OMIA 002306-9940 : Fecundity, BMP15-related in Ovis aries

In other species: pig

Category: Reproductive system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 300247 (gene) , 300510 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2000

Species-specific description: The following OMIA entries relating to specific variants in the BMP15 gene and their impact on fecundity have been incorporated into this entry:

OMIA 000386-9940 Fecundity, Inverdale, FecX(I) (6th October 2021)

OMIA 001350-9940 Fecundity, Hanna, FecX(H) (6th October 2021)

OMIA 000384-9940 Fecundity, Galway, FecX(G) (6th October 2021)

OMIA 001719-9940 Fecundity, Belclare, FecX(B) (6th October 2021)

OMIA 001357-9940 Fecundity, Lacaune, FecX(L) (6th October 2021)

OMIA 001800-9940 Fecundity, Rasa Aragonesa, FecX(R) (6th October 2021)

OMIA 001798-9940 Fecundity, Grivette, FecX(Gr) (6th October 2021)

OMIA 001799-9940 Fecundity, Olkuska, FecX(O) (6th October 2021)

OMIA 002107-9940 Fecundity, Barbarine, FecX(Bar) (6th October 2021)

History: Davis et al. (1991): "In a flock of highly prolific Romney ewes obtained [in 1979 by screening for prolificacy] from Industry flocks, one ewe (A281), with a production record of 33 lambs born in 11 lambings, produced a number of female descendants with high ovulation rates. The mode of inheritance of this trait was determined In a series of four progeny tests of male descendants of this ewe. . . . [The results showed] for the first time the presence of a major gene for prolificacy specifically located on the X chromosome. The effect of the gene is to increase ovulation rate by about one additional egg per ewe. . . . At a meeting of the Committee on Genetic Nomenclature of Sheep and Goats (COGNOSAG) at Edinburgh in July 1990, the naming of this gene was decided. The name assigned to the gene is “Inverdale,” and the locus is “FecX"." As explained to FN by John McEwan in October 2021 (and documented by Davis (1999), the name Inverdale was created by George Davis, who combined the name of the Invermay Agricultural Research Centre (where the research had been conducted) with the common New Zealand practice of adding "dale" as a suffix when naming sheep breeds. Davis et al. (1991) named the high-fecundity variant FecX^I, with I indicating Inverdale.

Davis et al. (1994) reported that "Soon after the Inverdale discovery was publicised we were approached by a Romney breeder [Mac Hanna] from the central North Island of New Zealand who had some highly prolific ewes. . . . Collectively, [the available data from this flock] were strong evidence of a major gene for prolificacy in this flock." Matings of prolific ewes from this flock with a progeny-tested FecX(I) ram showed "that sheep in this [Hanna] flock have either the Inverdale gene or a gene allelomorphic with the Inverdale gene. This flock can be traced back 29 years and no South Island [the source of Inverdales] sheep were introduced during this time."

Inheritance: A segregation analysis of data from a flock of 549 Cambridge ewes maintained at the University of Wales, Bangor, indicated the presence of a gene of major effect on ovulation rate (number of ova shed), with a difference in performance between homozygotes ranging from 2.14 to 3.44 (Owen et al., 1990).

As reported by Davis et al. (1995), "Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females", suggesting that FecXI and FecXH are allelic at a single X-linked locus.

Mapping: Knowing that this gene is X-linked (see Inheritance section above), Galloway et al. (2000) used X-linked markers to map the gene to a region of chromosome OVAX orthologous with human Xp11.2–11.4. In this region lies the BMP15 gene "encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)) . . . [which] is a member of the transforming growth factor β (TGFβ) superfamily and is specifically expressed in oocytes, [but] its function is unknown". Thus BMP15 became a likely positional candidate gene. The same authors then mapped the sheep BMP15 gene to the same region of OVAX, with zero recombination to FecX(I), providing very strong support for BMP15 being the FecX(I) gene.

Demars et al. (2013) conducted a GWAS by genotyping 28 hyper-prolific and 11 control French Grivette ewes and 29 hyper-prolific and 34 control Polish Olkuska ewes with the Illumina OvineSNP50 chip. A single region on the X chromosome, including the prolificacy gene BMP15, was highlighted in both breeds. BMP15 was thus a highly likely positional candidate gene.

Markers: Chantepie et al. (2020): "A new single nucleotide polymorphism (OARX:50977717T > A, NC_019484) located on the X chromosome upstream of the BMP15 gene was evidenced to be highly associated with the prolificacy variability (P = 1.93E-11). The variant allele was called FecX N ... . In both NV [Noire du Velay] and BMC [Blanche du Massif Central], the FecX N allele frequency was estimated close to 0.10, and its effect on LS was estimated at +0.20 lamb per lambing at the heterozygous state. Homozygous FecX N carrier ewes were fertile with increased prolificacy in contrast to numerous mutations affecting BMP15. At the molecular level, FecX N was shown to decrease BMP15 promoter activity and supposed to impact BMP15 expression in the oocyte."

Calvo et al. (2020) “identified a novel polymorphism in exon 2 of BMP15 in 9 high prolific ewes by Sanger sequencing. This new mutation, called FecXRA, is a SNP (Oar3.1_X: g. 50970948C > T; NM_001114767.1: c.1172C > T) that produces an amino acid substitution (ENSOART00000010201: p.T400I) that is predicted to be deleterious and to alter the predicted secondary structure of the mature protein. … an association study was performed to validate and quantify the effects of the FecXGR and FecXRA alleles. Significant increased prolificacy of 0.52 ± 0.05, 0.42 ± 0.05 and 0.32 ± 0.01 were found when comparing FecXGR, FecXRA and FecXR heterozygous ewes to wild type homozygous ones. These effects are of the same order of magnitude as the effect of most of other known major genes for prolificacy. Only significant differences between FecXGR and FecXR were found among the three alleles associated with increased prolificacy. However, we cannot confirm the effect of the FecXRA allele at homozygous state because we did not find any homozygous ewes. These results confirm that these three alleles in the BMP15 gene that affect prolificacy co-segregate in Rasa aragonesa sheep.”

Çelikeloğlu et al. (2021) “polymorphisms in genes affecting litter size ... were detected in 60 uniparous and 60 multiparous ewes from Ramlıç and Dağlıç breeds. … PCR and DNA sequencing analyses were conducted, and 36, 4, and 11 SNPs in Ramlıç and 40, 3, and 11 SNPs in Dağlıç were detected in BMPR1B, BMP15, and GDF9 genes, respectively. A total of 16 SNPs in Ramlıç and 10 SNPs in Dağlıç breeds for three genes were found to be significant (P<0.05). The resulting analyses showed that four SNPs (g.49496G>A, c.1658A>C, c.2037C>T, c.2053C>T) of the BMPR1B gene and one deletion mutation (c.28_30delCTT) in the BMP15 gene of the Ramlıç breed as well as five SNPs (c.1487C>A, c.2492C>T, c.2523G>A, c.2880A>G, and c.2763G>A) of the BMPR1B gene of the Dağlıç breed have significant positive regression coefficients in the desired direction of the rare allele. The observed mutations have potential to be used as genetic markers in the selection of prolific animals for both breeds.”

Najafabadi et al. (2021) report an association between litter size and the variant c.31_33del, p.(L11del) in a small number of composite sheep in New Zealand. This variant was initially identified by Galloway et al. (2000). Najafabadi et al. (2021) acknowledge that analysis in a larger population is required to confirm these results, particularly as most other studies that analysed this variant did not identify an association with fecundity.

Di et al. (2021) sequenced the "entire ORF region of BMP15 ... in 154 Luzhong mutton ewes, and the novel variations were determined. The association between polymorphism in BMP15 and litter size was analyzed using a general linear model. Six out of a total of thirteen variations were identified to be novel. Association analysis indicated that four (SNPs ENSOART00000010201.1:c.352+342C>A, c.352+1232T>C, c.352+1165A>G and c.353-2036T>A) were significantly associated with litter size. The joint analysis among three major genes (BMP15, BMPR1B and GDF9) exhibited significant interaction effects in three combinations (FecB and c.352+1232T>C of BMP15; FecB and c.352+1165A>G of BMP15; c.352+342C>A of BMP15 and ENSOART00000014382.1:c.994G>A of GDF9)."

Molecular basis: Sequencing of the comparative positional candidate gene BMP15 by Galloway et al. (2000) revealed "A distinct single T→A transition occurs in FecXI carriers at nucleotide position 92 of the mature peptide . . . The mutation substitutes valine (V) with aspartic acid (D) at residue 31 (residue 299 of unprocessed protein) . . . The FecXI mutation is a non-conservative change in a highly conserved region of the protein."

These same authors also showed that the variant originating in the Hanna flock, which they called FecX(H), is due to a different mutation in the same gene: "A single C→T transition at nucleotide position 67 of the mature peptide coding region of FecXH carriers introduces a premature stop codon in the place of glutamic acid (Q) at amino-acid residue 23 (residue 291 of the unprocessed protein) . . . . Such premature truncation probably results in complete loss of BMP15 function."

Hanrahan et al. (2004) reported and named two variants, namely FecX(G), where G indicates Galway (c.718C>T; p.(Gln239STOP); and FecX(B), where B indicates Belclare (c.1100G>T; p.(S367I)).

Bodin et al. (2007) reported a causal mutation in the Lacaune breed as "a C53Y missense nonconservative substitution [in BMP15] leading to the aminoacidic change of a cysteine with a tyrosine in the mature peptide of the protein. As for other mutations found in the same gene, this is associated with an increased ovulation rate and sterility in heterozygous and homozygous animals, respectively. Further in vitro studies showed that the C53Y mutation was responsible for the impairment of the maturation process of the BMP15 protein, resulting in a defective secretion of both the precursor and mature peptide".

Martinez-Royo et al. (2008) reported "a new naturally occurring mutation in the BMP15 gene from the ovine Rasa Aragonesa breed is described. This mutation is a deletion of 17 bp that leads to an altered amino acid sequence and introduces a premature stop codon in the protein. Highly significant associations (P < 0.0001) were found between the estimated breeding value for prolificacy and the genotype of BMP15 in Rasa Aragonesa animals with high and low breeding values for this trait. As for other mutations in BMP15, this new mutation is associated with increased prolificacy and sterility in heterozygous and homozygous ewes respectively".

Following the results described in the Mapping section, sequencing of BMP15 in the French Grivette breed revealed six polymorphisms, one of which (950C>T; T317I) was strongly associated with fecundity. Genotyping of this polymorphism in additional randomly chosen ewes confirmed the effect, with TT homozygotes having an average ovulation rate of 4.58 compared with 2.94 for CT and 2.53 for CC ewes, with corresponding averages for litter size being 2.50 for TT, 1.93 for CT and 1.83 for CC (Demars et al., 2013). In the Polish Olkuska breed, sequencing of BMP15 revealed six polymorphisms, one of which (1009A>C; N337H) was strongly associated with ovulation rate. Genotyping of this polymorphism in additional randomly chosen ewes confirmed the effect, with CC homozygotes having an average ovulation rate of 3.28 compared with 2.02 for CA and 1.52 for AA ewes, with corresponding averages for litter size being 3.05 for CC, 2.46 for CA and 1.84 for AA (Demars et al., 2013). The authors note that for both variants, the high fecundity of homozygous mutant ewes is "in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations".

Lassoued et al. (2017) reported a likely causal variant in the Tunisian Barbarine breed as "a composite polymorphism associating a single nucleotide substitution (c.301G > T), a 3 bp deletion (c.302_304delCTA) and a C insertion (c.310insC) in the ovine BMP15 cDNA leading to a frame shift at protein position 101". Lassoued et al. (2017) summarised the effect of this variant as: "Calculated in the “W” flock, the FecX Bar allele increased OR by 0.7 ova and LS by 0.3 lambs (p = 0.08)."

Control: Even though prolificacy is not regarded as a disorder, it is worth noting that in some situations, farmers prefer to not have prolific ewes. The discovery of the DNA basis of this form of prolificacy should enable breeders to better plan matings so as to avoid producing such ewes, if they so wish. (text written by FN, with thanks to Julie Demars)

Breeds: Belclare (Sheep) (VBO_0001322), Cambridge (Sheep) (VBO_0001355), Grivette (Sheep) (VBO_0001428), Lacaune (Sheep) (VBO_0001474), Noir du Velay, France (Sheep) (VBO_0015495), Olkuska (Sheep) (VBO_0001539), Rasa Aragonesa, Spain (Sheep) (VBO_0015863), Romney (Sheep) (VBO_0001581), Tunisian Barbary (Sheep) (VBO_0001658).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
BMP15 bone morphogenetic protein 15 Ovis aries X NC_056080.1 (54290315..54283635) BMP15 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
244 Belclare (Sheep) Cambridge (Sheep) Fecundity, Belclare BMP15 FecX(B) missense Naturally occurring variant Oar_rambouillet_v1.0 X g.56594843C>A c.1100G>T p.(S367I) 2004 14627550 The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.
238 Olkuska (Sheep) Fecundity, Olkuska BMP15 FecX(O) missense Naturally occurring variant Oar_rambouillet_v1.0 X g.56594934T>G c.1009A>C p.(N337H) Protein and cDNA positions based on NP_001108239.1 and NM_001114767.1, respectively. 2013 23637641 The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.
236 Lacaune (Sheep) Fecundity, Lacaune BMP15 FecX(L) missense Naturally occurring variant Oar_rambouillet_v1.0 X g.56594981C>T c.962G>A p.(C321Y) cDNA position based on NP_001108239.1 2007 17038554 The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.
237 Grivette (Sheep) Fecundity, Grivette BMP15 FecX(Gr) missense Naturally occurring variant Oar_rambouillet_v1.0 X g.56594993G>A c.950C>T p.(T317I) protein and cDNA positions based on NP_001108239.1 and NM_001114767.1, respectively 2013 23637641 The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.
235 Romney Marsh (Sheep) Fecundity, Inverdale BMP15 FecX(I) missense Naturally occurring variant Oar_rambouillet_v1.0 X g.56595047A>T c.896T>A p.(V299D) protein and cDNA positions based on NP_001108239.1 and NM_001114767.1, respectively rs398521635 2000 10888873 The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.
335 Romney Marsh (Sheep) Fecundity, Hanna BMP15 FecX(H) nonsense (stop-gain) Naturally occurring variant Oar_rambouillet_v1.0 X g.56595072G>A c.871C>T p.(Q291*) previously listed as c.1184C>T; protein and cDNA position based on NP_001108239.1 and NM_001114767.1, respectively rs413916687 2000 10888873
334 Cambridge (Sheep) Fecundity, Galway BMP15 FecX(G) nonsense (stop-gain) Naturally occurring variant Oar_rambouillet_v1.0 X g.56595225G>A c.718C>T p.(Q239*) rs425019156 2004 14627550
521 Rasa Aragonesa, Spain (Sheep) Fecundity, Rasa Aragonesa BMP15 FecX(R) deletion, small (<=20) Naturally occurring variant Oar_rambouillet_v1.0 X g.56595467_56595483del c.460_476del p.(W154Nfs*55) published as c.525_541delTGGGTCCAGAAAAGCCC based on AF236079, protein and cDNA position in table based on NP_001108239.1 and NM_001114767.1, respectively 2008 18355397 The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.
755 Tunisian Barbary (Sheep) Fecundity, Barbarine BMP15 FecX(Bar) complex rearrangement Naturally occurring variant Oar_rambouillet_v1.0 X g.[56600937insG;56600945_56600947del;56600948C>A] c.[301G>T;302_304delCTA;310insC] p.(A101Cfs*113) "a composite polymorphism associating a single nucleotide substitution (c.301G > T), a 3 bp deletion (c.302_304delCTA) and a C insertion (c.310insC) in the ovine BMP15 cDNA leading to a frame shift at protein position 101" - cDNA positions based on NM_001114767 2017 28506298
1341 Rasa Aragonesa, Spain (Sheep) Fecundity BMP15 FecX(RA) missense Naturally occurring variant Oar_v3.1 X g.50970948C>T c.1172C>T p.(T400I) protein position based on ENSOART00000010201 2020 31927415
1345 Blanc Du Massif Central (Sheep) Noir du Velay, France (Sheep) Fecundity BMP15 FecX(N) regulatory Naturally occurring variant Oar_v3.1 X g.50977717T>A 2020 32636872

