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  • Review Article
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Alternative splicing and evolution: diversification, exon definition and function

Nature Reviews Genetics volume 11, pages 345–355 (2010)Cite this article

Subjects

Key Points

  • Alternative splicing (AS) is a major contributor to transcriptome and proteome diversity. Evolutionary studies help to address questions that are fundamental to understanding this important process.

  • The main mechanism for exon selection in higher eukaryotes is exon definition: the splicing machinery is placed across exons, constraining their length.

  • Early eukaryotic ancestors are rich in introns, contain degenerate splicing signals and complex spliceosomes, and share homology of splicing factors in different species. These observations suggest an early eukaryotic origin of AS.

  • There are three known evolutionary mechanisms that could account for the appearance of an alternatively spliced exon: exon shuffling (a form of gene duplication), exonization of intronic sequences and transition of a constitutive exon to an alternative exon. The formation of an alternative exon permits new functions to be established without eliminating the original function of the protein.

  • Alu elements — primate-specific reteroelements — substantially contribute to the creation of new alternative exons, which can enhance the genomic repertoire.

  • Defining an alternative exon enables understanding of how splicing affects genome evolution. Comparative studies show conservation that indicates functionality, and these studies can help to identify factors that are involved in exon definition.

  • Recently, it was found that exons have increased nucleosome occupancy levels compared with introns; the nucleosome might act as a 'speed bump' on the exons, slowing RNA polymerase II. Exons were also found to be enriched in certain histone modifications.

  • This nucleosome positioning in exons encourages the 'correct' location of molecular interactions across the exon, which contributes to the exon definition mechanism and suggests another level of complexity in eukaryotic splicing regulation.

Abstract

Over the past decade, it has been shown that alternative splicing (AS) is a major mechanism for the enhancement of transcriptome and proteome diversity, particularly in mammals. Splicing can be found in species from bacteria to humans, but its prevalence and characteristics vary considerably. Evolutionary studies are helping to address questions that are fundamental to understanding this important process: how and when did AS evolve? Which AS events are functional? What are the evolutionary forces that shaped, and continue to shape, AS? And what determines whether an exon is spliced in a constitutive or alternative manner? In this Review, we summarize the current knowledge of AS and evolution and provide insights into some of these unresolved questions.

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Figure 1: The splicing machinery.
Figure 2: Transition from constitutive to alternative splicing.
Figure 3: The 'speed bump' model.

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Acknowledgements

We thank D. Hollander for preparing the figures.

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Authors and Affiliations

  1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, 69978, Ramat Aviv, Israel

    Hadas Keren, Galit Lev-Maor & Gil Ast

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  1. Hadas Keren
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  2. Galit Lev-Maor
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  3. Gil Ast
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Correspondence to Hadas Keren.

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Glossary

Spliceosome

A ribonucleoprotein complex that is involved in splicing of nuclear precursor mRNA (pre-mRNA). It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNPs, which recognize and assemble on exon–intron boundaries to catalyse intron processing of the pre-mRNA.

Nucleosome

The basic unit of chromatin, containing ∼147 bp of DNA wrapped around a histone octamer (which is composed of two copies each of histone 3 (H3), H4, H2A and H2B).

Basal splicing

A conserved mRNA splicing mechanism. It is composed of the splicing signals and the core of the machinery is formed by five spliceosomal small nuclear ribonucleoproteins and an unknown number of proteins.

Alu

An interspersed DNA sequence of 300 bp that belongs to the short interspersed element (SINE) family and is found in the genome of primates. Alu elements are composed of a head-to-tail dimer in which the first monomer is 140 bp long and the second is 170 bp long. In humans, there are ∼1.1 million copies of Alu elements, of which ∼500,000 copies are located in introns.

Retroelement

A mobile genetic element. Its DNA is transcribed into RNA, which is reverse-transcribed into DNA and then inserted into a new location in the genome.

Serine/arginine proteins

A group of highly conserved serine- and arginine-rich splicing regulatory proteins in metazoans.

Heterogenous nuclear ribonucleoproteins

A large set of proteins that bind the precursor mRNA and regulate splicing.

Nonsense-mediated decay

The process by which the cell destroys mRNAs that are untranslatable due to the presence of a premature stop codon in the coding region.

Excavates

A major kingdom of unicellular eukaryotes, often known as Excavata. The phylogenetic category Excavata contains a variety of free-living and symbiotic forms, and also includes some important parasites of humans.

Chromalveolates

A hypothetical 'supergroup' of protists, including apicomplexa, dinoflagellates, ciliates, heterokonts, haptophytes and cryptomonads, all of which are suggested to have diverged from an ancient common ancestor that acquired a plastid by secondary endosymbiosis with a red alga.

Substitution alternative splicing

An alternative splicing pattern in which one of two amino acid sequences is included in the protein.

Mutually exclusive alternative splicing

Only one of a set of two or more exons in a gene is included in the final transcript.

Modular proteins

Proteins created by intronic recombination. According to the exon shuffling theory, each exon encodes a single protein domain (a 'module'), and the process of shuffling creates a new chimeric protein from the combination of domains (or 'modules').

Transposable elements

Segments of genetic material that are capable of changing their location in the genome of an organism.

Orphan genes

Genes that do not share any homology with genes from other species.

Splicing regulatory elements

Specific cis-acting RNA sequence elements that are present in introns or in exons. They are bound by trans-acting splicing regulatory proteins (repressors and activators), which regulate alternative splicing.

Purifying selection

Selection against deleterious alleles that arise in a population, preventing their increase in frequency and assuring their eventual disappearance from the gene pool.

Pseudoexons

Precursor mRNA sequences that resemble exons — both in their size and in the presence of flanking splice-site sequences — but that are not normally recognized by the splicing machinery.

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Keren, H., Lev-Maor, G. & Ast, G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11, 345–355 (2010). https://doi.org/10.1038/nrg2776

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