SERpredict: Detection of tissue- or tumor-specific isoforms generated through exonization of transposable elements

BioMed Central Page 1 of 12 (page number not for citation purposes) BMC Genetics Open Access Software SERpredict: Detection of tissue- or tumor-specific isoforms generated through exonization of transposable elements Britta Mersch1, Noa Sela2, Gil Ast2, Sándor Suhai1 and Agnes Hotz- Wagenblatt*1 Address: 1Department of Molecular Biophysics, German Cancer Research Center (DKFZ), Heidelberg, Germany and 2Department of Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Email: Britta Mersch - b.mersch@dkfz.de; Noa Sela - noasela@post.tau.ac.il; Gil Ast - gilast@post.tau.ac.il; Sándor Suhai - s.suhai@dkfz.de; Agnes Hotz-Wagenblatt* - hotz-wagenblatt@dkfz.de * Corresponding author Abstract Background: Transposed elements (TEs) are known to affect transcriptomes, because either new exons are generated from intronic transposed elements (this is called exonization), or the element inserts into the exon, leading to a new transcript. Several examples in the literature show that isoforms generated by an exonization are specific to a certain tissue (for example the heart muscle) or inflict a disease. Thus, exonizations can have negative effects for the transcriptome of an organism. Results: As we aimed at detecting other tissue- or tumor-specific isoforms in human and mouse genomes which were generated through exonization of a transposed element, we designed the automated analysis pipeline SERpredict (SER = Specific Exonized Retroelement) making use of Bayesian Statistics. With this pipeline, we found several genes in which a transposed element formed a tissue- or tumor-specific isoform. Conclusion: Our results show that SERpredict produces relevant results, demonstrating the importance of transposed elements in shaping both the human and the mouse transcriptomes. The effect of transposed elements on the human transcriptome is several times higher than the effect on the mouse transcriptome, due to the contribution of the primate-specific Alu elements. Background Transposed elements (TEs) are sequences of DNA that can move from one position to another in the genome. There are two classes of transposed elements, the DNA trans- posons and the retroelements. DNA transposons usually move by cut and paste using the transposase enzyme. In contrast, retroelements are genetic elements that integrate in a genome via an RNA intermediate which is reverse- transcribed to DNA. In mammals, almost half the genome is comprised of TEs: around 45% of the human genome is made up of them. This translates to millions of elements, so that on average, every gene in our genome contains about 3 transposed elements. Transposed elements com- prise approximately 37% of the mouse genome. The human and mouse genome sequences show that TEs have played an important role in shaping the genomes [1,2]. The human genome contains retroelements such as Published: 6 November 2007 BMC Genetics 2007, 8:78 doi:10.1186/1471-2156-8-78 Received: 24 May 2007 Accepted: 6 November 2007 This article is available from: http://www.biomedcentral.com/1471-2156/8/78 © 2007 Mersch et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. BMC Genetics 2007, 8:78 http://www.biomedcentral.com/1471-2156/8/78 Page 2 of 12 (page number not for citation purposes) Alu, which is a short interspersed element (SINE), MIR (mammalian interspersed repeat) as well as LINE-1 (L1), LINE-2 (L2) and CR1 (L3). The last three of the given fam- ilies of retroelements are termed long interspersed ele- ments. In addition, the human genome contains LTR elements such as MaLR (mammalian apparent LTR-retro- transposon), ERVL and ERV1 (endogenous retroviruses) as well as DNA transposons where common families are MER1 and MER2. The mouse genome contains MIR ele- ments as well as rodent-specific SINEs such as B1 (homol- ogous to the left arm of the Alu), B2, B4 and ID as well as LINEs such as L1, L2 and CR1. Similar to the human genome, the mouse genome contains LTRs and DNA transposons. With approximately 1 million copies, Alu is the most frequently encountered TE in the human genome. In mouse, B1 and L1 are the elements with the highest number of copies (B1: 500,000 copies, L1: 800,000 copies). Through splicing processes ("exonizations"), small pieces of transposed elements can be inserted into mature mRNAs. These exonizations are caused by motifs that resemble consensus splice sites in both strands of the TEs [3]. The transposed elements do not only contain these splice sites but also polyadenylation sites, promoters, enhancers and silencers. Therefore, they can add a variety of functions to their targeted genes [4-6]. Mutations within intronic TEs may yield active splice sites which can be used instead of

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