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year. > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > >
2021 Çelikeloğlu, K., Tekerli, M., Erdoğan, M., Koçak, S., Hacan, Ö., Bozkurt, Z. :
An investigation of the effects of BMPR1B, BMP15, and GDF9 genes on litter size in Ramlıç and Dağlıç sheep. Arch Anim Breed 64:223-230, 2021. Pubmed reference: 34159253. DOI: 10.5194/aab-64-223-2021.
Derks, M.F.L., Steensma, M. :
Review: Balancing selection for deleterious alleles in livestock. Front Genet 12:761728, 2021. Pubmed reference: 34925454. DOI: 10.3389/fgene.2021.761728.
Di, R., Wang, F., Yu, P., Wang, X., He, X., Mwacharo, J.M., Pan, L., Chu, M. :
Detection of novel variations related to litter size in BMP15 gene of Luzhong mutton sheep (Ovis aries). Animals (Basel) 11:3528, 2021. Pubmed reference: 34944305. DOI: 10.3390/ani11123528.
Najafabadi, H.A., Khansefid, M., Mahmoud, G.G., Haruna, I.L., Zhou, H., Hickford, J.G.H. :
Identification of sequence variation in the oocyte-derived bone morphogenetic protein 15 (BMP15) gene (BMP15) associated with litter size in New Zealand sheep (Ovis aries) breeds. Mol Biol Rep :, 2021. Pubmed reference: 34379287. DOI: 10.1007/s11033-021-06627-z.
Niu, Z.G., Qin, J., Jiang, Y., Ding, X.D., Ding, Y.G., Tang, S., Shi, H.C. :
The identification of mutation in BMP15 gene associated with litter size in Xinjiang Cele Black sheep. Animals (Basel) 11:, 2021. Pubmed reference: 33802361. DOI: 10.3390/ani11030668.
2020 Calvo, J.H., Chantepie, L., Serrano, M., Sarto, M.P., Iguacel, L.P., Jiménez, M.Á., Alabart, J.L., Folch, J., Fabre, S., Lahoz, B. :
A new allele in the BMP15 gene (FecXRA) that affects prolificacy co-segregates with FecXR and FecXGR in Rasa aragonesa sheep. Theriogenology 144:107-111, 2020. Pubmed reference: 31927415. DOI: 10.1016/j.theriogenology.2020.01.010.
Chantepie, L., Bodin, L., Sarry, J., Woloszyn, F., Plisson-Petit, F., Ruesche, J., Drouilhet, L., Fabre, S. :
Genome-wide identification of a regulatory mutation in BMP15 controlling prolificacy in sheep. Front Genet 11:585, 2020. Pubmed reference: 32636872. DOI: 10.3389/fgene.2020.00585.
Smołucha, G., Piórkowska, K., Ropka-Molik, K., Sikora, J. :
Use of the HRM Method in Quick Identification of FecX<sup>O</sup> Mutation in Highly Prolific Olkuska Sheep. Animals (Basel) 10:, 2020. Pubmed reference: 32423016. DOI: 10.3390/ani10050844.
2019 Mohamed, S.E.I., Ahmed, R.M., Jawasreh, K.I.Z., Salih, M.A.M., Abdelhalim, D.M., Abdelgadir, A.W., Obeidat, M.T., Musa, L.M.A., Ahmed, M.A. :
Genetic polymorphisms of fecundity genes in Watish Sudanese desert sheep. Vet World 13:614-621, 2019. Pubmed reference: 32546903. DOI: 10.14202/vetworld.2020.614-621.
2018 Abdoli, R., Ziaeddin Mirhoseini, S., Ghavi Hossein-Zadeh, N., Zamani, P. :
Screening for Causative Mutations of Major Prolificacy Genes in Iranian Fat-Tailed Sheep. Int J Fertil Steril 12:51-55, 2018. Pubmed reference: 29334207. DOI: 10.22074/ijfs.2018.5247.
Amini, H.-R., Ajaki, A., Majid Farahi, M., Mitra Heidari, M., Ahmad Pirali, A., Forouzanfar, M., Eghbalsaied, S. :
The novel T755C mutation in BMP15 is associated with the litter size of Iranian Afshari, Ghezel, and Shal breeds. Archiv fuer Tierzucht 61:153-160, 2018. DOI: DOI:10.5194/aab-61-153-2018.
Nagdy, H., Mahmoud, K.G.M., Kandiel, M.M.M., Helmy, N.A., Ibrahim, S.S., Nawito, M.F., Othman, O.E. :
PCR-RFLP of bone morphogenetic protein 15 (BMP15/FecX) gene as a candidate for prolificacy in sheep. Int J Vet Sci Med 6:S68-S72, 2018. Pubmed reference: 30761324. DOI: 10.1016/j.ijvsm.2018.01.001.
Tang, J., Hu, W., Di, R., Liu, Q., Wang, X., Zhang, X., Zhang, J., Chu, M. :
Expression analysis of the prolific candidate genes, BMPR1B, BMP15, and GDF9 in small tail Han ewes with three fecundity (FecB Gene) genotypes. Animals (Basel) 8:, 2018. Pubmed reference: 30274220. DOI: 10.3390/ani8100166.
2017 Ahmad, H.I., Liu, G., Jiang, X., Edallew, S.G., Wassie, T., Tesema, B., Yun, Y., Pan, L., Liu, C., Chong, Y., Yu, Z.J., Jilong, H. :
Maximum-likelihood approaches reveal signatures of positive selection in BMP15 and GDF9 genes modulating ovarian function in mammalian female fertility. Ecol Evol 7:8895-8902, 2017. Pubmed reference: 29177034. DOI: 10.1002/ece3.3336.
El-Seedy, A.S., Hashem, N.M., El-Azrak, K.M., Nour El-Din, A., Ramadan, T.A., Taha, T.A., Salem, M.H. :
Genetic screening of FecB, FecX<sup>G</sup> and FecX<sup>I</sup> mutations and their linkage with litter size in Barki and Rahmani sheep breeds. Reprod Domest Anim 52:1133-1137, 2017. Pubmed reference: 28585345. DOI: 10.1111/rda.13002.
Heaton, M.P., Smith, T.P.L., Freking, B.A., Workman, A.M., Bennett, G.L., Carnahan, J.K., Kalbfleisch, T.S. :
Using sheep genomes from diverse U.S. breeds to identify missense variants in genes affecting fecundity. F1000Res 6:1303, 2017. Pubmed reference: 28928950. DOI: 10.12688/f1000research.12216.1.
Lassoued, N., Benkhlil, Z., Woloszyn, F., Rejeb, A., Aouina, M., Rekik, M., Fabre, S., Bedhiaf-Romdhani, S. :
FecX (Bar) a Novel BMP15 mutation responsible for prolificacy and female sterility in Tunisian Barbarine Sheep. BMC Genet 18:43, 2017. Pubmed reference: 28506298. DOI: 10.1186/s12863-017-0510-x.
2015 Paz, E., Quiñones, J., Bravo, S., Montaldo, H.H., Sepúlveda, N. :
Genotyping of BMPR1B, BMP15 and GDF9 genes in Chilean sheep breeds and association with prolificacy. Anim Genet 46:98-9, 2015. Pubmed reference: 25530177. DOI: 10.1111/age.12254.
Zamani, P., Nadri, S., Saffaripour, R., Ahmadi, A., Dashti, F., Abdoli, R. :
A new mutation in exon 2 of the bone morphogenetic protein 15 gene is associated with increase in prolificacy of Mehraban and Lori sheep. Trop Anim Health Prod 47:855-60, 2015. Pubmed reference: 25860388. DOI: 10.1007/s11250-015-0799-2.
2013 Demars, J., Fabre, S., Sarry, J., Rossetti, R., Gilbert, H., Persani, L., Tosser-Klopp, G., Mulsant, P., Nowak, Z., Drobik, W., Martyniuk, E., Bodin, L. :
Genome-wide association studies identify two novel BMP15 mutations responsible for an atypical hyperprolificacy phenotype in sheep. PLoS Genet 9:e1003482, 2013. Pubmed reference: 23637641. DOI: 10.1371/journal.pgen.1003482.
Farhadi, A., Genualdo, V., Perucatti, A., Hafezian, S.H., Rahimi-Mianji, G., De Lorenzi, L., Parma, P., Iannuzzi, L., Iannuzzi, A. :
Comparative FISH mapping of BMPR1B, BMP15 and GDF9 fecundity genes on cattle, river buffalo, sheep and goat chromosomes. J Genet 92:595-7, 2013. Pubmed reference: 24371182. DOI: 10.1007/s12041-013-0301-8.
Juengel, J.L., Davis, G.H., McNatty, K.P. :
Using sheep lines with mutations in single genes to better understand ovarian function. Reproduction 146:R111-23, 2013. Pubmed reference: 23801782. DOI: 10.1530/REP-12-0509.
Lahoz, B., Alabart, J.L., Folch, J., Sánchez, P., Echegoyen, E., Cocero, M.J. :
Influence of the FecX(R) allele in heterozygous ewes on follicular population and outcomes of IVP and ET using LOPU-derived oocytes. Reprod Domest Anim 48:717-23, 2013. Pubmed reference: 23438026. DOI: 10.1111/rda.12150.
Mullen, M.P., Hanrahan, J.P., Howard, D.J., Powell, R. :
Investigation of prolific sheep from UK and Ireland for evidence on origin of the mutations in BMP15 (FecX(G), FecX(B)) and GDF9 (FecG(H)) in Belclare and Cambridge sheep. PLoS One 8:e53172, 2013. Pubmed reference: 23301039. DOI: 10.1371/journal.pone.0053172.
Shabir, M., Ganai, T.A., Misra, S.S., Shah, R., Ahmad, T. :
Polymorphism study of growth differentiation factor 9B (GDF9B) gene and its association with reproductive traits in sheep. Gene 515:432-8, 2013. Pubmed reference: 23266806. DOI: 10.1016/j.gene.2012.12.018.
2011 Demmers, K.J., Smaill, B., Davis, G.H., Dodds, K.G., Juengel, J.L. :
Heterozygous Inverdale ewes show increased ovulation rate sensitivity to pre-mating nutrition. Reprod Fertil Dev 23:866-75, 2011. Pubmed reference: 21871206. DOI: 10.1071/RD10344.
Lahoz, B., Alabart, J.L., Jurado, J.J., Calvo, J.H., Martínez-Royo, A., Fantova, E., Folch, J. :
Effect of the FecX(R) polymorphism in the bone morphogenetic protein 15 gene on natural or equine chorionic gonadotropin-induced ovulation rate and litter size in Rasa Aragonesa ewes and implications for on-farm application. J Anim Sci 89:3522-30, 2011. Pubmed reference: 21622876. DOI: 10.2527/jas.2010-3828.
Roy, J., Polley, S., De, S., Mukherjee, A., Batabyal, S., Pan, S., Brahma, B., Datta, T.K., Goswami, S.L. :
Polymorphism of fecundity genes (FecB, FecX, and FecG) in the Indian Bonpala sheep. Anim Biotechnol 22:151-62, 2011. Pubmed reference: 21774623. DOI: 10.1080/10495398.2011.589239.
2010 Barzegari, A., Atashpaz, S., Ghabili, K., Nemati, Z., Rustaei, M., Azarbaijani, R. :
Polymorphisms in GDF9 and BMP15 associated with fertility and ovulation rate in Moghani and Ghezel sheep in Iran. Reprod Domest Anim 45:666-9, 2010. Pubmed reference: 19144040. DOI: 10.1111/j.1439-0531.2008.01327.x.
Polley, S., De, S., Brahma, B., Mukherjee, A., Vinesh, P.V., Batabyal, S., Arora, J.S., Pan, S., Samanta, A.K., Datta, T.K., Goswami, S.L. :
Polymorphism of BMPR1B, BMP15 and GDF9 fecundity genes in prolific Garole sheep. Trop Anim Health Prod 42:985-93, 2010. Pubmed reference: 20020203. DOI: 10.1007/s11250-009-9518-1.
2009 Drouilhet, L., Lecerf, F., Bodin, L., Fabre, S., Mulsant, P. :
Fine mapping of the FecL locus influencing prolificacy in Lacaune sheep. Anim Genet 40:804-12, 2009. Pubmed reference: 19466934. DOI: 10.1111/j.1365-2052.2009.01919.x.
Martinez-Royo, A., Dervishi, E., Alabart, J.L., Jurado, J.J., Folch, J., Calvo, J.H. :
Freemartinism and FecXR allele determination in replacement ewes of the Rasa Aragonesa sheep breed by duplex PCR. Theriogenology 72:1148-52, 2009. Pubmed reference: 19773062. DOI: 10.1016/j.theriogenology.2009.06.029.
McNatty, K.P., Heath, D.A., Hudson, N.L., Lun, S., Juengel, J.L., Moore, L.G. :
Gonadotrophin-responsiveness of granulosa cells from bone morphogenetic protein 15 heterozygous mutant sheep. Reproduction 138:545-51, 2009. Pubmed reference: 19535491. DOI: 10.1530/REP-09-0154.
Monteagudo, L.V., Ponz, R., Tejedor, M.T., Laviña, A., Sierra, I. :
A 17 bp deletion in the Bone Morphogenetic Protein 15 (BMP15) gene is associated to increased prolificacy in the Rasa Aragonesa sheep breed. Anim Reprod Sci 110:139-46, 2009. Pubmed reference: 18282670. DOI: 10.1016/j.anireprosci.2008.01.005.
2008 Hayashi, K., O'Connell, A.R., Juengel, J.L., McNatty, K.P., Davis, G.H., Bazer, F.W., Spencer, T.E. :
Postnatal uterine development in Inverdale ewe lambs. Reproduction 135:357-65, 2008. Pubmed reference: 18299429. DOI: 10.1530/REP-07-0323.
Martinez-Royo, A., Jurado, J.J., Smulders, J.P., Martí, J.I., Alabart, J.L., Roche, A., Fantova, E., Bodin, L., Mulsant, P., Serrano, M., Folch, J., Calvo, J.H. :
A deletion in the bone morphogenetic protein 15 gene causes sterility and increased prolificacy in Rasa Aragonesa sheep. Anim Genet 39:294-7, 2008. Pubmed reference: 18355397. DOI: 10.1111/j.1365-2052.2008.01707.x.
2007 Bodin, L., Di Pasquale, E., Fabre, S., Bontoux, M., Monget, P., Persani, L., Mulsant, P. :
A novel mutation in the bone morphogenetic protein 15 gene causing defective protein secretion is associated with both increased ovulation rate and sterility in Lacaune sheep. Endocrinology 148:393-400, 2007. Pubmed reference: 17038554. DOI: 10.1210/en.2006-0764.
Chu, MX., Liu, ZH., Jiao, CL., He, YQ., Fang, L., Ye, SC., Chen, GH., Wang, JY. :
Mutations in BMPR-IB and BMP-15 genes are associated with litter size in Small Tailed Han sheep (Ovis aries). J Anim Sci 85:598-603, 2007. Pubmed reference: 17040942. DOI: 10.2527/jas.2006-324.
2006 Alink, F.M., Robinson, J.J., Mylne, M.J., Kenyon, P., Watt, R.G., Wood, M.J., McEvoy, T.G. :
Number of ovulations in Texel x Scottish hill ewes carrying the Inverdale fecundity (FecX(I)) gene. Vet Rec 159:154-6, 2006. Pubmed reference: 16877682.
Davis, GH., Balakrishnan, L., Ross, IK., Wilson, T., Galloway, SM., Lumsden, BM., Hanrahan, JP., Mullen, M., Mao, XZ., Wang, GL., Zhao, ZS., Zeng, YQ., Robinson, JJ., Mavrogenis, AP., Papachristoforou, C., Peter, C., Baumung, R., Cardyn, P., Boujenane, I., Cockett, NE., Eythorsdottir, E., Arranz, JJ., Notter, DR. :
Investigation of the Booroola (FecB) and Inverdale (FecX(I)) mutations in 21 prolific breeds and strains of sheep sampled in 13 countries. Anim Reprod Sci 92:87-96, 2006. Pubmed reference: 15982834. DOI: 10.1016/j.anireprosci.2005.06.001.
Fabre, S., Pierre, A., Mulsant, P., Bodin, L., Di Pasquale, E., Persani, L., Monget, P., Monniaux, D. :
Regulation of ovulation rate in mammals: contribution of sheep genetic models. Reprod Biol Endocrinol 4:20, 2006. Pubmed reference: 16611365. DOI: 10.1186/1477-7827-4-20.
Gemmell, N.J., Slate, J. :
Heterozygote advantage for fecundity. PLoS One 1:e125, 2006. Pubmed reference: 17205129. DOI: 10.1371/journal.pone.0000125.
McNatty, K.P., Lawrence, S., Groome, N.P., Meerasahib, M.F., Hudson, N.L., Whiting, L., Heath, D.A., Juengel, J.L. :
Meat and Livestock Association Plenary Lecture 2005. Oocyte signalling molecules and their effects on reproduction in ruminants. Reprod Fertil Dev 18:403-12, 2006. Pubmed reference: 16737633. DOI: 10.1071/rd05104.
2005 Chu, MX., Sang, LH., Wang, JY., Fang, L., Ye, SC. :
[Study on BMP15 and GDF9 as candidate genes for prolificacy of Small Tail Han sheep] Yi Chuan Xue Bao 32:38-45, 2005. Pubmed reference: 15715436.
Davis, GH. :
Major genes affecting ovulation rate in sheep. Genet Sel Evol 37 Suppl 1:S11-23, 2005. Pubmed reference: 15601592. DOI: 10.1051/gse:2004026.
McNatty, K.P., Smith, P., Moore, L.G., Reader, K., Lun, S., Hanrahan, J.P., Groome, N.P., Laitinen, M., Ritvos, O., Juengel, J.L. :
Oocyte-expressed genes affecting ovulation rate. Mol Cell Endocrinol 234:57-66, 2005. Pubmed reference: 15836953. DOI: 10.1016/j.mce.2004.08.013.
Moore, RK., Shimasaki, S. :
Molecular biology and physiological role of the oocyte factor, BMP-15. Mol Cell Endocrinol 234:67-73, 2005. Pubmed reference: 15836954. DOI: 10.1016/j.mce.2004.10.012.
2004 Davis, GH. :
Fecundity genes in sheep. Anim Reprod Sci 82-83:247-53, 2004. Pubmed reference: 15271457. DOI: 10.1016/j.anireprosci.2004.04.001.
Hanrahan, JP., Gregan, SM., Mulsant, P., Mullen, M., Davis, GH., Powell, R., Galloway, SM. :
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). Biol Reprod 70:900-9, 2004. Pubmed reference: 14627550. DOI: 10.1095/biolreprod.103.023093.
Juengel, J.L., Hudson, N.L., Whiting, L., McNatty, K.P. :
Effects of immunization against bone morphogenetic protein 15 and growth differentiation factor 9 on ovulation rate, fertilization, and pregnancy in ewes. Biol Reprod 70:557-61, 2004. Pubmed reference: 14585806. DOI: 10.1095/biolreprod.103.023333.
Juengel, JL., Bodensteiner, KJ., Heath, DA., Hudson, NL., Moeller, CL., Smith, P., Galloway, SM., Davis, GH., Sawyer, HR., McNatty, KP. :
Physiology of GDF9 and BMP15 signalling molecules. Anim Reprod Sci 82-83:447-60, 2004. Pubmed reference: 15271472. DOI: 10.1016/j.anireprosci.2004.04.021.
Liao, W.X., Moore, R.K., Shimasaki, S. :
Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors bone morphogenetic protein-15 and growth and differentiation factor-9. J Biol Chem 279:17391-6, 2004. Pubmed reference: 14970198. DOI: 10.1074/jbc.M401050200.
Souza, C.J., González-Bulnes, A., Campbell, B.K., McNeilly, A.S., Baird, D.T. :
Mechanisms of action of the principal prolific genes and their application to sheep production. Reprod Fertil Dev 16:395-401, 2004. Pubmed reference: 15315738. DOI: 10.10371/RD04038.
2003 Hanrahan, J.P. :
Aspects of reproductive performance in small ruminants--opportunities and challenges. Reprod Suppl 61:15-26, 2003. Pubmed reference: 14635923.
Liao, W.X., Moore, R.K., Otsuka, F., Shimasaki, S. :
Effect of intracellular interactions on the processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9. Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep. J Biol Chem 278:3713-9, 2003. Pubmed reference: 12446716. DOI: 10.1074/jbc.M210598200.
2002 Davis, G.H., Galloway, S.A., Ross, I.K., Gregan, S.M., Ward, J., Nimbkar, B.V., Ghalsasi, P.M., Nimbkar, C., Gray, G.D., Subandriyo., Inounu, I., Tiesnamurti, B., Martyniuk, E., Eythorsdottir, E., Mulsant, P., Lecerf, F., Hanrahan, J.P., Bradford, G.E., Wilson, T. :
DNA tests in prolific sheep from eight countries provide new evidence on origin of the Booroola (FecB) mutation Biology of Reproduction 66:1869-1874, 2002. Pubmed reference: 12021074.
Galloway, S.M., Gregan, S.M., Wilson, T., McNatty, K.P., Juengel, J.L., Ritvos, O., Davis, G.H. :
Bmp15 mutations and ovarian function. Mol Cell Endocrinol 191:15-8, 2002. Pubmed reference: 12044914.
Juengel, J.L., Hudson, N.L., Heath, D.A., Smith, P., Reader, K.L., Lawrence, S.B., O'Connell, A.R., Laitinen, M.P., Cranfield, M., Groome, N.P., Ritvos, O., McNatty, K.P. :
Growth differentiation factor 9 and bone morphogenetic protein 15 are essential for ovarian follicular development in sheep. Biol Reprod 67:1777-89, 2002. Pubmed reference: 12444053. DOI: 10.1095/biolreprod.102.007146.
Monget, P., Fabre, S., Mulsant, P., Lecerf, F., Elsen, J.M., Mazerbourg, S., Pisselet, C., Monniaux, D. :
Regulation of ovarian folliculogenesis by IGF and BMP system in domestic animals. Domest Anim Endocrinol 23:139-54, 2002. Pubmed reference: 12142233.
2001 Davis, G.H., Bruce, G.D., Dodds, K.G. :
Ovulation rate and litter size of prolific Inverdale (FecX I) and Hanna (FecX H) sheep Proceedings AAABG 14:175-178, 2001.
McNatty, K.P., Juengel, J.L., Wilson, T., Galloway, S.M., Davis, G.H. :
Genetic mutations influencing ovulation rate in sheep Reproduction, Fertility and Development 13:549-555, 2001. Pubmed reference: 11999305.
Montgomery, G.W., Galloway, S.M., Davis, G.H., McNatty, K.P. :
Genes controlling ovulation rate in sheep Reproduction 121:843-852, 2001. Pubmed reference: 11373170.
2000 Bodensteiner, K.J., McNatty, K.P., Clay, C.M., Moeller, C.L., Sawyer, H.R. :
Expression of growth and differentiation factor-9 in the ovaries of fetal sheep homozygous or heterozygous for the inverdale prolificacy gene (FecX(I)). Biol Reprod 62:1479-85, 2000. Pubmed reference: 10819747.
Galloway, S.M., McNatty, K.P., Cambridge, L.M., Laitinen, M.P.E., Juengel, J.L., Jokiranta, T.S., McLaren, R.J., Luiro, K., Dodds, K.G., Montgomery, G.W., Beattie, A.E., Davis, G.H., Ritvos, O. :
Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner Nature Genetics 25:279-283, 2000. Pubmed reference: 10888873. DOI: 10.1038/77033.
Juengel, J.L., Quirke, L.D., Tisdall, D.J., Smith, P., Hudson, N.L., McNatty, K.P. :
Gene expression in abnormal ovarian structures of ewes homozygous for the Inverdale prolificacy gene Biology of Reproduction 62:1467-1478, 2000. Pubmed reference: 10819746.
Mandiki, S.N.M., Noel, B., Bister, J.L., Peeters, R., Beerlandt, G., Decuypere, E., Visscher, A., Suess, R., Kaulfuss, K.H., Paquay, R. :
Pre-ovulatory follicular characteristics and ovulation rates in different breed crosses, carriers or non-carriers of the Booroola or Cambridge fecundity gene Animal Reproduction Science 63:77-88, 2000. Pubmed reference: 10967242.
