In other species: pig , goat

Categories: Reproductive system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 300247 (gene) , 300510 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Disease-related: 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. Ji et al. (2023) “performed an association analysis of the 13 new mutations and 7 known ovine prolificacy-related mutations [in the BMPRIB, GDF9, BMP15, LEPR, and B4GALNT2 genes] with litter size in Ujimqin, the F1 population of Dorper × Ujimqin crossbred, and the F1 population of Suffolk × Ujimqin crossbred. The results suggested that BMPR1B c.746A>G (FecB), GDF9 c.994A>G ... [variant G6 reported by Hanrahan et al. (2004)], and BMP15 c.31_33CTTinsdel (B1) may be potentially effective genetic markers to improve the litter size in sheep.” 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).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: