Genome-wide association studies identify two novel BMP15 mutations responsible for an atypical hyperprolificacy phenotype in sheep
2013
Demars, Julie | Fabre, Stéphane | Sarry, Julien, J. | Rossetti, Raffaella | Gilbert, Hélène | Persani, Luca | Tosser-Klopp, Gwenola | Mulsant, Philippe | Nowak, Zuzanna | Drobik, Wioleta | Martyniuk, Elzbieta | Bodin, Loys, L. | Laboratoire de Génétique Cellulaire (LGC) ; Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT) ; Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT) | Ecole Nationale Vétérinaire de Toulouse (ENVT) ; Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT) | Institut National de la Recherche Agronomique (INRA) | Physiologie de la reproduction et des comportements [Nouzilly] (PRC) ; Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS) | Université de Tours (UT) | Institut Français du Cheval et de l'Equitation | Università degli Studi di Milano = University of Milan (UNIMI) | Warsaw University of Life Sciences (SGGW) | Station d'Amélioration Génétique des Animaux (SAGA) ; Institut National de la Recherche Agronomique (INRA) | This work was supported by grants from France via Agence National pour la Recherche (http://www.agence-nationale-recherche.fr /) (ANR 2010 BLANC grant 160801, MONOPOLY) and EC (FP7/2007–2013), grant 245140, “3SR”, Sustainable Solutions for Small Ruminants (http://www.3srbreeding.eu/), WP4 (this publication reflects only the authors' views and the EC is not liable for any use that may be made of the information contained herein), and the DEGERAM Program (FNADT, FEDER, CR Midi Pyrénées, Auvergne et Limousin). This work was partially supported by Telethon Foundation, Italy (grant GGP09126 to LP).
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显示更多 [+] 显示较少 [-]英语. 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 1E205 and 1E207. 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 (pFecX Gr = 5.98E206 and pFecX O = 2.55E208). Homozygous ewes for the mutated allele showed a significantly increased prolificacy (FecXGr/FecXGr, LS = 2.5060.65 versus FecX+/FecXGr, LS = 1.9360.42, p,1E203 and FecXO/FecXO, OR = 3.2860.85 versus FecX+/FecXO, OR = 2.0260.47, p,1E203). Both mutations are located in very well conserved motifs of the protein and altered the BMP15 signaling activity in vitro using a MP-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 women9s fertility disorders.
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