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Alternative splicing and RNA selection pressure — evolutionary consequences for eukaryotic genomes

Key Points

  • Global analyses of alternative splicing indicate that it is widespread in human and other multicellular eukaryotic organisms. ESTs and microarray data suggest that nearly three-quarters of human multi-exon genes are alternatively spliced.

  • The frequency of transcript inclusion is an important determinant of the evolution of an alternatively spliced exon. Most minor-form alternative exons are 'young', suggesting that alternative splicing is associated with an increased rate of new exon creation in mammalian genomes.

  • Alternative splicing provides a general strategy for relaxing negative selection pressure against evolutionary changes. It can open near-neutral pathways for evolution of gene structure and recruitment of novel protein-coding sequences.

  • The frequency of alternative splicing in a multi-gene family is negatively correlated with the size of the family, indicating that alternative splicing and gene duplication are inversely correlated evolutionary mechanisms.

  • Evolutionarily conserved alternatively spliced exons have greatly reduced synonymous substitution rates, and have highly conserved flanking intronic regions. Tissue-specific exons exhibit a similar pattern. These data provide evidence for widespread RNA selection pressure in mammalian genes owing to constraints of alternative splicing regulation.

  • Genome-wide analyses of synonymous and non-synonymous substitution rates indicate that two types of selection pressure — selection on protein function and selection on RNA splicing — act very differently on alternatively spliced exons.

  • Splicing mutations have important roles in human diseases.

Abstract

Genome-wide analyses of alternative splicing have established its nearly ubiquitous role in gene regulation in many organisms. Genome sequencing and comparative genomics have made it possible to look in detail at the evolutionary history of specific alternative exons or splice sites, resulting in a flurry of publications in recent years. Here, we consider how alternative splicing has contributed to the evolution of modern genomes, and discuss constraints on evolution associated with alternative splicing that might have important medical implications.

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Figure 1: Patterns of alternative splicing.
Figure 2: Defining the conservation of alternative splicing.
Figure 3: Creation of a new functional alternative exon of p75TNFR from an Alu element.
Figure 4: Conservation of human constitutive and alternatively spliced exons in mouse orthologues.
Figure 5: Alternative splicing opens neutral paths for an accelerated rate of new exon creation.

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Acknowledgements

We thank D. Black and B. Blencowe for comments on our manuscript, and S. Mount for discussions. This work was supported by grants from the US National Institutes of Health and the US Department of Energy, and a Ph.D. dissertation fellowship from the University of California, Los Angeles, to Y.X.

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RCSB Protein Data Bank

Glossary

Alu

A class of retrotransposons that belongs to the primate-specific family of short interspersed elements.

Nonsense-mediated decay

An mRNA surveillance mechanism for removing aberrant mRNAs with premature termination codons.

Major-form exons

Alternatively spliced exons with high exon-inclusion levels — they are usually included in the transcripts.

Minor-form exons

Alternatively spliced exons with low exon-inclusion levels — they are usually excluded from the transcripts.

Outgroup

In phylogenetic analysis, the taxon that is most distant from all the other taxa of interest. For example, human is an outgroup to mouse and rat.

Subfunctionalization

Two duplicated genes specialize to perform complementary functions.

Ancestral alternatively spliced exons

Exons that are alternatively spliced in the transcripts of two species, suggesting that alternative splicing was present in the common ancestor of these species.

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Xing, Y., Lee, C. Alternative splicing and RNA selection pressure — evolutionary consequences for eukaryotic genomes. Nat Rev Genet 7, 499–509 (2006). https://doi.org/10.1038/nrg1896

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