Mutations identified in sheep at the
Major genes increasing litter size were identified in certain sheep breeds. These genes include BMPR‐1B, BMP15, GDF9 and B4GALNT2, FecX2. Polish Olkuska sheep is a high‐fecundity sheep breed; while some animals might give birth to just one or two lambs, there are Olkuska ewes which have six or even seven lambs/lambing. Fertility of this breed is caused by mutation in the major gene FecXO (BMP15 gene), but analysis of polymorphism at the locus GDF9 revealed presence of four polymorphisms: G447A (L159L), A978G (G326G), G994A (V332I) and G1111A (V371M). Substitutions V371 and V332I are missense mutations found in the sequence encoding active GDF9 protein. V371 polymorphism has also an effect on litter size in Olkuska breed ewes. Study of genes associated with litter size in Olkuska sheep is of high importance, as they could be used in breeding programmes as selection markers for increasing production efficiency.
- litter size
- Olkuska sheep
Currently, more than 1200 sheep breeds differing in many production features, including fertility, are known globally. Ewes usually give birth to one or two lambs/litter. However, there are certain highly prolific breeds—such as
Most mutations increasing ovulation levels and the number of lambs born to an ewe were identified in genes encoding proteins belonging to the family of transforming growth factors TGF‐β: BMPR1B (bone morphogenetic protein receptor‐1B), BMP15 (bone morphogenetic protein 15) and GDF9 (growth differentiation factor 9). In addition, mutations FecLL in Lacaune breed on chromosome 11 and FecX2W (fecundity gene
1.1. FecB mutation in the bone morphogenetic protein receptor 1B (
Booroola was the first major gene (FecB) significantly influencing level of ovulation and litter size in sheep to be identified . The effect of FecB mutation (Q249R) identified in Booroola Merino breed in the gene of bone morphogenetic protein receptor
Many authors have shown high fertility of carriers of FecBB+ genotype, among others in Garole‐223% lamb production , Hu‐210%, Han‐240%  and Javanese breeds‐259% . Research results in Indian sheep of Muzaffarnagari breed engendered some discussion, as presence of ewes with FecB gene that still had single births was proven, and share of sheep with genotypes FecBBBand FecBB+ was identified as 3.47 and 41.73%, respectively .
In antral follicles of FecBB+ ewes, a decrease in granulosa cell proliferation and premature expression of LH receptors were observed . Appearance of FecB mutation in sheep compared with ewes devoid of mutation is associated with higher number of growing small cavitary (antral) follicles on the ovaries. Both total number of granulosa cells and total secretion of estradiol and inhibins in the ovaries of FecBBB ewes still remain the same as in ewes with FecB++ genotype. Significant impact of gene FecB on development of ovaries during foetal life is also observed, including,
1.2. Mutations in the gene of bone morphogenetic protein 15 (
1.2.1. Protein BMP15
BMP15 protein together with growth factor 9 (GDF9) plays an important role in folliculogenesis [13, 14]. Its paracrine action affects granulosa cells, theca cells and the oocyte itself .
1.2.2. Polymorphism in the
In mammals, formation of BMP15 protein is determined by action of a single gene on chromosome X . An encoded sequence with a length of 1179 bp is contained in two exons separated by an intron of 5400 bp in length. mRNA translation produces a peptide built of 393 amino acids, and the resulting mature protein has a length of 125 amino acids . Mutations identified in the
|Variant||Base change||Coding base bp||Coding residue*||Amino acids change||Mutation/reference|
Substitution of FecXH detected in Hanna sheep causes introduction of a stop codon in place of glutamine in position 23 of amino acid residue of mature protein. Transition C>T observed in the case of FecXG in Galoway and Cambridge breeds, also introduces a premature stop codon in place of glutamine at position 31 of the polypeptide chain. As concerns carriers of these mutations, heterozygotes show increased levels of ovulation, while homozygotes with two copies of the gene are infertile .
A similar phenotype is observed for FecXI mutation, where hydrophobic valine is substituted for asparagine at position 31 of mature protein. This leads to changes in electrostatic potential of the region involved in formation of dimers—this, in turn, interferes with dimerization and consequently leads to the elimination of biological effects of BMP15. Homozygous ewes are infertile due to folliculogenesis being arrested at initial stage of the process .
