Thus far we have considered only protein-coding variants generated by alternative splicing from one TU. The FANTOM3 annotation revealed 82 non-canonical in-frame and nine frame-shifted protein fusion candidates produced from two TUs. Probably, the fusions are the result of transcriptional readthrough of two closely positioned head-to-tail oriented TUs followed by cif-splicing of the hybrid pre-mRNA. Originally, the phenomenon was noted in a study of UEV1-KUA and predicted to be more widespread than expected (Thompson et al 2000).
In FANTOM3 most of the in-frame fusions were observed among paralogues, including members of the Ly49 natural killer cell receptor family members. Since the transcript fusions have the potential to alter signal transduction properties and/or MHC class I specificities they may represent yet another feature of the stochastic tissue cell-specific natural killer cell receptor activation that generate qualitative differences in immune responses. Since the fusion transcripts use the promoter of the first TU it is unclear when transcription results in two distinct transcripts or one fusion transcript. One possibility is that both pre-mRNAs are produced, but the expression level of splicing factors in a tissue cell determines whether the hybrid pre-mRNA is correctly spliced or subject to NDM.
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