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      Genes con efecto mayor sobre la fertilidad de ovejas: Revisión Translated title: Genes with major effect on fertility in sheep: Review

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          Abstract

          El estudio genético en razas de ovejas que naturalmente presentan altas tasas de ovulación (TO) y de prolificidad, ha permitido detectar la participación de varios genes. Entre ellos están los relacionados a la superfamilia del factor de crecimiento transformante β (BMPRIB, GDF9 y BMP-15), así como de otros genes con efecto mayor, tales como el "distal-less homeobox 3" (FecL), el receptor de estrógenos (ESR), el receptor de prolactina (PRLR) y el de las inhibinas (INHA y INHB). Sin embargo, las ovejas homocigotas para la mayoría de las variantes alélicas en BMP-15 o GDF9 son estériles, por lo que es importante el entendimiento de las bases genéticas y moleculares de estos polimorfismos, para su uso en programas racionales de mejoramiento genético con énfasis en la prolificidad. El polimorfismo en el gen de la melatonina (MTNR1) se ha asociado con la no estacionalidad reproductiva en ovejas. La selección en varias razas de ovejas para estas características ha reducido significativamente el anestro estacional, mostrando actividad reproductiva durante la primavera y el verano. Sin embargo, parece ser que estos genes en algunas razas pueden estar interactuando aditivamente, y una variante alélica en una raza puede no aparecer en otra, o bien dos al mismo tiempo, por lo que son variados los mecanismos genéticos que afectan la tasa ovulatoria y prolificidad.

          Translated abstract

          The genetic study on sheep breeds with naturally high ovulation rate (OR) and prolificacy, has allowed to detect the participation of several genes. Among them there are the ones related to the transforming growth factor-beta superfamily (BMPRIB, GDF9 and BMP-15), as well as to other genes with major effect, such as the distal-less homeobox 3' (FecL), estrogen receptor (ESR), prolactin receptor (PRLR) and inhibin receptor (INHA and INHB). However, sheep homozygous for the majority of the allelic variants in BMP-15 or GDF9 are sterile, for which it is important the understanding of the genetic and molecular basis of these polymorphisms, for their use in rational programs of genetic improvement on prolificacy. Polymorphism in the melatonin gene (MTNR1) has been associated with non-reproductive seasonality in sheep. Selecting several sheep breeds for these characteristics has significantly reduced the seasonal anoestrus, showing reproductive activity during spring and summer. It seems that these genes in some breeds may be interacting additively and an allelic variant in a breed may not be present in other, or two be present at the same time; therefore, the understanding of the genetic mechanisms that affect ovulation rate and prolificacy are important for the selection of reproductive traits.

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          The Booroola (FecB) phenotype is associated with a mutation in the bone morphogenetic receptor type 1 B (BMPR1B) gene.

          Genetic variations in ovulation rate which occur in different breeds of sheep provide useful models to explore the mechanisms regulating the development of antral follicles. The Booroola gene, an autosomal mutation that affects ovulation rate, has been known for over two decades and despite intensive research it has not yet been identified. Using resources from human genome mapping and known data about gene linkage and chromosome location in the sheep, we selected the gene encoding the Bone Morphogenetic Protein receptor (BMPR) type 1 B (ALK-6) as a candidate site for the mutation. The BMPR1B gene in the human is located at the region linked with the Booroola mutation, syntenic to chromosome 6 in the sheep. A fragment of the sheep BMPR1B gene was cloned from an ovarian cDNA and the deduced aminoacid (AA) sequence is over 98% homologous to the known mammalian sequences. cDNA and genomic DNA from 20 Booroola genotypes were screened and two point mutation were found in the kinase domain of the receptor, one at base 746 of the coding region (A in the ++ to a G in FF animals) which results in a change from a glutamine in the wild type to a arginine in the Booroola animals. Another point mutation was identified at position 1113, (C to A) but this mutation does not change the coding aminoacid. The first mutation was confirmed in genomic DNA from 10 ewes from an independent Brazilian flock which segregates the Booroola phenotype. In all instances homozygous FecB gene carrier (n=11) had only the 746 A to G mutation, non gene carriers (n=14) had only the wild type sequence and heterozygote gene carriers (n=5) had both sequences. This mutation in the subdomain 3 of the kinase domain could result in an alteration in the expression and/or phosphorylation of SMADs, resulting in the phenotype characteristic of the Booroola animals which is the 'precocious' development of a large number of small antral follicles resulting in increased ovulation rate.
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            Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner.

