In other species: dog , goat

Categories: Reproductive system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601918 (gene) , 618014 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: no

Key variant known: yes

Year key variant first reported: 2004

Species-specific symbol: FecG

Species-specific description: The following OMIA entries relating to specific variants in the GDF9 gene and their impact on fecundity have been incorporated into this entry: OMIA:001961-9940 Fecundity, Vacaria, FecG(V) (4th October 2021) OMIA:001763-9940 Fecundity, Norwegian White Sheep (4th October 2021) OMIA:001559-9940 Fecundity, Embrapa, FecG(E) (4th October 2021) OMIA:001801-9940 Fecundity, High fertility, FecG(H) (5th October 2021) OMIA:000385-9940 Fecundity, Thoka, FecG(T) (5th October)

History: A segregation analysis of Icelandic sheep by Jonmundsson and Adalsteinsson (1985) provided substantial evidence for a gene of large effect on litter size. These authors named the gene Thoka, after the ewe from which the gene appears to have originated. Heterozygotes give birth to an extra 0.64 lambs, on average. In a segregation analysis of data from a Cheviot flock into which the Thoka gene was introduced via Icelandic rams, Walling et al. (2002) confirmed the existence of a gene of large effect on fecundity, but there was some evidence that this gene was present in the flock before the Icelandic introduction. Since this evidence is only preliminary, the gene will be assumed to be Thoka until further evidence is assembled [FN 13 Jan 2003] Hanrahan et al. (2004) reported a mutation in the gene GDF9 "associated with increased ovulation rate in heterozygous carriers and sterility in homozygous carriers" in the Irish Cambridge and Belclare breeds. They also reported that "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."

Molecular basis: Hanrahan et al. (2004) identified a variant c.1184C>T, p.(S395F) which they named FecG(H), with G indicating the GDF9 gene and H indicating high fertility. These authors reported that "The effect of FecGH was 1.79 ± 0.548 (P < 0.01) in Belclare ewes and 2.35 ± 0.386 (P < 0.001) in Cambridge ewes" and that "All ewes that were homozygous for FecGH . . . were sterile". Nicol et al. (2009) identified the causal mutation of Thoka fecundity as "a single base change (A1279C) resulting in a non-conservative amino acid change (S109R) in the C-terminus of the mature GDF9 protein, which is normally expressed in oocytes at all stages of development". Silva et al. (2011) reported a missense mutation (c.1034T>G; p.Phe345Cys) in the GDF9 gene of Brazilian Santa Inês sheep, giving rise to increases of 82% and 58% for ovulation rate and prolificacy, respectively, compared with homozygous wild-type. They named this allele FecG(E), where E stands for Embrapa, the Brazilian Agricultural Research Corporation. Using the sheep SNP50 bead chip to conduct a GWAS for litter size estimated breeding value (EBV) on 378 progeny-tested Norwegian White Sheep rams, Våge et al. (2013) identified a QTL on chromosome OAR5, very near to the GDF9 gene, mutations in which have large effects on fecundity in other breeds of sheep. Subsequent sequencing of this gene in the most extreme sires revealed a SNP "(c.1111G>A), responsible for a Val->Met substitution at position 371 (V371M). This polymorphism has previously been identified in Belclare and Cambridge sheep, but was not found to be associated with fertility." The authors concluded that "Based on the estimated breeding values, daughters of AI rams homozygous for c.1111A will produce minimum 0.46 - 0.57 additional lambs compared to daughters of wild-type rams." Mullen and Hanrahan (2014) reported the same variant as having a significant effect on fecundity in Finnish Landrace (Finnsheep), and proposed that the variant be named FecG(F), where F is for Finnsheep. Souza et al. (2014) reported a variant in the GDF9 gene in the Ile de France breed in Brazil. The authors described its effect as "Vacaria heterozygotes had higher OR (P<0.001), averaging 2.1 +/- 0.1 when compared to 1.2 +/- 0.1 in wild-type ewes. The OR was also influenced by age, increasing in the second and third breeding seasons (P<0.001). In flocks segregating this allele, the LS was higher in mutant sheep (P<0.001), averaging 1.61 +/- 0.07 in heterozygotes and 1.29 +/- 0.03 in wild-type ewes. Analysis of homozygote reproductive tract morphology revealed uterine and ovarian hypoplasia. Ovarian follicles continue to develop up to small antral stages, although with abnormal oocyte morphology and altered arrangement of granulosa cells. After the collapse of the oocyte in most follicles, the remaining cells formed clusters that persisted in the ovary." Souza et al. (2014) named the variant Vacaria FecG(v) "after the city where the first flocks with this polymorphism were located". They reported it as a missense mutation: c.943C>T; p.Arg315Cys in the cleavage site of the propeptide encoded by GDF9. Bravo et al. (2016): Sequencing of the GDF9 revealed eight single nucleotide polymorphisms (SNPs), including seven documented and one novel SNP, named FecGA (Araucana) [c.750G>A; (p.Arg250Arg), ss1947221108] ... . Both the c.978A>G and c.994G>A SNPs [variant G5 and G6 reported by Hanrahan et al. (2004)] showed an association with LS (P < 0.05), but only c.994G>A is non-silent, leading to a p.Val332Ile substitution in a mature protein. ... Our results suggest that c.978A>G and c.994G>A SNPs are genetic markers for fecundity in ACS." Pérez-Ruiz et al. (2020) reported the FecG(E) variant having a major effect on fecundity in the Mexican Pelibuey breed. Holm et al. (2021) "analyzed samples from Icelandic sheep with the aim of identifying the genetic cause of the Icelandic Loa phenotype using three previously identified prolificacy genes as candidates. We demonstrate that a 4-bp frameshift deletion positioned in the mature region of the GDF9 protein in the Loa animals is a likely causal mutation for the observed increase in prolificacy; however, sequencing showed that not all ewes with a high number of offspring carried the deletion, suggesting the presence of a second mutation segregating within this group of animals." Zhao et al. (2023): "In this study, a single base editing system was used to edit the FecB and GDF9 gene to achieve a targeted site mutation from A to G and from C to T in Ouler Tibetan sheep fibroblasts, and to test its editing efficiency." This study involves genetically modified organisms (GMO) 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.”

Breeds: Belclare (Sheep) (VBO_0001322), Cambridge (Sheep) (VBO_0001355), Criollo araucana, Chile (Sheep) (VBO_0015719), Finnish Landrace (Sheep) (VBO_0001414), Gammelnorsk spaelsau, Norway (Sheep) (VBO_0016295), Icelandic (Sheep) (VBO_0001442), Ile-De-France (Sheep) (VBO_0001444), Pelibuey, Mexico (Sheep) (VBO_0015035), Santa Ines, Brazil (Sheep) (VBO_0015203).
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: