In other species: goat

Categories: Reproductive system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 134720 (trait) , 609441 (trait) , 603248 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: no

Key variant known: yes

Year key variant first reported: 2001

Species-specific name: Booroola

Species-specific symbol: FecB(B)

Species-specific description: On their farm called 'Booroola' near Cooma in New South Wales, Australia, the Seears brothers developed a prolific strain of Merino, with an average litter size of more than 2, in contrast to the usual litter size of Merinos, which is less than 1. Sheep from this flock were studied by the CSIRO (Helen Turner, Laurie Piper, Bernie Bindon and colleagues), and it was eventually shown that the prolificacy of the Booroola strain was due to a single gene of large effect, which acts additively for both ovulation rate and litter size (Piper and Bindon, 1982; Davis et al., 1982; Piper et al., 1985). The difference between homozygotes is approximately 2.7-3.0 in ovulation rate and 1.1-1.7 in litter size. The genetical and physiological basis of the Booroola's prolificacy was also studied extensively by New Zealand researchers, who provided one of the first examples of the practical application of gene mapping in sheep, by mapping the Booroola gene to chromosome 6 (Montgomery et al., 1993, 1994), as described in the Mapping section below. Analysis of reproductive data from three breeds of Indonesian sheep (Javanese Thin Tail, Javanese Fat Tail, Semarang) produced substantial evidence for the presence of a gene of large effect on ovulation rate and litter size in all three breeds (Bradford et al., 1986). The difference between homozygotes was estimated to be 2.6 for ovulation rate and 1.8-2.0 for litter size. Since all three breeds are thought to have intermated from time to time, it was not considered surprising that apparently the same gene occurs in all three breeds. Davis et al. (2002) showed that this gene is actually the Booroola mutation, FecB(B). They concluded "It is unknown whether Javanese Thin-tailed sheep acquired the Booroola gene directly from Garole sheep from India or via Merinos from Australia."

History: The first reports of the segregation of a major gene for fecundity in Booroola Merinos were by Piper et al. (1982; both papers) and Davis et al. (1982).

Mapping: The first attempts to linkage-map the FecB gene involved just 18 polymorphic protein markers (Tate et al., 1992) and 11 polymorphic blood markers (Nguyen et al., 1992). In neither case was any marker linked to FecB, thus enabling the researchers to exclude regions of the as-yet unknown sheep genome in the vicinity of those markers. The following year, still "in the absence of any genetic map for sheep", Montgomery et al. (1993) assembled a veritable arsenal of 137 markers: "55 known RFLPs, 58 random sheep microsatellites and 24 random RFLP markers". Two of the microsatellites were found to be linked to FecB, namely OarAE101 (13cM) and OarHH55 (20cM). More importantly, an RFLP in the SPP1 gene was also found to be linked to FecB (14 cM). Noting that SPP1 in humans is located on chromosome HSA4q, Montgomery et al. (1993) then examined RFLPs in other genes in that region of HSA4q, and found another HSA4q gene linked to FecB, namely EGF (26 cM). The authors concluded that the most likely location of the FecB gene in the sheep genome is between the sheep versions of SPP1 and EGF. It is an interesting sign of the then times that the actual sheep chromosome on which these markers are located had not yet been determined. Consequently, the title of the paper referred to the FecB gene having been mapped to "a region of human chromosome 4q". The importance of this result at that time is indicated by the paper appearing in Nature Genetics, and by the results stimulating Dr McKusick to create an entry entitled "Fecundity gene, Booroola, of sheep, homolog of" in the human gene catalogue OMIM (see above link to OMIM 134720). The identity of the chromosome was revealed the next year, when Montgomery et al. (1994) used a sheepxhamster somatic cell hydrid panel to physically map the markers linked to FecB, to sheep chromosome OVA6. The following year, Montgomery et al. (1995) reported that some fine-mapping in the FecB region had narrowed down the region to near the centromere of OVA6.

Markers: 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.” Mo et al. (2021) used Sanger sequencing to detect five SNPs (rs427897187 G > A, rs418841713 A > G, rs159952533 T > C, rs429416173 C > A and rs403555643 A > G) in the BMPR1B gene in Small Tail Han, Hu, Mongolian, Oula, Gansu Alpine Fine-wool, Dorper and Australian White sheep. The authors proposed that rs427897187 G > A and rs403555643 A > G could be useful markers to improve litter size in Chinese indigenous sheep breeding.
Cao et al. (2024) "investigate SNPs in the BMPR1B gene via whole genome sequence (WGS) data from 2409 individuals of 75 sheep breeds worldwide. ... a total of 9688 variants were screened, among which 15 were coding variants and 8 were novel changes. ... one synonymous mutation (g.30050773C > T) was found to be likely under selection and is potentially associated with fecundity in Duolang sheep."

Molecular basis: The molecular basis of FecB was finally resolved by three independent groups of researchers, in three separate papers published within a month of each other in 2001. Working on New Zealand Booroola sheep, Wilson et al. (2001; published 1 April) fine-mapped FecB to a 4cM region of OVA6, and then identified a microsatellite marker (JL36) with zero recombination with FecB, homologous with HSA4q21-24. The most likely candidate gene in this region was the gene encoding the receptor for BMP-IB, i.e. the BMPR-IB gene. Sequencing of the ovine BMPR-IB gene revealed "a point mutation (an A to G transition) at position 830 . . . This translates to a change from a glutamine (neutral/polar amino acid) to an arginine (basic amino acid) at position 249 of the protein [Q249R] . . . in the intracellular kinase signaling domain of the BMPR-IB. Glutamine is conserved at this position in most of the type I receptors." Working on a flock of Booroolas in France, Mulsant et al. (2001; 24 April) did their own fine-mapping and comparative mapping, also ending up with the BMPR-IB gene as the most likely comparative positional candidate. Sequencing revealed the same Q249R mutation. Working with Booroola sheep in Edinburgh and Brazil, Souza et al. (2001; 1 May) also zeroed in on BMPR-IB as the most likely comparative positional candidate gene, and identified the same Q249R mutation. Chu et al. (2007) showed that the fecundity of the Small Tailed Han breed is due to the segregation of the FecB(B) mutation (Q249R) in the BMPR1B gene and the FecX(G) mutation (Q239Ter) of the BMP15 gene (OMIA 002306-9940). Akhatayeva et al. (2021) evaluated “the association between polymorphisms in this gene and sheep litter size from all appropriate studies. As a result, among 41 polymorphisms in the ovine BMPRIB [BMPR1B] gene, eight variants, including p.Q249R (g.746A > G), g.29362047T > C, g.29427689G > A, BMPR1B-2 (ss:1960972599), g.29382337G > A, g.29382340G > A, rs1092293287 (10 bp insertion/deletion) and g.29380965A > G were found to be associated with litter size in sheep.” 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 BMPR1B, 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.” Zhou et al. (2023) used prime editing to generate sheep with the FecBB p.Q249R variant. (This study involves genetically modified organisms (GMO)).

Breeds: Booroola (Sheep) (VBO_0001345), Duolang, China (Sheep) (VBO_0015741), Ekor Tipis, Indonesia (Sheep) (VBO_0016006), Javanese Fat Tail, Indonesia (Sheep) (VBO_0016876), Semarang, Indonesia (Sheep) (VBO_0016877), Small Tailed Han, China (Sheep) (VBO_0015757).
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: