Alternative Splicing May Not Be the Key to Proteome Complexity

Michael L. Tress, Federico Abascal, Alfonso Valencia
<span title="">2017</span> <i title="Elsevier BV"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/rg373qd4c5a2npre7o4rshhyyi" style="color: black;">TIBS -Trends in Biochemical Sciences. Regular ed</a> </i> &nbsp;
Alternative splicing is commonly believed to be a major source of cellular protein diversity. However, although many thousands of alternatively spliced transcripts are routinely detected in RNA-seq studies, reliable large-scale mass spectrometry-based proteomics [ 1 3 _ T D $ D I F F ] analyses identify only a small fraction of annotated alternative isoforms. The clearest finding from proteomics experiments is that most human genes have a single main protein isoform, while those alternative
more &raquo; ... orms that are identified tend to be the most biologically plausible: those with the most cross-species conservation and those that do not compromise functional domains. Indeed, most alternative exons do not seem to be under selective pressure, suggesting that a large majority of predicted alternative transcripts may not even be translated into proteins. One Gene, One Protein or One Gene, Many Proteins? Alternative splicing of messenger RNA produces a wide variety of differently spliced RNA transcripts that may be translated into diverse protein products. The presence of alternatively spliced transcripts is unequivocally supported by expressed sequence tag and cDNA sequence evidence [1], microarray data [2], and RNA-seq data [3, 4] . It has been estimated that most multiexon human genes can undergo alternative splicing [5] . Manual genome annotation projects [1, 6, 7] have added substantial numbers of alternatively spliced transcripts to reference databases in recent years; the current version of the GENCODE human gene set (v24) [1] contains 82 141 coding sequence (CDS) distinct protein-coding transcripts. Many estimates for the number of transcripts expressed in human cells are even higher; a recent large-scale RNA-seq analysis [3] found multiple splice variants for 72% of annotated human genes, while another predicted that 205 000 transcripts had protein-coding potential, which would mean more than ten variants per annotated gene [8] . The breadth of alternative splicing detectable at the transcript level has led to claims that alternative protein isoforms could be the key to mammalian complexity [9] . How much of this alternative splicing is functional at the protein level is a long-standing open question of great importance for understanding eukaryotic biology (Box 1).
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