Introns & Alternative Splicing
Most eukaryotic genes are split by introns - non-coding sequences between exons. The spliceosome removes introns. By including or excluding different exons, the cell can produce multiple different proteins from a single gene. This is alternative splicing.
The Numbers
The human genome has about 20,000 protein-coding genes but produces about 100,000+ distinct proteins. Alternative splicing is the main reason. Over 90% of multi-exon human genes undergo alternative splicing in at least some tissue or condition.
Types of Alternative Splicing
- Exon skipping: an exon is included in some tissues, excluded in others.
- Alternative 5’ or 3’ splice sites: the same exon is used but with a shifted boundary.
- Intron retention: an intron is left in the mature mRNA.
- Mutually exclusive exons: exon A or exon B is included, never both.
Why Introns Exist
Introns are evolutionarily ancient but vary widely. Their functional value is debated, but they clearly:
- Enable alternative splicing to produce proteome diversity.
- Allow exon shuffling over evolutionary time (introns let exons recombine without disrupting coding sequence).
- Sometimes contain regulatory elements like enhancers or noncoding RNAs.
Bacterial genes lack introns. Eukaryotes tolerate the costs of splicing because alternative splicing is so valuable.
Why can the human genome encode about 20,000 genes but produce ~100,000 proteins?
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Alternative splicing. By including or excluding different exons during splicing, a single gene can produce multiple mRNA isoforms, each encoding a different protein. Combined with post-translational modifications, this produces the much larger proteome diversity from a relatively small number of genes.
What is exon skipping?
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Exon skipping is an alternative splicing pattern in which a normally included exon is skipped in some transcripts, producing an mRNA missing that exon. The resulting protein lacks the amino acids encoded by the skipped exon. Cells use exon skipping to produce tissue-specific protein variants from a single gene.
Why might a single amino acid mutation in a gene produce no protein at all?
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Splice site mutations. If a mutation destroys a splice site (the GU at a 5' site or AG at a 3' site), splicing fails. Introns are retained or wrong junctions are used, producing frameshifts and premature stop codons that trigger nonsense-mediated decay of the mRNA. The gene essentially produces no functional protein. Beta-thalassemia includes famous examples.