FecXB mutation found in
One copy of the allele FecXI (Inverdale) or FecXH (Hanna) results in ovulation level increase of +0.8–1.0 CL, significantly affecting size of the litter by +0.6 lamb. Homozygous FecXII and FecXHH Hanna ewes are sterile; in their small and poorly developed ovaries, follicles are provided with a single layer of granulosa cells . In FecXI+ sheep, follicles were determined to be of a smaller diameter than those produced in ovaries of homozygotes devoid of mutation. However, FecXI+ ewes present a greater number of mature preovulatory dominant follicles of smaller diameter, and therefore do not differ in the level of estradiol and inhibin from non‐mutated ones . Preovulatory follicles are also characterized by early maturation, which determines greater secretion of FSH and early formation of LH receptors .
Studies by Bodin et al.  on prolific sheep of Lacaune breed showed presence of FecXL mutation, leading to substitution of cysteine for tyrosine at position 53 of the BMP15 chain. Just as observed in the case of polymorphisms (FecXI, FecXH, FecXG and FecXB), also this change in gene structure causes increased level of ovulation in heterozygous ewes and infertility in homozygotes.
Lacaune sheep are, next to Hanna, Inverdale, Cambridge, Belclare and small‐tail Han breeds, an example where increase in litter size is determined by the presence of two major genes: FecXL and FecL on autosomal chromosome 11 .
In Aragonesa FecXR ewes, a 17 bp deletion results in a frameshift and appearance of a stop codon, even before the coding region of mature protein. The consequence of this mutation is an 85% modification in the propeptide sequence, specifically limitation of its size to 45 amino acids out of 245 present in the original propeptide. Heterozygous ewes are very highly fecund, while the presence of two copies of the mutated gene leads to a blockage of follicular development at initial growth state and female infertility. FecXR+ ewes have an average of 2.66 lamb/litter compared to flock average of 1.36. Presence of one copy of the gene resulted in litter size increase of +1.3 lamb .
A mutation in the gene
Recent research in phenomenon of high fertility of ewes of the African breed Barbarine (167% annual lamb crop) showed presence of another substitution in the gene encoding
1.2.3. Mutations in the growth differentiation factor 9 (
220.127.116.11. Protein GDF9
Growth differentiation factor 9 (GDF9) is another protein belonging to TGF‐β family. This peptide regulates development of ovarian follicles in rodents and ruminants (sheep), as well as humans [12, 29]. It has been shown that its synthesis, similarly as in the case of BMP15, occurs in the oocyte . Mice lacking functional protein GDF9 (GDF9KO) were infertile, their follicle growth was arrested at primary follicle stage, with granulosa cells layer not properly formed, and changes in the zona pellucida. Oocytes were excessively enlarged and surrounded by a single layer of deformed granulosa cells, or oocyte was not observed in the follicle whatsoever [30, 31]. Growth differentiation factor 9 as a multi‐functional protein is responsible for follicular growth from its early stage—it initiates and regulates folliculogenesis and oocyte development. It has autocrine effects on oocytes, plays a role in their development and maturation, and paracrine effects on somatic cells, inhibits expression of luteinizing hormone receptor gene and stimulating synthesis of hyaluronic acid [32, 33].
18.104.22.168. Polymorphism in the
The gene encoding protein GDF9 was found to be located in sheep on chromosome 5 . The gene consists of two exons, with length of 397 and 968 bp, respectively. Its total length is 5644 bp, with coding sequence comprised of 1359 nucleotides .
A number of mutations (Table 2) were identified in gene
|Variant||Base change||Coding base bp||Coding residue*||Amino acids change||Mutation/reference|
Mutation FecGH (G8) occurs within the sequence responsible for coupling a protein to the receptor and is a missense mutation. As a result, synthesized protein exhibits less affinity for the cell surface receptor. Ewes with one copy of the gene with FecGH mutation have higher ovulation level. Early maturation of small secondary follicles, inhibition of their growth and earlier ovulation of a larger number of oocytes were noted . Most likely, early maturation of the developing follicles is associated with inhibition of FSH receptor expression at mRNA level due to the absence of biologically active GDF9 . The fact that the FecGH mutation determines the decrease in quantity of active form of GDF9 was confirmed by immunization of ewes, which caused increase in ovulation level . Presence of FecGH resulted in increased litter size in Belclare sheep, from 1.98 in animals lacking the mutation to 2.67 lamb/litter in heterozygotes; for Cambridge sheep, the litter size surged from 2.27 to 4.28 lamb/litter.
Phenotypic effect similar to FecGH was observed for FecGT mutation in Icelandic Thoka sheep breed .
