A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as a result of: translocation, interstitial deletion, or chromosomal inversion.
A schematic showing the ways a fusion gene can occur at a chromosomal level.
Contents
- 1 History
- 2 Oncogenes
- 3 Evolution
- 4 Detection
- 5 Research applications
- 6 See also
- 7 References
- 8 External links
History
The first fusion gene[1] was discovered in cancer cells in 1960 in the collaboration between Peter Nowell who worked in Pennsylvania School of Medicine and David Hungerford who was a graduate student doing a thesis on human chromosomes at the Institute for Cancer Research.[2] Using Edwin Osgood’s method, they cultured human leukemic cells which came from patients with chronic myelogenous leukemia (CML).[3] They observed an extension in the length of chromosome 9 and a shortening of chromosome 22 in comparison to normal versions. This chromosomal abnormality, which is found in the genome of a majority of CML cases, involves a reciprocal translocation between chromosomes 9 and 22. It is called the Philadelphia chromosome, after the city where it was first observed.[4] Two fused genes are formed, one on each of the altered chromosomes. Later, scientists learned that the fusion gene on chromosome 22 produced an abnormal protein, which was associated with the development of CML. However, it is not entirely clear that a single chromosomal translocation event is enough to enable progression of the tumor.[5]
At present, scientists have identified 358 gene fusions involving 337 different genes. These genes are all described in the main subtypes of human neoplasia.[6] The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker.[7]
Oncogenes
It has been known for 30 years that the corresponding gene fusion plays an important role in tumorgenesis.[8] Fusion genes can contribute to tumor formation because fusion genes can produce much more active abnormal protein than non-fusion genes.Often, fusion genes are oncogenes that cause cancer; these include BCR-ABL,[9] TEL-AML1 (ALL with t(12 ; 21)), AML1-ETO (M2 AML with t(8 ; 21)), and TMPRSS2-ERG with an interstitial deletion on chromosome 21, often occurring in prostate cancer.[10] In the case of TMPRSS2-ERG, by disrupting androgen receptor (AR) signaling and inhibiting AR expression by oncogenic ETS transcription factor, the fusion product regulate the prostate cancer.[11] Most fusion genes are found from hematological cancers, sarcomas, and prostate cancer.[12][13]
Oncogenic fusion genes may lead to a gene product with a new or different function from the two fusion partners. Alternatively, a proto-oncogene is fused to a strong promoter, and thereby the oncogenic function is set to function by an upregulation caused by the strong promoter of the upstream fusion partner. The latter is common in lymphomas, where oncogenes are juxtaposed to the promoters of the immunoglobulin genes.[14] Oncogenic fusion transcripts may also be caused by trans-splicing or read-through events.[15]
Since chromosomal translocations play such a significant role in neoplasia, a specialized database of chromosomal aberrations and gene fusions in cancer has been created. This database is called Mitelman Database of Chromosome Aberrations and Gene Fusions in Cacner[16]
Diagnostics
Presence of certain chromosomal aberrations and their resulting fusion genes is commonly used within cancer diagnostics in order to set a precise diagnosis. Chromosome banding analysis, fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) are common methods employed at diagnostic laboratories. These methods all have their distinct shortcomings due to the very complex nature of cancer genomes. Recent developments such as high-throughput sequencing[17] and custom DNA microarrays bear promise of introduction of more efficient methods.[18]
Evolution
Gene fusion plays a key role in the evolution of gene architecture. We can observe its effect if gene fusion occurs in coding sequences.[19] Duplication, sequence divergence, and recombination are the major contributors at work in gene evolution.[20] Those events probably can produce new genes from already exist part. When gene fusion happens in non-coding sequence region, it can lead to the misregulation of the expression of a gene now under the control of the cis-regulatory sequence of another gene. If it happens in coding sequences, gene fusion cause the assembly of a new gene, then it allows the appearance of new functions by adding peptide modules into multi domain protein.[21] The detecting methods to inventory gene fusion events on a large biological scale can provide insights about the multi modular architecture of proteins. [22][23][24]
Detection
In recent years, next generation sequencing technology has already become available to screen known and novel gene fusion events on a genome wide scale. However, the precondition for large scale detection is a paired-end sequencing of the cell's transcriptome. The direction of fusion gene detection is mainly towards data analysis and visualization. Some researchers already developed a new tool called Transcriptome Viewer (TViewer) to directly visuzlize detected gene fusions on the transcript level.[25]
Research applications
Biologists may also deliberately create fusion genes for research purposes. The fusion of reporter genes to the regulatory elements of genes of interest allows researches to study gene expression. Reporter gene fusions can be used to measure activity levels of gene regulators, identify the regulatory sites of genes (including the signals required), identify various genes that are regulated in response to the same stimulus, and artificially control the expression of desired genes in particular cells.[26] For example, by creating a fusion gene of a protein of interest and green fluorescent protein, the protein of interest may be observed in cells or tissue using fluorescence microscopy.[27] The protein synthesized when a fusion gene is expressed is called a fusion protein.
