Evidence for widespread subfunctionalization of splice forms in vertebrate genomes

Abstract

Gene duplication and alternative splicing are important sources of proteomic diversity. Despite research indicating that gene duplication and alternative splicing are negatively correlated, the evolutionary relationship between the two remains unclear. One manner in which alternative splicing and gene duplication may be related is through the process of subfunctionalization, in which an alternatively spliced gene upon duplication divides distinct splice isoforms among the newly generated daughter genes, in this way reducing the number of alternatively spliced transcripts duplicate genes produce. Previously, it has been shown that splice form subfunctionalization will result in duplicate pairs with divergent exon structure when distinct isoforms become fixed in each paralog. However, the effects of exon structure divergence between paralogs have never before been studied on a genome-wide scale. Here, using genomic data from human, mouse, and zebrafish, we demonstrate that gene duplication followed by exon structure divergence between paralogs results in a significant reduction in levels of alternative splicing. In addition, by comparing the exon structure of zebrafish duplicates to the co-orthologous human gene, we have demonstrated that a considerable fraction of exon divergent duplicates maintain the structural signature of splice form subfunctionalization. Furthermore, we find that paralogs with divergent exon structure demonstrate reduced breadth of expression in a variety of tissues when compared to paralogs with identical exon structures and singletons. Taken together, our results are consistent with subfunctionalization partitioning alternatively spliced isoforms among duplicate genes and as such highlight the relationship between gene duplication and alternative splicing.

Alternative splicing and the evolution of phenotypic novelty

“…Other examples of duplicate genes retained and evolving to resemble ancestral alternative splicing isoforms preceding gene duplication are characterized in the MITF [55], FoxP [56] and Syn-Timp families [57]. Moreover, two genome-wide studies have shown that alternatively spliced genes are more likely to be found as duplicate copies in vertebrates [58] and fungi [59].…”

Evolution of selenophosphate synthetases: emergence and relocation of function through independent duplications and recurrent subfunctionalization

“…However, other than the ascidian SPS genes reported here, only a handful of cases have been so far reported: the eukaryotic splicing factor U2AF1 in vertebrates (Pacheco et al 2004), the ey gene in Drosophila (also known as Pax6) (Dominguez et al 2004), and the mitf gene in fishes (Altschmied et al 2002). Very recently, Lambert et al (2015) suggested that this phenomenon could be widespread during vertebrate evolution.…”

The rapid evolution of alternative splicing in plants

“…To reduce the background noise, any EEJ with multiple AS types, low number of support reads (less than five) or orthologous EEJ pair have different AS types were removed. The conservation levels (conserved, lost or gained in the other species) were used as the output of the model and the difference of features that were known to be important to AS and AS conservation (Su et al, 2006; Kelley et al, 2014; Li et al, 2014; Lambert et al, 2015; Rosenberg et al, 2015) (listed in Supplemental file 2) between two species were used as input to train the model. Yass v1.15 (Noe and Kucherov, 2005) was used to align the SS’ flanking sequences (combined 50 bp upstream and downstream sequences of 5’/3’ splice site, 100 bp in total) of each orthologous EEJ pair, the similarity was calculated as: (length of alignment - number of gaps - number of mismatches) / (total sequence length).…”

“…Distinctive features that distinguish alternatively spliced exons/introns from constitutively spliced exons/introns can be used to accurately predict the specific AS type (Koren et al, 2007; Braunschweig et al, 2014). Furthermore, other factors including secondary and tertiary RNA structures, chromatin remodeling, insertion of transposable elements (TEs) and gene duplication (GD) may also be involved in regulating AS (Liu et al, 1995; Sorek et al, 2002; Donahue et al, 2006; Su et al, 2006; Kolasinska-Zwierz et al, 2009; Schwartz et al, 2009; Warf and Berglund, 2010; Lambert et al, 2015). However, the extent to which changes in these factors contributed to the evolutionary history of AS in vertebrates remains largely unclear.…”