OMIA 000386-9940 : Fecundity, Inverdale, FecX(I) in Ovis aries

Possibly relevant human trait(s) and/or gene(s) (MIM number): 300510

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 symbol: FecX(I)

Species-specific description: This X-linked fecundity gene was discovered in offspring from a prolific Romney ewe that had been screened from a commercial flock as part of the foundation of a prolific experimental flock in New Zealand in 1979. Heterozygous ewes ovulate approximately one extra egg, and give birth to approximately 0.6 extra lambs. Unfortunately, homozygous ewes have 'streak' ovaries: underdeveloped, non-functional, flattened structures about one-eighth the size of normal ovaries. Males with this gene have normal fertility.

Inheritance: In the first report of this major gene for fecundity, Davis et al. (1991) showed that it is X-linked.

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.

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."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
BMP15 bone morphogenetic protein 15 Ovis aries X NC_019484.2 (50986718..50980229) BMP15 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Romney Marsh Fecundity, Inverdale, FecX(I) BMP15 missense c.T>A p.V299D 2000 10888873

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.
2013 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.
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.
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 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 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.
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.
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.
2005 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.
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.
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.
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.
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 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.
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.
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 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.
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.
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.

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