See also
References
- ^ Mitelman, F; Johansson, B; Mertens, F (2007). "The impact of translocations and gene fusions on cancer causation". Nature reviews. Cancer 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217.
- ^ Nowell, PC; Hungerford, DA (1960). "A minute chromosome in chronic granulocytic leukemia" (PDF). Science 132 (3438): 1488–1501 [1497]. Bibcode:1960Sci...132.1488. doi:10.1126/science.132.3438.1488.
- ^ Osgood, E.E.; Krippaehhe, M.L. (1955). "The gradient tissue culture method". Experimental Cell Research 9 (1): 116–127. doi:10.1016/0014-4827(55)90165-8. PMID 13241514.
- ^ Nowell, PC; Hungerford, DA (1960). "A minute chromosome in chronic granulocytic leukemia" (PDF). Science 132 (3438): 1488–1501 [1497]. Bibcode:1960Sci...132.1488. doi:10.1126/science.132.3438.1488.
- ^ Tosato, Valentina; Gruning, Nana-Maria; Breitenbach, Michael; Arnak, Remigiusz; Ralser, Markus; Bruschi, Carlo V. (2013). "Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells". Frontiers in ONCOLOGY 2 (212). doi:10.3389/fonc.2012.00212.
- ^ Mitelman, F; Johansson, B; Mertens, F (2007). "The impact of translocations and gene fusions on cancer causation". Nature reviews. Cancer 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217.
- ^ Prensner, John; Chinnaiya, Arul (2009). "Oncogenic gene fusions in epithelial carcinomas". Curr. Opin. Genet. Dev 19 (1): 82–91. doi:10.1016/j.gde.2008.11.008. PMID 19233641.
- ^ Edwards, Paul (2009). "Fusion genes and chromosome translocations in the common epithelial cancers". Journal of Pathology 220 (2): 244–254. doi:10.1002/path.2632. PMID 19921709.
- ^ Nowell, PC; Hungerford, DA (1960). "A minute chromosome in chronic granulocytic leukemia" (PDF). Science 132 (3438): 1488–1501 [1497]. Bibcode:1960Sci...132.1488. doi:10.1126/science.132.3438.1488.
- ^ Tomlins, SA; Rhodes, DR; Perner, S; Dhanasekaran, SM; Mehra, R; Sun, XW; Varambally, S; Cao, X; et al. (2005). "Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer". Science 310 (5748): 644–8. Bibcode:2005Sci...310..644T. doi:10.1126/science.1117679. PMID 16254181.
- ^ Yu, Jindan; Yu, Jianjun (2010). "An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression Cancer Cell.". Cancer Cell 17 (5): 443–454. doi:10.1016/j.ccr.2010.03.018. PMC 2874722. PMID 20478527.
- ^ Mitelman, F; Johansson, B; Mertens, F (2007). "The impact of translocations and gene fusions on cancer causation". Nature reviews. Cancer 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217.
- ^ Teixeira, MR (2006). "Recurrent fusion oncogenes in carcinomas". Critical reviews in oncogenesis 12 (3–4): 257–71. doi:10.1615/critrevoncog.v12.i3-4.40. PMID 17425505.
- ^ Vega, F; Medeiros, LJ (2003). "Chromosomal translocations involved in non-Hodgkin lymphomas". Archives of pathology & laboratory medicine 127 (9): 1148–60. doi:10.1043/1543-2165(2003)127<1148:CTIINL>2.0.CO;2 (inactive 2015-02-01). PMID 12946230.
- ^ Nacu, S; Yuan, W; Kan, Z; Bhatt, D; Rivers, CS; Stinson, J; Peters, BA; Modrusan, Z; Jung, K; Seshagiri, Somasekar; Wu, Thomas D (2011). "Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples". BMC Med Genomics 4 (1): 11. doi:10.1186/1755-8794-4-11. PMC 3041646. PMID 21261984.
- ^ Mitelman F; Johansson B; Mertens F. "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer".
