The Evolutionary Landscape of Alternative Splicing in Vertebrate Species

Abstract

How species with similar repertoires of protein-coding genes differ so markedly at the phenotypic level is poorly understood. By comparing organ transcriptomes from vertebrate species spanning ~350 million years of evolution, we observed significant differences in alternative splicing complexity between vertebrate lineages, with the highest complexity in primates. Within 6 million years, the splicing profiles of physiologically equivalent organs diverged such that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are cis-directed. However, a subset of pronounced splicing changes are predicted to remodel protein interactions involving trans-acting regulators. These events likely further contributed to the diversification of splicing and other transcriptomic changes that underlie phenotypic differences among vertebrate species.

The landscape of human mutually exclusive splicing

“…To validate the predicted MXE candidates, we made use of over 15 billion publically available RNA‐Seq reads, selecting 515 samples comprising 31 tissues and organs, 12 cell lines and seven developmental stages (Barbosa‐Morais et al , 2012; Djebali et al , 2012; Tilgner et al , 2012; Xue et al , 2013; Yan et al , 2013; Fagerberg et al , 2014; Dataset EV1). The data were chosen to encompass common and rare potential splice events in a broad range of tissues, cell types and embryonic stages.…”

“…While tissue‐specific gene expression is conserved between birds and mammals, the alternative splicing of cassette exons is conserved only in brain, heart and muscles and is mainly lineage‐specific (Barbosa‐Morais et al , 2012; Merkin et al , 2012). Accordingly, a core set of only ~500 exons was found with conserved alternative splicing in mammals and high sequence conservation, which was a small subset of the thousands of cassette exons identified in total.…”

“…High‐throughput studies suggested that not only 95–100% of all multi‐exon genes in human are affected (Pan et al , 2008; Wang et al , 2008; Gerstein et al , 2014) but also that alternative splicing patterns strongly diverged between vertebrate lineages implying a pronounced role in the evolution of phenotypic complexity (Barbosa‐Morais et al , 2012; Merkin et al , 2012). Five types of alternative splicing have been identified to contribute to most mRNA isoforms, which are differential exon inclusion (exon skipping), intron retention, alternative 5′ and 3′ exon splicing, and mutually exclusive splicing (Blencowe, 2006; Pan et al , 2008; Wang et al , 2008; Nilsen & Graveley, 2010).…”

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

“…Splicing factors themselves demonstrate high species conservation (Barbosa‐Morais et al ., 2006), whereas patterns of alternative splicing are partially determined by genetic differences and may be species specific. Splicing patterns show drastically more interspecies variability than gene expression with only 50% of alternatively expressed isoforms being conserved between species (Barbosa‐Morais et al ., 2012). Alternatively regulated splice sites demonstrating temporal, spatial or reactive expression are less likely to show species conservation (Garg & Green, 2007).…”

Expression and function analysis of two naturally truncated MyD88 variants in the Pacific oyster Crassostrea gigas

“…In the aspect of post-translation regulation, alternative splicing is one of the basic means to increase the biodiversity of proteins in organisms by which one gene sequence codes for multi-variants of proteins [7,8]. The different variants often display dominant negative effect due to the lack of key domain, such as a dominant negative Protein Kinase A mutation [9].…”