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Alternative splicing as a source of phenotypic diversity

Abstract

A major goal of evolutionary genetics is to understand the genetic processes that give rise to phenotypic diversity in multicellular organisms. Alternative splicing generates multiple transcripts from a single gene, enriching the diversity of proteins and phenotypic traits. It is well established that alternative splicing contributes to key innovations over long evolutionary timescales, such as brain development in bilaterians. However, recent developments in long-read sequencing and the generation of high-quality genome assemblies for diverse organisms has facilitated comparisons of splicing profiles between closely related species, providing insights into how alternative splicing evolves over shorter timescales. Although most splicing variants are probably non-functional, alternative splicing is nonetheless emerging as a dynamic, evolutionarily labile process that can facilitate adaptation and contribute to species divergence.

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Fig. 1: Patterns of alternative splicing.
Fig. 2: Role of alternative splicing in sex determination.
Fig. 3: Genetic basis of novel splice forms and patterns.
Fig. 4: Alternative splicing can underpin morphological evolution.
Fig. 5: Divergent alternative splicing can mediate lineage-specific adaptations.

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Acknowledgements

The authors thank everyone at the Insect Evolution and Genomics Group at the University of Cambridge for useful discussion and comments on the manuscript, and G. Simpson and J. Valcárcel for helpful discussions. This research was funded in part by the Wellcome Trust (grants 206194 and 218328). C.D.J. was supported by a European Research Council (grant 339873 Speciation Genetics) and the UK Biotechnology and Biological Sciences Research Council (grant BB/R007500/1). C.W.J.S. received funding from a Wellcome Trust Investigator award (209368/Z/17/Z). We thank A. Jacob for generating the consensus sequences in Fig. 1c.

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Glossary

Alternative splicing

The process of selecting different combinations of splice sites within the pre-mRNAs of a gene, resulting in mature mRNA transcripts that differ in composition. These transcripts may result in different protein isoforms with potentially divergent functions.

Cassette exons

Alternative exons that can be included or skipped from the spliced mRNA.

Cis-regulatory elements

Genetic regions that regulate the expression of a coding sequence on the same DNA strand.

Effective population size

The number of individuals in an idealized population that would show the same amount of genetic drift as observed in the real population.

Exon definition

A process in which pairs of splice sites are first recognized, and splicing complexes assembled, across exons.

Introgression

The transfer of genetic material between two species owing to hybridization and subsequent backcrossing with one of the species.

Intron definition

A process in which pairs of splice sites are recognized and then splicing complexes are assembled directly across the intron to be spliced out.

Poison exons

Exons that introduce in-frame premature termination codons, frequently in all three reading frames.

Purifying selection

The removal of deleterious alleles from a population by natural selection.

Quantitative trait loci

(QTL). Regions of the genome whose variation is associated with a particular quantitative trait.

Spliceosome

The large macromolecular complex composed of proteins and small nuclear RNAs that functions as the basal splicing machinery.

Trans-regulatory factors

Cellular factors (RNA or protein) that regulate the expression of a coding sequence on a different DNA strand to which it is encoded.

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Wright, C.J., Smith, C.W.J. & Jiggins, C.D. Alternative splicing as a source of phenotypic diversity. Nat Rev Genet (2022). https://doi.org/10.1038/s41576-022-00514-4

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