Abstract
Some sheep breeds are naturally prolific, and they are very informative for the studies of reproductive genetics and physiology. Major genes increasing litter size (LS) and ovulation rate (OR) were suspected in the French Grivette and the Polish Olkuska sheep populations, respectively. To identify genetic variants responsible for the highly prolific phenotype in these two breeds, genome-wide association studies (GWAS) followed by complementary genetic and functional analyses were performed. Highly prolific ewes (cases) and normal prolific ewes (controls) from each breed were genotyped using the Illumina OvineSNP50 Genotyping Beadchip. In both populations, an X chromosome region, close to the BMP15 gene, harbored clusters of markers with suggestive evidence of association at significance levels between 1E−05 and 1E−07. The BMP15 candidate gene was then sequenced, and two novel non-conservative mutations called FecXGr and FecXO were identified in the Grivette and Olkuska breeds, respectively. The two mutations were associated with the highly prolific phenotype (pFecXGr = 5.98E−06 and pFecXO = 2.55E−08). Homozygous ewes for the mutated allele showed a significantly increased prolificacy (FecXGr/FecXGr, LS = 2.50±0.65 versus FecX+/FecXGr, LS = 1.93±0.42, p<1E−03 and FecXO/FecXO, OR = 3.28±0.85 versus FecX+/FecXO, OR = 2.02±0.47, p<1E−03). Both mutations are located in very well conserved motifs of the protein and altered the BMP15 signaling activity in vitro using a BMP-responsive luciferase test in COV434 granulosa cells. Thus, we have identified two novel mutations in the BMP15 gene associated with increased LS and OR. Notably, homozygous FecXGr/FecXGr Grivette and homozygous FecXO/FecXO Olkuska ewes are hyperprolific in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations. Our results bring new insights into the key role played by the BMP15 protein in ovarian function and could contribute to a better understanding of the pathogenesis of women′s fertility disorders.
Highlights
There is strong evidence supporting the concept that oocyte plays a central role in follicle growth and developmental regulation [1,2,3]
Some sheep breeds are naturally prolific since they carry major genes affecting ovulation rate and litter size
Through a genome-wide association studies (GWAS) conducted in two sheep breeds using highly prolific ewes as cases and normal prolific ewes as controls, we identified an X chromosome locus close to the Bone Morphogenetic Protein 15 (BMP15) gene in both breeds
Summary
There is strong evidence supporting the concept that oocyte plays a central role in follicle growth and developmental regulation [1,2,3]. It has been established that ovary-derived transforming growth factor-ß (TGFß) family members play an integral role during folliculogenesis. The two paracrine factors Bone Morphogenetic Protein 15 (BMP15) and Growth and Differentiation Factor 9 (GDF9) stimulate follicle growth [4,5], promote granulosa cell proliferation [6,7], influence cell-survival signaling [8,9] and modulate other growth factors and hormones [10,11,12]. The identification of BMP15, GDF9 and Bone Morphogenetic Protein Receptor 1B (BMPR1B) gene mutations (Table 1) as the causal mechanism underlying either the highly prolific or infertile phenotypes of several sheep breeds in a dosage-sensitive manner highlighted the crucial role these genes play in ovarian function.
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