The results of research conducted on Brazilian Santa Ines breed indicate that presence of a mutation called FecGE (Embrapa) in
2. Genes determining litter size in Olkuska sheep
2.1. Mutations in the
Analysing reasons behind high fertility of the prolific Olkuska sheep breed, neither FecXI mutation in
Substitution of N237K was identified outside the coding region of mature peptide in most studied ewes, and no connection with their fertility was demonstrated. FecXO was located in exon 2, in the coding sequence of mature protein (position 69 aa), right next to the sites of the mutations FecXI, FecXH, FecXL and FecXB found, respectively, at positions 39, 23, 53 and 99 aa of mature protein.
Two alleles (A and C) and three genotypes (AA, AC and CC) were found for the A1009C mutation identified in the sequence encoding BMP15 mature protein. The C allele (with N337H mutation) had a frequency of 0.55 and ewes with one (AC) and two (CC) copies of the gene constituted 56 (AC) and 27% (CC) of the animals, respectively .
2.1.1. Effects of N337H mutation on litter size of Olkuska sheep
Analysis of effects of mutation N337H on litter size of ewes showed a significant impact of polymorphism on prolificacy, which in sheep of genotype FecX++ was 1.74 ± 0.55 lamb/litter, with 2.47 ± 0.77 and 2.98 ± 1.50 lamb/litter for FecX+O and FecXOO genotypes, respectively . Very similar results showed Demars et al.  for genotypes FecX++, FecX+O and FecXOO namely, 1.84, 2.46 and 3.05, respectively.
Changes in litter size in subsequent lambings of Olkuska ewes show an increase in fecundity correlated with increasing age of a mother. The maximum size of litter in FecXOO ewes was noted in their third lambing, with ewes giving birth to an average of 3 lambs/litter. However, for mothers with genotype FecX++, litter size continued to increase up to their fourth lambing, when the litter size reached 2.25 lambs . Increase in the number of lambs in the first three consecutive lambings, and then subsequent decrease in litter size has been demonstrated in studies on other highly prolific sheep breeds. Liu et al.  showed that average litter size for FecBBB homozygotes in small‐tail Han sheep was 2.47 in the first lambing of an ewe, and 3.17 for older mothers. Increase in litter size as ewes were aging was also observed in Chinese Hu breed. Carriers of
2.1.2. Litter size in Olkuska sheep population
In all herds of sheep breeds with a segregating major gene, distribution of litter size similar to the one determined in Olkuska sheep, that is, with high proportion of twin births and large share of triplets and larger litters, was determined. Distribution analysis of litters of Olkuska ewes showed that 29% of FecXOO mothers gave birth to four or more lambs in a litter, including sextuplets and septuplets. In the most numerous group of FecX+O ewes, only 14% of animals showed similar litter size, and among sheep of genotype FecX++ no litters of such size were observed (Table 4).
|Gene/genotype||Litter size of ewes (lambs)|
|1||2||3||4||5, 6, 7|
In the case of FecX++, the proportion of triplets was also only 11.2% . A much smaller share of quadruplet and lager litters was found in Javanese FecBBB ewes (16%) . The most common litter sizes in Garole FecBB+ sheep were twins, single births and triplets; accounting for, respectively, 65, 21 and 5% of the total . In turn, share of quadruplet and triplet litters in FecBBB ewes of Javanese breed was, 34 and 20%, respectively, with an average litter size of 2.5 lamb/litter . Interestingly, in the flock of Olkuska sheep, for mothers with genotypes FecXOO and FecX+O singleton births were twice less frequent than for FecX++ ewes (16 vs. 33%). Share of twin births decreased along with appearance of additional alleles with the mutation; among FecX++ewes they accounted for 55% of litters, and for genotype FecXOOonly for 27%. In the population of Olkuska sheep with average annual lamb production of 218%, the distribution of litters of various sizes was: 21.7% of singletons, 41% of twins, 24.6% of triplets and 12.7% of quadruplets and larger. Thus, the share of litters larger than triplet is as high as 37.1%. In Garole sheep, characterized by slightly lower prolificacy (168–187%), the proportion of mothers with twins, triplets and quadruplets was 65, 21 and 5%, respectively . Similar differences in distribution of litter size were observed in a herd of Chevoit‐Thoka sheep . With an average litter size of 2.23 lamb/litter, the authors found similar share of twin litters (56.5%) in this population, but noted a much smaller share of births with quadruplet and larger litters (3.1%). High frequency of twin births, reaching 47% of the studied population, was demonstrated in Thoka‐Chevoit sheep; this breed was also characterized by a high share of singleton births (35%) . A much smaller share of multiple births in comparison with data collected for Olkuska sheep was demonstrated in Aragonese breed with 120–150% fecundity: 66.4% of singleton litters, 28.4% of twin ones, but only 1.9% of triplets. It should be noted that among more than 2000 ewes studied, only three gave birth to quadruplets and only one to quintuplets. For sheep lacking the FecXR mutation, only singleton births were noted .