1999 Davis, G.H. :
Early history of the Inverdale gene In: Data and Legends: 50 Years of Invermay 1949-1999 (Ed. G. Shackell) AgResearch Invermay, Mosgiel, NZ :85-91, 1999.
Reynaud, K., Hanrahan, J.P., Donovan, A., Driancourt, M.A. :
Markers of follicle function in Belclare-cross ewes differing widely in ovulation rate. J Reprod Fertil 116:51-61, 1999. Pubmed reference: 10505056.
1998 Davis, G.H., Morris, C.A., Dodds, K.G. :
Genetic studies of prolificacy in new zealand sheep Animal Science 67:289-297, 1998.
1997 Ap Dewi, I., Owen, J.B., Axford, R.F.E., Beiginassiri, M.T. :
Selection for high and low prolificacy in Cambridge sheep Animal Science 65:209-215, 1997.
Glazko, V.I., Owen, J.B., Apdewi, I., Axford, R.F.E. :
An association of haemoglobin protein (hbb) with ovulation rate in Cambridge sheep Animal Science 64:279-282, 1997.
Mcleod, B.J., Fenton, L.F., Davis, G.H., Bruce, G.D., Manley, T.R., Johnstone, P.D. :
Identifying infertile homozygous Inverdale (Fecx(I)) ewe lambs on the basis of genotype differences in reproductive hormone concentrations Animal Reproduction Science 47:291-302, 1997. Pubmed reference: 9360768.
Smith, P., O, W.S., Corrigan, K.A., Smith, T., Lundy, T., Davis, G.H., Mcnatty, K.P. :
Ovarian morphology and endocrine characteristics of female sheep fetuses that are heterozygous or homozygous for the Inverdale prolificacy gene (FecX(I)) Biology of Reproduction 57:1183-1192, 1997. Pubmed reference: 9369186.
1995 Davis, G.H., McEwan, J.C., Fennessy, P.F., Dodds, K.G. :
Discovery of the Inverdale gene (FecX) Proceedings of the New Zealand Society of Animal Production 55:289-290, 1995. DOI: 10.13140/2.1.4467.0088.
McNatty, K.P., Smith, P., Hudson, N.L., Heath, D.A., Tisdall, D.J., WSO, Brawtal, R. :
Development of the sheep ovary during fetal and early neonatal life and the effect of fecundity genes Journal of Reproduction and Fertility Suppl. 49:123-135, 1995.
1994 Davis, G.H., Bruce, G.D., Reid, P.J. :
Breeding implications of the streak ovary condition in homozygous FecXI/FecXI Inverdale sheep Proceedings of the 5th World Congress on Genetics Applied to Livestock Production 19:249–252, 1994.
1993 Brawtal, R., Mcnatty, K.P., Smith, P., Heath, D.A., Hudson, N.L., Phillips, D.J., Mcleod, B.J., Davis, G.H. :
Ovaries of Ewes Homozygous for the X-Linked Inverdale Gene (FecX(1)) Are Devoid of Secondary and Tertiary Follicles But Contain Many Abnormal Structures Biology of Reproduction 49:895-907, 1993. Pubmed reference: 8286585.
Davis, G.H., Dodds, K.G., Mcewan, J.C., Fennessy, P.F. :
Liveweight, Fleece Weight and Prolificacy of Romney Ewes Carrying the Inverdale Prolificacy Gene (FecX1) Located on the X-Chromosome Livestock Production Science 34:83-91, 1993.
Shackell, G.H., Hudson, N.L., Heath, D.A., Lun, S., Shaw, L., Condell, L., Blay, L.R., Mcnatty, K.P. :
Plasma Gonadotropin Concentrations and Ovarian Characteristics in Inverdale Ewes That Are Heterozygous for a Major Gene (FecX(1)) on the X-Chromosome That Influences Ovulation Rate Biology of Reproduction 48:1150-1156, 1993. Pubmed reference: 8386945.
1992 Davis, G.H., McEwan, J.C., Fennessy, P.F., Dodds, K.G., McNatty, K.P., O, W.S. :
Infertility due to bilateral ovarian hypoplasia in sheep homozygous (FecXI FecXI) for the Inverdale prolificacy gene located on the X chromosome. Biol Reprod 46:636-40, 1992. Pubmed reference: 1533540.
Montgomery, G.W., Mcnatty, K.P., Davis, G.H. :
Physiology and Molecular Genetics of Mutations That Increase Ovulation Rate in Sheep Endocrine Reviews 13:309-328, 1992. Pubmed reference: 1618165.
Swarbrick, P.A., Schmack, A.E., Crawford, A.M. :
MAF45, a Highly Polymorphic Marker for the Pseudoautosomal Region of the Sheep Genome, Is Not Linked to the FecX(1) (Inverdale) Gene Genomics 13:849-851, 1992. Pubmed reference: 1639413.
1991 Davis, G.H., Mcewan, J.C., Fennessy, P.F., Dodds, K.G., Farquhar, P.A. :
Evidence for the Presence of a Major Gene Influencing Ovulation Rate on the X-Chromosome of Sheep Biology of Reproduction 44:620-624, 1991. Pubmed reference: 2043732.
1990 Owen, J.B., Whitaker, C.J., Axford, R.F.E., Dewi, I.A. :
Expected Consequences of the Segregation of a Major Gene in a Sheep Population in Relation to Observations on the Ovulation Rate of a Flock of Cambridge Sheep Animal Production 51:277-282, 1990.
1989 Hanrahan, J.P., Owen, J.B. :
Single gene effects on ovulation rate in Cambrideg ewes Proceedings of the 40th Annual Meeting, European Association of Animal Production, Summaries 1:65 only (abstract), 1989.
1985 Hanrahan, J.P., Owen, J.B. :
Variation and repeatability of ovulation rate in Cambridge ewes Animal Production 40:529 only (abstract), 1985.

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