductive improvements in a phenotypic selection based on observable data are pretty low and limited. However, ovulation rate and litter size in sheep are important fertility traits, and they have high economic values for breeders [72]. The ovulation rate mainly determines the productivity of sheep. Ovulation rate and litter size are expressed in only one gender and can only be recorded relatively late in the animal's lifespan. Focusing on improving fertility traits will have a long-term impact on the profitability of the sheep production system [73]. For more than a decade, sheep have been used by many researchers as an essential model organism to identify genes that control reproductive functions such as high fertility rate and ovarian follicle selection and also to investigate the physiological mechanisms involved in this reproductive system. Strong evidence was detected for major genes controlling prolificacy in sheep [74]. Specifically, the genetic influence on prolificacy variability in sheep has demonstrated that many genetic mutations have essential roles in controlling the ovulation rate. Those genes were tested in several populations based on the patterns of phenotypic segregation. Therefore, the selection of breeding animals will be more effective based on genotyping for relevant candidate genes to improve fertility and fecundity traits such as ovulation rate and litter size in small ruminants.

In a study conducted in this context, it was observed that sheep developed from the Booroola Merino strain had an autosomal mutation that increased the ovulation rate by approximately one and a half ova [75]. Therefore, it was an excellent candidate to investigate the mechanisms controlling ovulation rate in mammals [74, 76]. It was reported that the Booroola fecundity gene (FecB) has a partial dominant effect on litter size due to embryonic loss in homozygous carrier animals with high ovulation rates [77]. Subsequently, it was observed that, on average, one copy of the FecB gene enhanced the number of offspring by about 1.5, with increasing ovulation rates of about 1.65 ova per copy of the gene. The gene was accurately mapped to chromosome (Chr) 6 in a region where the bone morphogenetic protein receptor 1B (BMPR1B) was located in sheep [78]. This region is syntenic to Chr 3 or 5 in mice and Chr 4 in humans [79].

Moreover, the other major gene was detected, increasing ovulation rate and litter size in Inverdale sheep. The Inverdale fecundity gene (FecXI) has been located on the X chromosome and increases ovulation rates in the heterozygous ewes [80]. But, homozygous ewes are observed to be infertile due to lack of follicle development [81]. Another fecundity gene (FecXH) was also identified successfully on the X chromosome in the Hanna sheep population [82]. Both FecXI and FecXH were mapped in the bone morphogenetic protein 15 (BMP15) site. However, different point mutations were identified in the BMP15 gene in Inverdale and Hanna sheep

### *The Incidence of Ovulation and Detection of Genes Associated with Ovulation and Twinning… DOI: http://dx.doi.org/10.5772/intechopen.99936*

populations. If ewes are heterozygotes for any of them, it causes to increase ovulation rate to two-three ova. However, if sheep is homozygous for Booroola mutation, it dramatically raises ovulation rate from 5 to 14 [83]. Another study investigating the ovulation rate records obtained from daughters of ewes inseminated by Coopworth rams to understand the inheritance pattern of ovulation rate also proved that there was another maternally inherited gene affecting productivity traits located on the X chromosome (FecX2w). But the location of this gene is entirely different from the gene on Inverdale FecX locus [80]. The findings of studies conducted about four decades ago have guided many subsequent types of research on this subject, in which sheep are extensively used as model organisms in this subject.

Currently, the segregation of five major genes that affect ovulation rate and prolificacy has been characterized at the molecular level in various sheep and goat breeds that cause significant phenotypic variations. Overall the detected genes are bone morphogenetic protein receptor, type 1B (BMPR1B; in Booroola Merino, Javanese, Small Tail Han, Hu, Garole, and Kendrapada breeds) [78, 84, 85], bone morphogenetic protein 15 (BMP15; in Inverdale, Hanna, Romney, Belclare, Cambridge, Galway, Lacaune, Raza Aragonesa, Olkuska, and Grivette breeds) [82], growth differentiation factor 9 (GDF9; in Belclare, Cambridge, Icelandic Thoka, Santa Ines, Embrapa, Finnish Landrace, Norwegian White Sheep, Ile de France, and Baluchi breeds) [86], beta-1,4-N-acetyl-galactosaminyl transferase 2 (B4GALNT2 in Lacaune) [87], and leptin receptor (LEPR in Davisdale sheep) [88]. Causative polymorphism studies in different prolific sheep breeds showed at least 12 identified allelic variants for the BMP15, BMPR1B, and GDF9 genes encompassed in the transforming growth factor-beta (TGF-β) signaling pathway secreted from the oocyte. TGF-β is significantly associated with ovulation rate, litter size, and prolificacy and thus plays a critical role in the folliculogenesis of small ruminants. Many studies reported that the mutations in TGF-β pathway-related genes enhanced ovulation rate (35–100%) in heterozygous animals [89]. Moreover, even if causative mutations for fecundity are not fully discovered, two other genetic variants were identified as FecX2W [90] and FecD [91], which are segregated in prolific sheep breeds in recent studies. Similarly, about 20 different candidate genes, including TGF-β related genes, were also detected to play a crucial role in regulating folliculogenesis and prolificacy-related traits in several goat breeds [28]. To improve the genetic makeup of animals affecting high productivity in livestock, over 30 small ruminants, mostly high-yielding sheep and few goat breeds, have been actively used in candidate gene studies that focused on detecting variation related to reproductive performance-related traits.