2.1.3. Effect of mutation N337H on litter size
In studies on effects of mutation N337H (FecXO) on litter size, it was shown that the effect on ovulation levels in O+ and OO ewes was an increase of +2 and +3.3 CL . Effect of the O+ copy of the gene was measured at +0.73 lamb, with the effect of two copies of the gene estimated at +1.07 lamb/litter. Analysing litter size over three first lambings of an ewe, the effect on O+ ewes was +0.62 lamb/litter, and +1.07 lamb for the OO genotype (Table 5) .
|Litter size of ewes||Genotype ||Mutation effect |
|Reproductive life span||1.74||2.47||2.98||O+: +0.73|
|Lambings: I–III||1.74||2.36||2.81||O+: 0.62|
Comparative analysis carried out on the basis of studies by many authors between litter size for carriers of one copy of the gene versus wild sheep genotypes for populations with a major segregating gene revealed that the data vary depending on breed, age and environment. In the presence of one copy of the gene (FecBB+), effect varies from +0.48 in Booroola
2.2. Mutations in the gene
Identification of variations in the gene sequence of
Presence of FecGH (G8) mutation was excluded . Thus, the Polish Olkuska breed can be classified as one of the few breeds in the world, where presence of polymorphisms has been confirmed both in the gene
Analysis of litter size distribution in sheep with GG and GA genotypes in the locus V371M (G7) revealed that the most frequently occurring litter size in GG ewes was twins (40.6%), followed by singletons (20.8%). Litters of quadruplets and larger accounted for 11.8% of all births. Among mothers with identified one allele with the GA mutation, the share of twin litters was twice smaller (20%), while litters with four and more lambs accounted for almost 50%. The share of single births was only 8.3% .
Also mutation V332I (G6) was found to be present in Olkuska sheep; with two alleles (G and A) and three genotypes (GG, AG and AA) found (Table 7).
The G allele appeared with a very high frequency of 0.84, and ewes of genotype GG accounted for 70% of all animals. Mothers with the GG genotype did not differ in average litter size from GA sheep, both over total duration of their productive life (2.24 ± 0.87 vs. 2.13 ± 0.91 lamb), and in the first three lambings (2.39 ± 0.90 vs. 2.30 ± 0.87) .
2.2.1. Effect of mutation V371M (G7) on litter size
Ewes with one allele with V371M substitution showed an increase in litter size of +0.55 lamb, while those with the V332I mutation showed a decrease of 0.18 lamb/litter . Thus, only in the presence of the A allele, the mutation V371M resulted in an increase in litter size. Mutations described earlier by Hanrahan et al. , namely: G3, G4, G5 and G6 were also detected in the case of Olkuska breed. However, impact of these mutations on prolificacy of ewes has not been studied.
In ewes of the Brazilian breed Santa Ines, a mutation that does not cause infertility has been identified in gene
Presence of the mutation G1 was also confirmed in Iranian Moghani and Ghezel breeds. Presence of three possible genotypes was identified, and all the ewes were fertile. Infertility was found in only one sheep, carrying also an additional copy of the gene FecXG in gene
3. Effect of N337H and V371M (G7) mutations on litter size
Determining effect of simultaneous presence of N337H (A1009C) and V371M (G7) mutations on fertility of Olkuska breed ewes showed that the largest number of lambs was born to FecXOO mothers that were carriers of V371M mutation (3.32 ± 0.26 lamb/litter) (Table 8).
|Trait||Combined genotype in |
|Litter size of ewes (LSM ± SE) (reproductive life span)||1.64 ± 0.11||2.26± 0.08||2.56 ± 0.19||2.64 ± 0.08||3.32 ± 0.26|
Effect of presence of both the allele N337H and V371M in ewes was similar to how presence of two copies of gene N337H affected the sheep, and amounted to +0.92 lambs/litter .