            Multiple ovulations are uncommon in humans, cattle and many breeds of sheep. Pituitary gonadotrophins and as yet unidentified ovarian factors precisely regulate follicular development so that, normally, only one follicle is selected to ovulate. The Inverdale (FecXI) sheep, however, carries a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes (FecXI/FecX+; ref. 1), but primary ovarian failure in homozygotes (FecXI/FecXI; ref. 2). Germ-cell development, formation of the follicle and the earliest stages of follicular growth are normal in FecXI/FecXI sheep, but follicular development beyond the primary stage is impaired. A second family unrelated to the Inverdale sheep also has the same X-linked phenotype (Hanna, FecXH). Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females. We report here that the FecXI locus maps to an orthologous chromosomal region syntenic to human Xp11.2-11.4, which contains BMP15, encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)). Whereas BMP15 is a member of the transforming growth factor beta (TGFbeta) superfamily and is specifically expressed in oocytes, its function is unknown. We show that independent germline point mutations exist in FecXI and FecXH carriers. These findings establish that BMP15 is essential for female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner.
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              Mutations in the genes for oocyte-derived growth factors GDF9 and BMP15 are associated with both increased ovulation rate and sterility in Cambridge and Belclare sheep (Ovis aries).

              Belclare and Cambridge are prolific sheep breeds, the origins of which involved selecting ewes with exceptionally high litter size records from commercial flocks. The variation in ovulation rate in both breeds is consistent with segregation of a gene (or genes) with a large effect on this trait. Sterile ewes, due to a failure of normal ovarian follicle development, occur in both breeds. New naturally occurring mutations in genes for the oocyte-derived growth factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are described. These mutations are associated with increased ovulation rate in heterozygous carriers and sterility in homozygous carriers in both breeds. This is the first time that a mutation in the gene for GDF9 has been found that causes increased ovulation rate and infertility in a manner similar to inactivating mutations in BMP15, and shows that GDF9 is essential for normal folliculogenesis in sheep. Furthermore, it is shown, for the first time in any species, that individuals with mutations in both GDF9 and BMP15 have a greater ovulation rate than sheep with either of the mutations separately.
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                Author and article information

                Journal
                rmcp
                Revista mexicana de ciencias pecuarias
                Rev. mex. de cienc. pecuarias
                Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias (Mérida, Yucatán, Mexico )
                2007-1124
                2448-6698
                March 2014
                : 5
                : 1
                : 107-130
                Affiliations
                [01] Villahermosa Tabasco orgnameUniversidad Juárez Autónoma de Tabasco orgdiv1División Académica de Ciencias Agropecuarias México carlos.luna@ 123456ujat.mx
                [02] orgnameUniversidad Nacional Autónoma de México orgdiv1Facultad de Medicina Veterinaria y Zootecnia orgdiv2Departamento de Genética y Bioestadística México
                Article
                S2007-11242014000100006 S2007-1124(14)00500100006
                227ce8f4-75a2-4529-9f82-fef63ccd0dcf

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 21 May 2012
                : 28 September 2012
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 85, Pages: 24
                Product

                SciELO Mexico

                Categories
                Revisión bibliográfica

                MTNR1,Inhibin,ESR,ALK6,BMPRIB,BMP-15,PRLR,Fecundity genes,Inhibina,BMPR1B,Genes de fecundidad

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