Alternative splicing is a substantial contributor to the high complexity of transcriptomes of multicellular eukaryotes. In this Review, we discuss the accumulated evidence that most of this complexity is reflected at the protein level and fundamentally shapes the physiology and pathology of organisms. This notion is supported not only by genome-wide analyses but, mainly, by detailed studies showing that global and gene-specific modulations of alternative splicing regulate highly diverse processes such as tissue-specific and species-specific cell differentiation, thermal regulation, neuron self-avoidance, infrared sensing, the Warburg effect, maintenance of telomere length, cancer and autism spectrum disorders (ASD). We also discuss how mastering the control of alternative splicing paved the way to clinically approved therapies for hereditary diseases.
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The authors apologize to those researchers whose work could not be cited owing to space constraints. They thank B. Blencowe for critical reading of the manuscript and L. Giono for the design of Fig. 3B. Work in the authors’ laboratory was supported by a joint grant from Familias Atrofia Muscular Espinal (FAME, Argentina) and CureSMA (USA), and grants from the Lounsbery Foundation (USA), the Universidad de Buenos Aires (UBACYT 20020170100046BA), the Agencia Nacional de Promoción Científica y Tecnológica of Argentina (PICT-2019 862) and the CONICET (PUE 22920170100062CO).
The authors declare no competing interests.
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National Human Genome Research Institute, National Institutes of Health (NIH): https://www.genome.gov/genetics-glossary/Exon
The exchange of the organic group R″ of an ester with the organic group R′ of an alcohol. In the second step of splicing, the uncleaved intron 3′ end is the (phosphodi)ester and the free exon is the alcohol. Following the reaction, the free intron becomes an alcohol and the joined exons form a phosphodiester bond.
- Cassette exons
Exons that as a whole are either included in or skipped from the mature mRNA.
- Class I exons
Exons whose inclusion in the mature mRNA is promoted by slow, and inhibited by fast, transcript elongation.
- Class II exons
Exons whose inclusion in the mature mRNA is inhibited by slow, and promoted by fast, transcript elongation.
- Nonsense-mediated decay
(NMD). An mRNA degradation mechanism that is coupled to splicing and translation and is triggered by premature stop codons.
- Detained introns
Introns that cause the mRNAs that harbour them to remain in the nucleus.
- γ-Aminobutyric acid A
(GABAA). A small organic molecule synthesized from the amino acid glutamic acid that acts as a neurotransmitter whose receptors are part of ligand-gated ion channels.
- Peptidergic secretion
The secretion of small polypeptides with neurotransmitter activity.
- Exon shuffling
A mechanism for the formation of new genes in eukaryotes during evolution, usually through recombination between introns of different genes, yielding novel rearranged genes with altered functions, without elimination of the original genes.
A type of evolutionary selective pressure. r-Selected species, such as bacteria, are small organisms with short life cycles and fast maturation that are able to rapidly populate new environments.
A type of evolutionary selective pressure. K-Selected species, such as pluricellular organisms with specialized tissues and organs, are bigger, have longer life cycles and slow maturation, and their colonization of new environments depends on their ability to adapt physiologically.
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Marasco, L.E., Kornblihtt, A.R. The physiology of alternative splicing. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00545-z
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