HYBRIDdb: a database of hybrid genes in the human genome
© Kim et al; licensee BioMed Central Ltd. 2007
Received: 26 September 2006
Accepted: 23 May 2007
Published: 23 May 2007
Hybrid genes are candidate risk factors for human tumors by inducing mutation, translocation, inversion, or rearrangement of genes. The occurrence of hybrid genes may also have given rise to new transcripts during hominid evolution.
HYBRIDdb is a database of hybrid genes in humans. This system encompasses the bioinformatics analysis of mRNA, EST, cDNA, and genomic DNA sequences in the INDC databases, and can be used to identify hybrid genes. We searched for hybrid genes among the 28,171 genes listed in the NCBI database, and analyzed their structural patterns in the human genome. The 2,344 gene pairs were detected as hybrid forms of transcriptional products. We classified the hybrid genes into two groups: chromosomal-mediated translocation fusion transcripts and transcription-mediated fusion transcripts.
The HYBRIDdb database will provide genome scientists with insight into potential roles for hybrid genes in human evolution and disease.
Hybrid genes are created by trans-splicing, sense/antisense transcription, genome rearrangement, or intergenic splicing between two genes [1–5]. The creation of new genes is a potential risk factor for tumor development, yet may also promote diversification by inducing gene substitution, translocation, inversion, or rearrangement [1, 6–8]. As a result, hybrid genes have the ability to be either harmful or advantageous to humans [9, 10].
Cancer genes have somatic mutations similar to chromosomal translocations that result in hybrid transcripts by apposing one gene to the regulatory regions of another. For example, a hybrid transcript is created by genomic rearrangement of the mixed-lineage leukemia (MLL) gene at 11q23 and the septin family (SEPT6) gene at Xq24 in acute leukemia patients . These rearrangements result in fusions with at least 40 other genes, resulting in expression of hybrid proteins with leukemogenic activity [12, 13]. Occasionally hybrid gene formations can also contribute to genomic diversity. Normal forms of UEV proteins are located in the nuclei of cells, while Kua proteins are distributed in endomembranes. The abnormal fusion transcript of these proteins, however, has new enzymatic activity that is associated with cytoplasmic structures [9, 14, 15]. Thus, UEV-Kua gene fusion may be a critical step toward creating a protein with a novel function. The result of splicing out the intergenic region is reported to be a new mechanism of intergenic splicing [15, 17]. For example, the HHLA1-OC90 fusion transcript is expressed by a heterologous HERV-H LTR promoter that is highly active in a teratocarcinoma cell line . Intergenic splicing also occurs between the SSF1 and P2Y11 genes on human chromosome 19 . The SSF1-P2Y11 gene fusion product is 5.6 kb mRNA in length and results in the addition of a potential ATP binding site in SSF1 . Trans-splicing joins two independently transcribed mRNA sequences at canonical exon-exon borders. Although this is a wide- spread phenomenon among lower eukaryotes, only a few isolated cases have been reported in mammals. In the hybrid CYP3A transcripts, CYP3A43 exon 1 is joined to distinct sets of CYP3A4 or CYP3A5 exons at canonical splice sites .
Although advanced cytogenetic banding experiments reveal important information about gene rearrangement mechanisms, experimental screening is costly, time consuming, and tedious. The translocation-mediated hybrid transcript using bioinformatic tools was examined [20, 21]. Kapranov et al. , Parra et al. , and Akiva et al.  have also analyzed the intergenic splicing-mediated gene fusion mechanism only in the human genome. Therefore, we describe the database, HYBRIDdb, which was designed to detect all of the human hybrid genes (chromosomal-mediated translocation, intergenic splicing-mediated, and few trans-splicing hybrid genes) from publicly available transcript sequences for the understanding of the complex gene catalog in normal and abnormal human tissues. We systematically identified hybrid genes from human sequences and discovered some unique features. Included in this database is a comprehensive list of hybrid genes created by trans-splicing, intergenic splicing, and genomic rearrangement between two human genes.
Construction and content
The human transcript (mRNA, EST, cDNA) and human genome sequences were downloaded from the NCBI database. Mobile elements in the human genome sequences were identified by RepeatMasker , and transposable element consensus sequences were identified by Repbase Update . Useful transcript information from tissues and pathology samples was obtained from NCBI genbank.
In silico identification of transcriptional hybrid genes
Utility and discussion
Transcriptional hybrid genes interface
The transcriptional hybrid gene was created by joining the transcript portions of two different genes in the human genome. Access to the database can be obtained in three ways. First, users may search for genes of interest using the HUGO symbol, and will retrieve sequences and detailed information from the NCBI data bank. Secondly, users may search interesting gene names by clicking on a list of genes on the view page according to their chromosome numbers. Moreover, it is possible for users to view the results of this search by clicking on genomic loci. Thirdly, users can view the results of this search by clicking on pathology information or tissue information, and they can also acquire mRNA sequences from the NCBI data bank for further study.
The graphic viewer shows hybrid gene events in the human genome that are represented by the exon-intron splicing structure of mRNAs/ESTs, and functional analysis from the conserved domain database using RPS-BLAST . The results page also includes tissue, pathology, and organ information about the target gene. Importantly, users can see detailed tissue, pathology, and organ information about the target gene in the table displayed on the results page.
HYBRIDdb is an integrated database for genome-wide hybrid genes in humans. This system can identify hybrid genes containing hybrid transcripts created by chromosomal-mediated translocation and intergenic splicing-mediated gene fusion. HYBRIDdb is constantly being updated with new human gene databases from available sources. We also plan to supplement this database with hybrid genes from other mammalian species so that they can be directly compared with hybrid genes from humans. Our work should provide insight into roles for hybrid genes in human evolution and disease.
Availability and requirements
HYBRIDdb is publicly available at the URL http://www.primate.or.kr/hybriddb. Questions and comments are welcomed through the site.
Basic Local Alignment Search Tool
Common Gateway Interface
Expressed Sequence Tag
Human Genome Organization
International Nucleotide Sequence Databases
National Center for Biotechnology Information
Reversed Position Specific Blast
This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0620150-1). We thank to UJ Jo for his technical assistance.
- Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR: A census of human cancer genes. Nature Rev Cancer. 2004, 4: 177-183. 10.1038/nrc1299.View ArticleGoogle Scholar
- Mitelman F, Johansson B, Mertens F: Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genet. 2004, 36: 331-334. 10.1038/ng1335.PubMedView ArticleGoogle Scholar
- Romani A, Guerra E, Trerotola M, Alberti S: Detection and analysis of spliced chimeric mRNAs in sequence databanks. Nucleic Acids Res. 2003, 31: e17-10.1093/nar/gng017.PubMed CentralPubMedView ArticleGoogle Scholar
- Dahary D, Elroy-Stein O, Sorek R: Naturally occurring antisense: transcriptional leakage or real overlap?. Genome Res. 2005, 15: 364-368. 10.1101/gr.3308405.PubMed CentralPubMedView ArticleGoogle Scholar
- Finta C, Zaphiropoulos PG: Intergenic mRNA molecules resulting from trans-splicing. J Biol Chem. 2002, 277: 5882-5890. 10.1074/jbc.M109175200.PubMedView ArticleGoogle Scholar
- Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA: The sequence of the human genome. Science. 2001, 291: 1304-1351. 10.1126/science.1058040.PubMedView ArticleGoogle Scholar
- Marcotte EM, Pellegrini M, Ng HL, Rice DW, Yeates TO, Eisenberg D: Detecting protein function and protein-protein interactions from genome sequences. Science. 1999, 285: 751-753. 10.1126/science.285.5428.751.PubMedView ArticleGoogle Scholar
