Gene Ontology
What is ontology?
Gene ontology (GO) is a bioinformatic tool that is comprised of many databases. These databases enable a gene product to be described using standardized terms (2). There are three domains of gene ontology, namely, biological processes, molecular function and cellular components. The biological process is defined as the overall function of a given gene product. Molecular function describes the activities of the gene product on a molecular level. Lastly, cellular components describe where the gene product resides in the cell. Gene ontology is an invaluable tool for researchers by uniting databases and incorporating consistent terminology when describing gene products. Below are the GO functions of the ACVR1 gene:
What is ontology?
Gene ontology (GO) is a bioinformatic tool that is comprised of many databases. These databases enable a gene product to be described using standardized terms (2). There are three domains of gene ontology, namely, biological processes, molecular function and cellular components. The biological process is defined as the overall function of a given gene product. Molecular function describes the activities of the gene product on a molecular level. Lastly, cellular components describe where the gene product resides in the cell. Gene ontology is an invaluable tool for researchers by uniting databases and incorporating consistent terminology when describing gene products. Below are the GO functions of the ACVR1 gene:
Biological Process
Bone morphogenetic protein signalling pathway G1/S transition of mitotic cell cycle Negative regulation of activin receptor signaling Negative regulation of apoptotic process TGF beta receptor signaling pathway Regulation of ossification Protein phosphorylation Positive regulation of osteoblast differentiation Positive regulation of bone mineralization Negative regulation of signal transduction |
Molecular Function
ATP binding Smad binding Activin receptor activity, type I Follstatin binding protein binding Protein homodimerization activity Protein serine/threonine kinase activity TGF-beta binding |
Cellular Components
Activin receptor component Integral to plasma membrane |
Analysis:
The information derived from the gene ontology search is consistent with what would be expected given the phenotype of the disease. In people with FOP, soft tissue damage orchestrates gene expression changes that cause extensive overgrowth of bone. The mutation resides in the activin A receptor, a transmembrane protein with the capacity to receive signals from the outside and stimulate signaling inside the cell that ultimately induces gene expression changes to form bone. However, the mutation in FOP patients resides in the TGF-beta component of the transmembrane protein, thus making the protein induce signals in the absence of the ligand. Normally, this receptor can be inhibited by the FKBP12 inhibitor binding to the TGF-beta domain of the protein and consequently prevents signaling. The mutation enables inappropriate signaling of the ACVR1 due to the fact the receptor cannot be properly inhibited by the FKBP12 inhibitor. Implications of the ACVR1 receptor being active in muscle, connective tissue and ligaments are that downstream signaling incur gene expression of bone forming genes. As shown with the GO term outputs, the biological processes include the bone morphogenetic signaling pathway (which facilitates bone and cartilage formation), regulation of ossification, osteoblast differentiation as well as bone mineralization. This makes sense considering heterotopic bone growth is the fundamental feature that is indicative of FOP. Additionally, the literature supports the notion that the activin A receptor is localized in the plasma membrane and possesses serine and threonine kinase activity which when phosphorylated, stimulates signal transduction of the smad binding and the signaling of the bone morphogenetic pathway. What the gene ontology elucidates is that these terms indeed coincide with the literature as well as the disease phenotype.
The information derived from the gene ontology search is consistent with what would be expected given the phenotype of the disease. In people with FOP, soft tissue damage orchestrates gene expression changes that cause extensive overgrowth of bone. The mutation resides in the activin A receptor, a transmembrane protein with the capacity to receive signals from the outside and stimulate signaling inside the cell that ultimately induces gene expression changes to form bone. However, the mutation in FOP patients resides in the TGF-beta component of the transmembrane protein, thus making the protein induce signals in the absence of the ligand. Normally, this receptor can be inhibited by the FKBP12 inhibitor binding to the TGF-beta domain of the protein and consequently prevents signaling. The mutation enables inappropriate signaling of the ACVR1 due to the fact the receptor cannot be properly inhibited by the FKBP12 inhibitor. Implications of the ACVR1 receptor being active in muscle, connective tissue and ligaments are that downstream signaling incur gene expression of bone forming genes. As shown with the GO term outputs, the biological processes include the bone morphogenetic signaling pathway (which facilitates bone and cartilage formation), regulation of ossification, osteoblast differentiation as well as bone mineralization. This makes sense considering heterotopic bone growth is the fundamental feature that is indicative of FOP. Additionally, the literature supports the notion that the activin A receptor is localized in the plasma membrane and possesses serine and threonine kinase activity which when phosphorylated, stimulates signal transduction of the smad binding and the signaling of the bone morphogenetic pathway. What the gene ontology elucidates is that these terms indeed coincide with the literature as well as the disease phenotype.
Image References:
1. https://toppgene.cchmc.org/files/GO.png
References:
1. Gene Ontology Consortium. An introduction to the Gene Ontology. Accessed 3/20/15 http://geneontology.org/page/documentation
2. Shore, E.M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525–527(2006). http://www.bio.davidson.edu/molecular/restricted/02bone/FOP_cause.pdf
3. Kaplan, F. S., Xu, M., Seemann, P., Connor, J. M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., GillessenKaesbach, G., Hoover-Fong, J., Koster, B., Pauli, R. M., Reardon, W., Zaidi, S. A., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., and Shore, E. M. (2009) Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1, Hum. Mutat. 30, 379–390. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921861/
4. Chakkalakal, S. A., Zhang, D., Culbert, A. L., Convente, M. R., Caron, R. J., Wright, A. C., Maidment, A. D. A., Kaplan, F. S. and Shore, E. M. (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J. Bone Miner. Res. 27, 1746-1756.. 7. "Fibrodysplasia Ossificans Progressiva." Genetics Home Reference. U.S. National Library of Medicine, 9 Feb. 2015. Web. 11 Feb. 2015. http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/jbmr.1637/pdf
5. Kaplan, Frederick S. ; Lounev, Vitali Y. ; Wang, Haitao ; Pignolo, Robert J. ; Shore, Eileen M. " Fibrodysplasia ossificans progressiva: a blueprint for the metamorphosis." Annals of the New York Academy of Sciences, 2011, Vol.12371(1), pp.5-10. http://www.ncbi.nlm.nih.gov/pubmed/22082359
1. https://toppgene.cchmc.org/files/GO.png
References:
1. Gene Ontology Consortium. An introduction to the Gene Ontology. Accessed 3/20/15 http://geneontology.org/page/documentation
2. Shore, E.M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525–527(2006). http://www.bio.davidson.edu/molecular/restricted/02bone/FOP_cause.pdf
3. Kaplan, F. S., Xu, M., Seemann, P., Connor, J. M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., GillessenKaesbach, G., Hoover-Fong, J., Koster, B., Pauli, R. M., Reardon, W., Zaidi, S. A., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., and Shore, E. M. (2009) Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1, Hum. Mutat. 30, 379–390. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921861/
4. Chakkalakal, S. A., Zhang, D., Culbert, A. L., Convente, M. R., Caron, R. J., Wright, A. C., Maidment, A. D. A., Kaplan, F. S. and Shore, E. M. (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J. Bone Miner. Res. 27, 1746-1756.. 7. "Fibrodysplasia Ossificans Progressiva." Genetics Home Reference. U.S. National Library of Medicine, 9 Feb. 2015. Web. 11 Feb. 2015. http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/jbmr.1637/pdf
5. Kaplan, Frederick S. ; Lounev, Vitali Y. ; Wang, Haitao ; Pignolo, Robert J. ; Shore, Eileen M. " Fibrodysplasia ossificans progressiva: a blueprint for the metamorphosis." Annals of the New York Academy of Sciences, 2011, Vol.12371(1), pp.5-10. http://www.ncbi.nlm.nih.gov/pubmed/22082359