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How did alternative splicing evolve?

Nature Reviews Genetics volume 5, pages 773–782 (2004)Cite this article

Key Points

  • Alternative splicing contributes significantly to human proteome complexity and explains the numerical disparity between the low number of human protein-coding genes and the number of human proteins.

  • The appearance of multi-intron genes probably predates that of alternative splicing, and constitutive splicing probably predates exon skipping.

  • Most of the higher eukaryotic organisms use alternative splicing, but some lower eukaryotes do not.

  • Our understanding of the origins of alternative splicing has been limited until recently; however, two theories — one sequence based, the other trans-factor based — have now been proposed.

  • Comparative analysis has recently provided important insights into the differences between alternative and constitutive sites, giving us hints about the steps involved in the evolution of alternative splicing.

  • The 5′ splice site reveals major differences between unicellular organisms such as yeasts and multicellular organisms such as mammals. These differences indicate that three positions in the intronic portion of the 5′ss are less conserved in mammals than in yeasts, whereas the last three positions of the exon are more conserved.

  • These differences are directly related to the plasticity of the 5′ splice sites of multicellular eukaryotes: 5′ss can be used in both constitutive and alternative splicing and for the regulation of the inclusion/skipping ratio in alternative splicing.

  • Alternative splicing might have originated as a result of relaxation of 5′ splice site recognition in organisms that originally could support only constitutive splicing.

Abstract

Alternative splicing creates transcriptome diversification, possibly leading to speciation. A large fraction of the protein-coding genes of multicellular organisms are alternatively spliced, although no regulated splicing has been detected in unicellular eukaryotes such as yeasts. A comparative analysis of unicellular and multicellular eukaryotic 5′ splice sites has revealed important differences — the plasticity of the 5′ splice sites of multicellular eukaryotes means that these sites can be used in both constitutive and alternative splicing, and for the regulation of the inclusion/skipping ratio in alternative splicing. So, alternative splicing might have originated as a result of relaxation of the 5′ splice site recognition in organisms that originally could support only constitutive splicing.

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Figure 1: The 5′ splice site of yeasts, humans and mice.
Figure 2: Exon and intron definition.
Figure 3: Types of alternative splicing.
Figure 4: Base paring between different types of 5′ss and U1 snRNA.

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Acknowledgements

I would like to thank I. Carmel, N. Sela and A. Goren for the assembly of the 5′ss datasets, and A. Weiner, M. Kupiec, E. V. Koonin and an anonymous referee for many helpful comments. G. A. is supported by grants from the Israel Academy of Science and, in part, by grants from the Israel Cancer Association, Familial Dysantonomia Hope, the MOP (research and development), India-Israel and the chief scientist of the Israel Health Ministry.

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

    Gil Ast

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DATABASES

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IKBKAP

ADARB2

FURTHER INFORMATION

Saccharomyces Genome Database

Schizosaccharomyces pombe Gene Database

Glossary

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.

SR PROTEINS

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

hnRNP PROTEINS

A large set of proteins that bind to pre-mRNA.

BRANCH SITE

A splicing signal located upstream of the 3′ end of the intron.

GROUP II INTRONS

Autocatalytic introns that are found in lower eukaryotic and prokaryotic organisms. These introns posses enzymatic properties that enable them to remove themselves from RNA precursor and ligate the flanking exons.

RETROTRANSPOSONS

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

GENE CONVERSION

A non-reciprocal recombination process that causes one sequence to be converted into the other.

STEM STRUCTURE

A region of base pairing between two stands of RNA or DNA.

HEMIASCOMYCETOUS YEASTS

A group of yeast that includes S. cerevisiae and at least 13 other yeasts species that have a small genome size and a low frequency of introns.

STACKING ENERGY

Energy contributions from base pair stacking.

WOBBLE SITE

Pairing between the codon and anticodons of tRNA at the last codon position. Wobble enables the anticodon base to form hydrogen bonds with bases other than those in standard base pairs.

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Ast, G. How did alternative splicing evolve?. Nat Rev Genet 5, 773–782 (2004). https://doi.org/10.1038/nrg1451

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