Why alternative splicing

The mRNA transcripts created from alternative splicing can translate into varying amino acid sequences that produce protein isoforms with different functions. The mechanisms that regulate alternative splicing 4 play a fundamental role in gene expression due to their spatial and temporal functions throughout biology.

What are the mechanisms of alternative splicing? When these pre-mRNA sequences undergo constitutive splicing, the removal of introns is followed by the joining of exons in their DNA-corresponding order. Alternative splicing deviates from this process through mechanisms that rearrange the pattern of exons into alternative coding sequences that translate to different proteins.

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The inclusion or splicing of an alternative exon is therefore determined by combinatorial effects, cellular abundance, and competitive binding between SR activators and hnRNP inhibitors. Alternative splicing outcomes depend on the stoichiometry and interactions of splicing activators and inhibitors, as well as the steric conformation and accessibility of the splicing sites.

On average, human transcripts contain approximately nine introns. Advances in high-throughput technologies, including next-generation RNA and DNA sequencing, have facilitated studies of genome-wide alternative splicing. Alternative splicing events are differentially regulated across different tissues and during development, as well as among individuals and populations. Studies indicate that alternative splicing of CD44, a protein involved in T-cell homing with 10 variable cassette exons and six distinct protein isoforms, is crucial for T-cell function.

The variable exons of CD44 encode portions of the membrane-proximal extracellular domain of the protein, and the presence of some of the variable exons has been shown to increase the association of CD44 with various proteins. Isoform expression is activation dependent. In comparison, activated T cells express multiple CD44 isoforms, thereby suggesting that CD44 alternative splicing is important for activation.

The scope and role of this vital regulatory mechanism still requires investigation on a genome-wide scale. It is now clear that alternative splicing is more widespread and complex than was initially thought. In addition, the role of alternative splicing in different human pathologies is also being revealed. As a result, improving our understanding of the mechanisms behind alternative splicing will present exciting opportunities for therapeutic development.

Check out our companion article for more on what alternative splicing means for your experiments. Symp Soc Exp Biol 12 — Cell 12 :1—8. PNAS 74 —5. Science — Cell 19 4 — Mol Carcinog. Hum Genet — New York: WH Freeman. Gene 1 :1—