Abstract
Alternative splicing (AS) and gene duplication (GD) both are processes that diversify the protein repertoire. Recent examples have shown that sequence changes introduced by AS may be comparable to those introduced by GD. In addition, the two processes are inversely correlated at the genomic scale: large gene families are depleted in splice variants and vice versa. All together, these data strongly suggest that both phenomena result in interchangeability between their effects. Here, we tested the extent to which this applies with respect to various protein characteristics. The amounts of AS and GD per gene are anticorrelated even when accounting for different gene functions or degrees of sequence divergence. In contrast, the two processes appear to be independent in their influence on variation in mRNA expression. Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions. We find that, in general, alternative splicing affects protein sequence and structure in a more drastic way than gene duplication and subsequent divergence. Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function. We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment.
Highlights
Alternative splicing (AS) and gene duplication (GD) are two main contributors to the diversity of the protein repertoire with enormous impact on protein sequence, structure, and function [1,2,3,4,5]
Genomic Analysis In accordance with recent findings [12,13], AS and GD are anticorrelated at the genomic level (Figure 2A)
In our analyses described below, we focus on gene families that have both alternative splice variants (ASþ) and gene duplicates (GDþ), i.e., gene with splice variants (ASþ)/gene with duplicates (GDþ), except in the case of local sequence identities, for which we extend our study to families AS–/GDþ and ASþ/GD
Summary
Alternative splicing (AS) and gene duplication (GD) are two main contributors to the diversity of the protein repertoire with enormous impact on protein sequence, structure, and function [1,2,3,4,5]. Structural studies have shown that insertions and deletions between gene duplicates tend to happen at sequence locations where they are less damaging [11], such as loops at solvent-accessible locations These restrictions will apply irrespective of the source of the changes and may introduce a certain degree of similarity between the sequence changes associated with GD and AS. Recent studies have shown that AS and GD are inversely correlated on a genome-wide scale [12,13], i.e., small gene families tend to have more genes with alternative splice variants than do large families These findings together—i.e., anecdotal examples, structural constraints, and anticorrelation at the genomic level—suggest that AS and GD are interchangeable sources of functional diversification [12].
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