- ^ Maher, CA; Kumar-Sinha, C; Cao, X; Kalyana-Sundaram, S; Han, B; Jing, X; Sam, L; Barrette, T; et al. (2009). "Transcriptome Sequencing to Detect Gene Fusions in Cancer". Nature 458 (7234): 97–101. Bibcode:2009Natur.458...97M. doi:10.1038/nature07638. PMC 2725402. PMID 19136943.
- ^ Skotheim, RI; Thomassen, GO; Eken, M; Lind, GE; Micci, F; Ribeiro, FR; Cerveira, N; Teixeira, MR; Heim, S; Rognes, Torbjørn; Lothe, Ragnhild A (2009). "A universal assay for detection of oncogenic fusion transcripts by oligo microarray analysis". Molecular cancer 8: 5. doi:10.1186/1476-4598-8-5. PMC 2633275. PMID 19152679.
- ^ Durrens, Pascal; Nikolski, Macha; Sherman, David (2008). "Fusion and Fission of Genes Define a Metric between Fungal Genomes". PLoS Comput Biol 4 (10): 443–454. Bibcode:2008PLSCB...4E0200D. doi:10.1371/journal.pcbi.1000200.
- ^ EE, Eichler (2001). "Recent duplication, domain accretion and the dynamic mutation of the human genome". Trends in Genetics 17 (11): 661–669. doi:10.1016/s0168-9525(01)02492-1. PMID 11672867.
- ^ Durrens, Pascal; Nikolski, Macha; Sherman, David (2008). "Fusion and Fission of Genes Define a Metric between Fungal Genomes". PLoS Comput Biol 4 (10): 443–454. Bibcode:2008PLSCB...4E0200D. doi:10.1371/journal.pcbi.1000200.
- ^ AJ, Enright; CA, Ouzounis (2001). "Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions". Genome Biology 2 (9): 341–347. doi:10.1186/gb-2001-2-9-research0034. PMID 11820254.
- ^ I, Yanai; C, DeLisi; Delisi, C. (2001). "Genes linked by fusion events are generally of the same functional category: a systematic analysis of 30 microbial genomes". Genome Biology 98 (14): 7940–7945. Bibcode:2001PNAS...98.7940Y. doi:10.1073/pnas.141236298.
- ^ S, Pasek; JL, Risler; Delisi, Charles (2006). "Genes linked by fusion events are generally of the same functional category: a systematic analysis of 30 microbial genomes". Bioinformatics 22 (14): 1418–1423. Bibcode:2001PNAS...98.7940Y. doi:10.1073/pnas.141236298.
- ^ Supper, 6. Jochen; Gugenmus, Claudia (2013). "Detecting and visualizing gene fusions. Methods". Methods 59 (1): 24–28. doi:10.1016/j.ymeth.2012.09.013.
- ^ al.], Leland H. Hartwell ... [et (2011). Genetics : from genes to genomes (4th ed.). New York: McGraw-Hill. pp. 533–534. ISBN 007352526X.
- ^ Prendergast, FG; Mann, KG (1978). "Chemical and physical properties of aequorin and the green fluorescent protein isolated from Aequorea forskålea". Biochemistry 17 (17): 3448–53. doi:10.1021/bi00610a004. PMID 28749.
External links
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Wikimedia Commons has media related to Fusion gene. |
- ChimerDB 2.0: a knowledgebase for fusion genes updated.
- dbCRID: a new, comprehensive database of human CR events and associated diseases (both tumor and non-tumor) with detailed documentation of the CR events.
- Mitelman Database: a database relates chromosomal aberrations to tumor characteristics, based either on individual cases or associations.
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Genetics: homologous recombination / mobile genetic elements
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| Primarily prokaryotic |
- Conjugation
- Transduction
- Transformation
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| Occurs in eukaryotes |
- Transfection
- Chromosomal crossover
- Gene conversion
- Fusion gene
- Horizontal gene transfer
- Sister chromatid exchange
- Transposon
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Index of genetics
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| Description |
- Gene expression
- DNA
- replication
- cycle
- recombination
- repair
- binding proteins
- Transcription
- factors
- regulators
- nucleic acids
- RNA
- RNA binding proteins
- ribonucleoproteins
- repeated sequence
- modification
- Translation
- ribosome
- modification
- nexins
- Proteins
- domains
- Structure
- primary
- secondary
- tertiary
- quaternary
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| Disease |
- Replication and repair
- Transcription factor
- Transcription
- Translation
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