The Evolutionary Landscape of Alternative Splicing in Vertebrate Species

  title={The Evolutionary Landscape of Alternative Splicing in Vertebrate Species},
  author={Nuno L. Barbosa-Morais and Manuel Irimia and Qun Pan and Hui Yuan Xiong and Serge Gueroussov and Leo J. Lee and Valentina Slobodeniuc and Claudia Kutter and Stephen Watt and Recep Çolak and TaeHyung Kim and Christine M. Misquitta-Ali and Michael D. Wilson and Philip M. Kim and Duncan T. Odom and Brendan J. Frey and Benjamin J. Blencowe},
  pages={1587 - 1593}
Whence Species Variation? Vertebrates have widely varying phenotypes that are at odds with their much more limited proteincoding genotypes and conserved messenger RNA expression patterns. Genes with multiple exons and introns can undergo alternative splicing, potentially resulting in multiple protein isoforms (see the Perspective by Papasaikas and Valcárcel). Barbosa-Morais et al. (p. 1587) and Merkin et al. (p. 1593) analyzed alternative splicing across the genomes of a variety of vertebrates… 

An alternative splicing event amplifies evolutionary differences between vertebrates

M mammalian-specific skipping of polypyrimidine tract–binding protein 1 (PTBP1) exon 9 alters the splicing regulatory activities of PTBP1 and affects the inclusion levels of numerous exons, suggesting that these changes contributed to evolutionary differences in the formation of vertebrate nervous systems.

Predominant Patterns of Splicing Evolution on Human, Chimpanzee, and Macaque Evolutionary Lineages

The evolution of splicing patterns based on transcriptome data from five tissues of humans, chimpanzees, rhesus macaques, and mice indicates that, despite their prevalence, constitutive-to-alternative exon transitions do not substantially contribute to long-term functional transcriptome changes, and changes in exon inclusion frequency appear to be functionally relevant.

Diversity and evolution of spliceosomal systems.

Consideration of spliceosomal systems in comparative context reveals a surprising and very complex portrait: in contrast to many expectations, gene structures in early eukaryotic ancestors were highly complex and "animal or plant-like" in many of their spliced structures, but now pronounced simplification of gene structures, splicing signals, and splicesomal machinery occurring independently in many lineages are revealed.

Widespread alternative and aberrant splicing revealed by lariat sequencing

The use of intron lariat sequencing to generate a comprehensive profile of splicing events in Schizosaccharomyces pombe suggests the spliceosome possesses far lower fidelity than previously appreciated, highlighting the potential contributions of alternative splicing in generating novel gene structures.

Predominant patterns of splicing evolution on human, chimpanzee and macaque evolutionary lineages

The evolution of splicing patterns based on transcriptome data from five tissues of humans, chimpanzees, rhesus macaques and mice indicates that, despite their prevalence, constitutive-to-alternative exon transitions do not substantially contribute to long-term functional transcriptome changes, but changes in exon inclusion frequency appear to be functionally relevant.

Global regulatory features of alternative splicing across tissues and within the nervous system of C. elegans

A rich layer of tissue-specific gene regulation at the level of alternative splicing in C. elegans that parallels the evolutionary forces and constraints observed across metazoa is indicated.

Mammalian splicing divergence is shaped by drift, buffering in trans, and a scaling law

It is demonstrated that non-adaptive mutations are often masked in tissues where accurate splicing likely is more important, and experimentally attribute such buffering effect to trans-regulatory splicing efficiency.

Evolution of splicing regulatory networks in Drosophila

A model in which differences in regulatory network architecture among classes of alternative splicing affect the evolution of splicing regulation is proposed, which helps define the mechanisms and constraints that influence splicing regulatory evolution and shows that networks regulating the four major classes ofAlternative splicing diverge through different genetic mechanisms.

Does conservation account for splicing patterns?

A computational model that predicts absolute percent-spliced-in of cassette exons more accurately than previous models, despite not using any ‘hand-crafted’ biological features such as motif counts, suggests that one mechanism for the evolutionary transition from constitutive to alternative splicing is the emergence of cis-acting splicing inhibitors.

The evolution of alternative splicing in Drosophila

While the number of total genes expressed increases during early embryonic development, the proportion of expressed genes that are alternatively spliced is highest in the very early embryo, before the onset of zygotic transcription, which indicates that females deposit a diversity of isoforms into the egg, consistent with abundant AS found in ovary.



Global analysis of alternative splicing differences between humans and chimpanzees.

An important role for alternative splicing is supported in establishing differences between humans and chimpanzees as well as in predicting diverse functions including gene expression, signal transduction, cell death, immune defense, and susceptibility to diseases.

Evolution of Nova-Dependent Splicing Regulation in the Brain

It is hypothesized that evolution of Nova-regulated splicing in higher vertebrates proceeds mainly through changes in cis-acting elements, that tissue-specific splicing might in some cases evolve in a single step corresponding to evolution of a YCAY cluster, and that the conservation level of YCays clusters relates to the functions encoded by the regulated RNAs.

Variation in alternative splicing across human tissues

This study distinguishes the human brain, testis and liver as having unusually high levels of AS, highlights differences in the types of AS occurring commonly in different tissues, and identifies candidate cis-regulatory elements and trans-acting factors likely to have important roles in tissue-specific AS in human cells.

Tissue-specific splicing factor gene expression signatures

This work uses a computational approach to analyze microarray-based gene expression profiles of splicing factors from mouse, chimpanzee and human tissues and shows that brain and testis, the two tissues with highest levels of alternative splicing events, have the largest number ofSplicing factor genes that are most highly differentially expressed.

Deciphering the splicing code

The assembly of a ‘splicing code’ is described, which uses combinations of hundreds of RNA features to predict tissue-dependent changes in alternative splicing for thousands of exons and facilitates the discovery and detailed characterization of regulatedAlternative splicing events on a genome-wide scale.

Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss

An analysis of 9,434 orthologous genes in human and mouse indicates that alternative splicing is associated with a large increase in frequency of recent exon creation and/or loss.

Systematic genome-wide annotation of spliceosomal proteins reveals differential gene family expansion.

This work describes a semiautomated computational pipeline to identify and annotate splicing factors in representative species of eukaryotes and reports several intronless genes amongst splicing proteins in mammals, suggesting that retrotransposition contributed to the complexity of the mammalian splicing apparatus.

Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons

It is found that 40% of new human exons are alternatively spliced, and most of these are cassette exons (exons that are either included or skipped in their entirety) with low inclusion rates, which suggests that de novo recruitment rather than shuffling is the major route by which exonsare added to genes.

The evolution of gene expression levels in mammalian organs

It is shown that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation.

Regulation of alternative splicing by the core spliceosomal machinery.

A role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors is demonstrated.