Studies conducted so far on interaction and potential interdependencies between different mutations within the loci of genes encoding transforming growth factors TGF‐β have shown that presence of one copy of the gene with a mutation in the locus of
4. Effect of N337H, G6 and G7 mutations on body weight
Mutations N337H, G6 and G7 detected in Olkuska sheep have no effect on body weight at 2, 28 and 56 days after birth . These results are consistent with observations conducted for sheep breeds with the major gene FecB, such as hybrids Rambouillet
5. G617A polymorphism in inhibin‐α gene (
Proteins encoded by the genes
To summarize, Olkuska sheep are among the few breeds with significant polymorphisms in genes coding proteins of the TDF‐beta family. Fecundity of this breed is determined not only by the presence of major gene FecXO (N337H,1009 > C) in
This work was supported by projects DS/KBZ/3242/2017.
Davis GH. Fecundity genes in sheep. Animal Reproduction Science. 2004; 82–83:247–253
Drouilhet L, Lecerf F, Bodin L, Fabre S, Mulsant P. Fine mapping of the FecL locus influencing prolificacy in Lacaune sheep. Animal Genetics. 2009; 40(6):1–9
Feary ES, Juengel JL, Smith P, French MC, O’Connel AR, Lawrence SB, Galloway SM, Davis GH, McNatty KP. Patterns of expression of messenger RNAs encoding GDF9, BMP15, TGFBR1, BMPR1B and BMPR2 during follicular development and characterization of ovarian follicular populations in ewes carrying the Woodlands FecX2W mutation. Biology of Reproduction. 2007; 77:990–998
Davis GH, Montgomery GW, Allison AJ, Kelly RW, Bray AR. Segregation of major gene influencing fecundity in progeny of Booroola sheep. New Zealand Journal of Agricultural Research. 1982; 25:525–529
Fogarty NM. Enviromental modulation of FecB expession. Use of the FecB (Booroola) gene in sheep breeding programs. In: Proceedings of International Workshop ACIAR; 11–12 November 2008; Maharashtra. India, Pune: ACIAR; 2009;133. pp. 66–69.
Fhamy MH, Mason IL. Less known and rare breeds. In: Fahmy MH, editor. Prolific Sheep. Willingford, UK: CAB International; 1996. pp. 178–186
Feng W, Ma Y, Zhang Z, Zhou D. Prolific breeds of China. In: Fahmy MH, editor. Prolific Sheep. Willingford, UK: CAB International; 1996. pp. 146–151
Inounu I, Iniguez L, Bradford GE, Subandriy O, Tiesnamurti B. Production performance of prolific Javanese ewes. Small Ruminant Research. 1993; 12:243–257
Singh RV, Sivakumar A, Sivashankar S, Das G. Evaluation of the Booroola FecB gene in Muzaffarnagari sheep. In: Proceedings of International Workshop ACIAR; 11–12 November 2008; Maharashtra. India‐Pune: ACIAR; 2009;133. pp. 223–224
Monget P, Fabre S, Mulsant P, Lecerf F, Elsen JM, Mazerbourg S, Pisselet C, Monniaux D. Regulation of ovarian folliculogenesis by IGF and BMP system in domestic animals. Domestic Animal Endocrinology. 2002; 23(1–2):139–154
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. Reproductive Biology and Endocrinology. 2006; 4:20
Montgomery GW, Galloway SM, Davis GH, McNatty KP. Genes controlling ovulations rate in sheep. Reproduction. 2001; 121:843–852
Moore RK, Shimasaki S. Molecular biology and physiological role of the oocyte factor BMP15. Molecular and Cellular Endocrinology. 2005; 234:67–73
Yan C, Wang P, DeMayo J, DeMayo FJ, Elvin JA, Carino C, Prasad CV, Skinner SS, Dunbar BS, Dube JL, Celeste AJ, Matzuk MM. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Molecular Endocrinology. 2001; 15(6):854–866
Rybak‐Krzyszkowska M, Grzyb A, Milewicz T, Krzaczkowska‐Sendrakowska M, Krzysiek J. Primary ovarian insufficiency in infertility clinic. Polish Journal of Endocrinology. 2004; 6:766–768
Otsuka F, Yamamoto S, Erickson GF, Shimasaki S. Bone morphogenetic protein‐15 inhibits follicle‐stimulating hormone (FSH) action by suppressing FSH receptor expression. The Journal of Biological Chemistry. 2001; 276:11387–11392
Moore RK, Erickson GF, Shimasaki S. Are BMP15 and GDF9 primary determinants of ovulation quota in mammals? Trends in Endocrinology and Metabolism. 2004; 15:356–361
Shimasaki S, Moore RK, Otsuka F, Erickson GF. The bone morphogenetic protein system in mammalian reproduction. Endocrinology Reviews. 2004; 25:72–101
McNatty KP, Smith P, Moore LG, Reader K, Lun S, Hanrahan JP, Groome NP, Laitinen M, Ritvos O, Juengel JL. Oocyte‐expressed genes affecting voulation rate. Molecular and Cellular Endocrinology. 2005; 234:57–66
Carabatsos MJ, Sellitto C, Goodenough DA, Albertini DF. Oocyte‐granulosa cell heterologous gap junctions are required for the coordination of nuclear and cytoplasmic meiotic competence. Developmental Biology. 2000; 226:167–179
Hanrahan JP, Gregan SM, Mulsant P, Mullen M, Davis G, 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). Biology of Reproduction. 2004; 70:900–909
Davis GH, Bruce GD, Dodds KG. Ovulation rate and litter size of prolific Inverdale (FecI) and Hanna (FecXH) sheep. Proceedings of Association for the Advancement of Animal Breeding and Genetics. 2001; 14:175–178
Shackell GH, Hudson NL, Heath NL, Lun S, Shaw L, Condell L, Blay LR, McNatty KP. Plasma gonadotropin concentrations and ovarian characteristics in Inverdale ewes that are heterozygous for major gene FecXI on the X chromosome that influences ovulation rate. Biology of Reproduction. 1993; 48:1150–1156
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. 2007; 148(1):393–400
Bodin L, Lecerf F, Bessicre M, Mulsant P. Features of major genes for ovulation in the Lacaune population. In: Proceedings of the 8th World Congress on Genetics Applied to Livestock Production WCGALP, Belo Horizonte; 13-18 August 2006, Belo Horizonte, MG, Brazil; 2006; 04–04. pp. 1–4.
Monteagudo LV, Ponz R, Tejedor MT, 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. Animal Reproduction Science. 2009; 110:139–146
Demars J, Fabre S, Sarry J, Rossetti R, Gilbert H, Persani L, Tosser‐Klopp, 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 Genetics. 2013; 9(4):e1003482. DOI: 1010.1371/journal.pgen.1003482
Vacca GM, Dhaouadi A, Rekik M, Carcangi, Pazzola M, Dettori ML. Prolificacy genotypes at BMPR 1R, BMP15 and GDF9 genes in North African sheep breeds. Small Ruminant Research. 2010; 88:67–71
McNatty KP, Galloway SM, Wilson T, Smith P, Hudson NL, O’Connell A, Bibby AH, Heath DA, Davis GH, Hanrahan JP, Juengel JL. Physiological effects of major genes affecting ovulation rate in sheep. Genetique Selection Evolution. 2005; 37:25–38
Juengel JL, Hudson NL, Heath DA, Smith P, Reader KL, Lawrence SB, O’Connell AR, Laitinen MPE, Cranfield M, Groome NP, Ritvos O, McNatty KP. Growth Differentiation Factor 9 and one Morphogenetic Protein 15 are essential for ovarian follicular development in sheep. Biology of Reproduction. 2002; 67:1777–1789
Elvin JA, Yan Ch, Wang P, Wolfman NM, Matzuk MM. Paracrine actions of growth differentiation factor‐9 in the mammalian ovary. Molecular Endocrinology. 1999; 13:1035–1048
Hayashi M, McGee EA, Min G, Klein C, Rose UM, Duin M, Hsueh AJW. Recombinant growth differentiation factor‐9 (GDF9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology. 1999; 3:1236–1244
Gilchrist RB, Ritter LJ, Cranfield M, Jeffery LA, Amato F, Scott SJ, Myllymaa S, Kaivo‐Oja N, Lnakinen H, Mottershead DG, Groome NP, Ritvos. Immunoneutralization of growth differentiation factor 9 reveals it partially account for mouse oocyte miogenic activity. Biology of Reproduction. 2004; 71:732–739
Bodensteiner KJ, McMNatty KP, Clay CM, Moeller CL, Sawyer H. Expression of growth differentiation factor‐9 in the ovaries of fetal sheep homozygous or heterozygous for the Inverdale Prolificacy Gene (FecXI). Biology of Reproduction. 2000; 62:1479–1485
McNatty KP, Moore LG, Hudson NL, Quirke LD, Lawrnce SB, Reader K, Hanrahan JP, Smith P, Groome NP, Laitinen M, Ritvos O, Juengel JL. The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. Reproduction. 2004; 128:379–386
Teixeira Filho FL, Baracat EC, Lee TH. Aberrant expression of growth differentiation factor‐9 in oocytes of women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2002; 87:1337–1344
Sadighi M, Bodensteiner KJ, Beattie AE, Galloway SM. Genetic mapping of ovine growth differentiation factor 9 (GDF9) to sheep chromosome 5. Animal Genetics. 2002; 33:224–248
Liao WX, Moore RK, Otsuka F, Shimasaki S. Effect on intracellular interactions on the processing and secretion of bone morphogenetic protein‐15 (BMP15) and growth and differentiation factor‐9—implication of the aberrant ovarian phenotype of BMP15 mutant sheep. The Journal of Biological Chemistry. 2003; 278:3713–3719
Liao WX, Moore RK, Shimasaki S. Functional and molecular characterization of naturally occurring mutation in oocyte‐secreted factors BMP15 and GDF9. The Journal of Biological Chemistry. 2004; 279(17):17391–17396
Nicol L, Bishop S, Pong‐Wong R, Bendixen Ch, Holm LE, Rhind SM, McNeilly MS. Homozygosity for a single base‐pair mutation in the oocyte‐specific GDF9 gene results in sterility in Thoka sheep. Reproduction. 2009; 138:921–933
Silva BDM, Castro EA, Souza CJH, Paiva SR, Sartori R, Franco MM, Azevedo HC, Silva TASN, Vieira AMC, Neves JP, Melo EO. A new polymorphism in the Growth Differentiation Factor 9 (GDF9 )gene is associated with increased ovulation rate and prolificacy in homozygous sheep. Animal Genetics. 2011; 42(1):89–92
Davis GH, Galloway SM, Ross IK, Gregan SM, Ward J, Nimbkar BV, Ghalsasi PM, Nimbkar C, Gray GD, Subandriyo Inounu I, Tiesnamurti B, Martyniuk E, Eythorsdottir E, Mulsant P, Lecerf F, Hanrahan JP, Bradford GE, Wilson T. DNA tests in prolific sheep from eight countries provide new evidence on origin of the Booroola (FecB) mutation. Biology of Reproduction. 2002; 66: 1869–1874
Kaczor U. 2011. Identyfikacja markerów plenności owiec olkuskich na podstawie polimorfizmu genów kodujących białka z rodziny TGF‐β [tesis]. Uniwersytet Rolniczy w Krakowie. Zeszyty Naukowe 479; 2011
Liu SF, Jiang YL, Du LX. Study of BMPR‐IR and BMP15 as candidate gene for fecundity in little tailed Han sheep. Acta Genetica Sinica. 2003; 30(8):755–760
Guan F, Liu SR, Shi GQ, Ai JT, Mao DG, Yang LG. Polymorphism of Fec B gene in nine sheep breeds or strains and its effects on litter size, lamb growth and development. Acta Genetica Sinica. 2006; 33(2):117–124
Kumar S, Mishra AK, Kolte AP, Arora AL, Singh D, Singh VK. Effects of the Booroola (FecB) genotypes on growth performance, ewe’s productivity efficiency and litter size in Garole x Malpura sheep. Animal Reproduction Science. 2008; 105(3–4):19–31
Kumar S, Mishra AK, Kolte AP, Dash SK, Karim SA. Screening for Booroola FecB and Galway FecXG mutation In Indian sheep. Small Ruminant Research. 2008; 80:57–61
Roberts VJ, Barth S, El‐Roeiy A, Yen SSC. Expression of inhibin/activin subunits and follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. The Journal of Clinical Endocrinology and Metabolism. 1993; 77:1402–1410
Adalsteinsson S, Jonmundson JV, Eythorsdottir E. The high fecundity Thoka gene in Icelandic sheep. Proceedings of the 40th Meeting of the European Association for Animal Production; 27–31 August 1989. Dublin, Ireland: EAAP; 1989;1.pp. 61–62
Walling GA, Bishop SC, Pong‐Wong R, Russel AJF, Rhind SM. Detection of a major gene for litter size in Thoka Cheviot sheep using Bayesian segregation analyses. Animal Science. 2002; 75:339–347
Meyer HH, Baker RL, Harvey TG, Hickey SM. Effects of Booroola merino breeding and the Fec(B) gene on performance of crosses with long wool breeds. 2. Effects on reproductive performance and weight of lamb weaned by young ewes. Lives Production Science. 1994; 39:191–200
Gootwine E, Reicher S, Rozov A. Prolificacy and lamb survival at birth in Awassi and Assaf sheep carrying the FecB (booroola) mutation. Animal Reproduction Science. 2008; 108:402–411
Guan F, Liu SR, Shi GQ, Yang LG. Polymorphism of FecB gene in nine sheep breeds or strains and its effects on litter size, lamb growth and development. Animal Reproduction Science. 2007; 99:44–52
Kumar S, Kolte A, Mishra AK, Arora AL, Singh V. Identification of Fecb mutation in Garolex Malpura sheep and its effect on litter size. Small Ruminant Research. 2006; 64:305–310
Melo EO, Silva BDM, Castro EA, Silva TASN, Paiva SR, Sartori R, Franco MM, Souza CJH, Neves JP. A novel mutation in the growth and differentiation factor 9 (GDF9) gene is associated, in homozygosis, with increased ovulation rate in Santa Ines sheep. Biology of Reproduction. 2008; 78:371
Barzegari A, Atashpaz S, Ghabili K, Nemati Z, Rustaei M, Azarbaijani R. Polymorphism in GDF9 and BMP15 associated with fertility and ovulation rate in Moghani and Ghezel sheep in Iran. Reproduction in Domestic Animals. 2010; 45:666–669
Polley S, De S, Brahma B, Mukherjee A, Vinesh PV, Batabyal S, Arora JS, Pan S, Samanta AK, Datta TK, Goswami SL. Polymorphism of BMPR1B, BMP15 and GDF9 fecundity genes in prolific Garole. Tropical Animal Health and Production. 2010; 42:985–993
Chang JT, Luo YZ, Hu J. Polymorphism of GDF9 as a candidate gene for fecundity in sheep. Journal of Gansu Agricultural University. 2009; 44(2):30–33
Chu M, Zhuang H, Zhang Y, Jin M, Di X, Cao G, Feng T, Fang L. Polymorphism of inhibin βB gene and its relation sheep with liter size in sheep. Animal Science. 2011; 82:57–61
Li BX, Chu MX, Wang JY. PCR‐SSCP analysis on growth differentiation factor 9 gene in sheep. Yi Chuan Xue Bao. 2003; 30:307–310
Willingham TD, Wardon DW, Thompson PV. Effect of FecB allele on birth weight and post‐weaning production traits of Rambouillet‐Booroola cross wethers. Texas Agriculture Experimental Station Research Report. Sheep and Goat, Wool and Mohair CpR; 2002. pp. 1–6.
Kleemann DO, Ponzoni RW, Stafford JE, Cutten IN, Grimson RJ. Growth and carcass characters of South Australian Merino and its crosses with the Booroola and Trangie Fertility Merino. Australian Journal of Experimental Agriculture. 1985; 25:750–757
Abella DF, Cognie Y, Thimonier J, Seck M, Blank MR. Effects of the FecB gene on birth weight, postnatal growth rate and puberty in Booroola x Merinos d’Arles ewe lambs. Animal Research. 2005; 54:283–288
Visscher AH, Dijkstra M, Lord EA, Suss R, Rosler HJ, Heylen K, Veerkamp RF. Maternal and lamb carrier effects of the Booroola gene on food intake growth and carcass quality of male lambs. Animal Science. 2000; 71:209–217
Gootwine E, Braw‐Tal R, Shalhevet A, Bor A, Zenou A. Reproductive performance of Assaf and Booroola‐assaf crossbred ewes and its association with plasma FSH levels and induced ovulation rate measured at prepuberty. Animal Reproduction Science. 1993; 31:69–81
Gootwine E, Rozov A, Bor A, Richer S. Carring the FecB (Booroola) mutation is associated with lower birth weight and slower post‐weaning growth rate for lambs, as well as a lighter mature body weight for ewes. Reproduction Fertility and Development. 2006; 18(4):433–437
Hiendleder S, Lewalski H, Jaeger H, Pracht P, Erhardt G. Nucleotide sequence of ovine α‐inhibin (INHA) gene and evaluation of RFLP marker effects on reproductive performance. Animal Genetics. 1996; 27(2):91–92
Hiendleder S, Lewalski H, Jaeger H, Pracht P, Erhardt G. Genomic cloning and comparative sequence analyses of different alleles of the ovine βA inhibin/activin INHA gene as a potential QTL for litter size. Animal Genetics. 1996; 27(2):119
Leyhe B, Hiendleder S, Jaeger C, Wassmuth R. Pronounced differences in the frequency TaqIβA inhibin allele between sheep breeds with different reproductive performance. Animal Genetics. 1994; 25(1):41–43