- Peltonen L, McKusick VA: Dissecting human disease in the postgenomic era. Science. 2001, 291: 1224-1229. 10.1126/science.291.5507.1224.PubMedView ArticleGoogle Scholar
- Long M: A new function evolved from gene fusion. Genome Res. 2000, 10: 1743-1756. 10.1101/gr.165700.View ArticleGoogle Scholar
- Courseaux A, Nahon JL: Birth of two chimeric genes in the hominidae lineage. Science. 2001, 291: 1293-1297. 10.1126/science.1057284.PubMedView ArticleGoogle Scholar
- Kadkol SS, Bruno A, Oh S, Schmidt ML, Lindgren V: MLL-SEPT6 fusion transcript with a novel sequence in an infant with acute myeloid leukemia. Cancer Genet Cytogenet. 2006, 168: 162-167. 10.1016/j.cancergencyto.2006.02.020.PubMedView ArticleGoogle Scholar
- Collins EC, Rabbitts TH: The promiscuous MLL gene links chromosomal translocations to cellular differentiation and tumour tropism. Trends Mol Med. 2002, 8: 436-442. 10.1016/S1471-4914(02)02397-3.PubMedView ArticleGoogle Scholar
- Eguchi M, Eguchi-Ishimae M, Greaves M: The role of the MLL gene in infant leukemia. Int J Hematol. 2003, 78: 390-401.PubMedView ArticleGoogle Scholar
- Kapranov P, Drenkow J, Cheng J, Long J, Helt G, Dike S, Gingeras TR: Examples of the complex architecture of the human transcriptome revealed by RACE and high-density tiling arrays. Genome Res. 2005, 15: 987-997. 10.1101/gr.3455305.PubMed CentralPubMedView ArticleGoogle Scholar
- Thomson TM, Lozano JJ, Loukili N, Carrio R, Serras F, Cormand B, Valeri M, Diaz VM, Abril J, Burset M: Fusion of the human gene for the polyubiquitination coeffector UEV1 with Kua, a newly identified gene. Genome Res. 2000, 10: 1743-1756. 10.1101/gr.GR-1405R.PubMed CentralPubMedView ArticleGoogle Scholar
- Parra G, Reymond A, Dabbouseh N, Dermitzakis ET, Castelo R, Thomson TM, Antonarakis SE, Guigo R: Tandem chimerism as a means to increase protein complexity in the human genome. Genome Res. 2006, 16: 37-44. 10.1101/gr.4145906.PubMed CentralPubMedView ArticleGoogle Scholar
- Akiva P, Toporik A, Edelheit S, Peretz Y, Diber A, Shemesh R, Novik A, Sorek R: Transcription-mediated gene fusion in the human genome. Genome Res. 2006, 16: 30-36. 10.1101/gr.4137606.PubMed CentralPubMedView ArticleGoogle Scholar
- Kowalski PE, Freeman JD, Mager DL: Intergenic splicing between a HERV-H endogenous retrovirus and two adjacent human genes. Genomics. 1999, 57: 371-379. 10.1006/geno.1999.5787.PubMedView ArticleGoogle Scholar
- Communi D, Suarez-Huerta N, Dussossoy D, Savi P, Boeynaems JM: Cotranscription and intergenic splicing of human P2Y11 and SSF1 genes. J Biol Chem. 2001, 276: 16561-16566. 10.1074/jbc.M009609200.PubMedView ArticleGoogle Scholar
- Hahn YS, Bera TE, Gehlhaus K, Kirsch IR, Pastan IH, Lee BK: Finding fusion genes resulting from chromosome rearrangement by analyzing the expressed sequence databases. Proc Natl Acad Sci USA. 2004, 101: 13257-13261. 10.1073/pnas.0405490101.PubMed CentralPubMedView ArticleGoogle Scholar
- Kim N, Kim P, Nam S, Shin S, Lee S: ChimerDB-a knowledgebase for fusion sequences. Nucleic Acid Res. 2006, 34: D21-D24. 10.1093/nar/gkj019.PubMed CentralPubMedView ArticleGoogle Scholar
- RepeatMasker. [http://repeatmasker.genome.washington.edu]
- Jurka J: Repbase update: a database and an electronic journal of repetitive elements. Trends Genet. 2000, 16: 418-420. 10.1016/S0168-9525(00)02093-X.PubMedView ArticleGoogle Scholar
- Florea L, Hartzell G, Zhang Z, Rubin GM, Miller W: A computer program for aligning a cDNA sequence with a genomic DNA sequence. Genome Res. 1998, 8: 967-974.PubMed CentralPubMedGoogle Scholar
- Zhang Z, Schwartz S, Wagner L, Miller W: A greedy algorithm for aligning DNA sequences. J Comput Biol. 2000, 7: 203-214. 10.1089/10665270050081478.PubMedView ArticleGoogle Scholar
- Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997, 25: 3389-3402. 10.1093/nar/25.17.3389.PubMed CentralPubMedView ArticleGoogle Scholar