Alternative splicing is a biological process that occurs after a gene’s DNA has been copied into an RNA molecule, known as pre-messenger RNA (pre-mRNA). This process modifies the pre-mRNA by selectively including or excluding certain segments called exons, while removing non-coding regions called introns. The remaining exons are then joined together in various combinations to form mature messenger RNA (mRNA) molecules. This post-transcriptional modification is a widespread phenomenon in eukaryotic organisms, including humans, and is considered a normal part of gene expression.
Generating Protein Diversity
Alternative splicing allows a single gene to produce multiple distinct protein versions, known as isoforms, which can have different structures and functions. This mechanism expands the functional output from an organism’s genome, enabling a relatively small number of genes to give rise to a larger and more diverse set of proteins. For instance, a single gene with seven exons could potentially create hundreds of protein combinations through alternative splicing.
Imagine a gene as a set of building blocks, where exons contain instructions for making a protein, and introns are non-coding spacers. Alternative splicing allows different combinations of these exon “blocks” to be assembled. This leads to various mRNA transcripts, each coding for a unique protein isoform.
One common mode of alternative splicing is “exon skipping,” where certain exons are entirely left out of the final mRNA sequence. Other variations include alternative 5′ or 3′ splice sites, where the cut-off points for exons are shifted, or intron retention, where an intron is kept in the mature mRNA. These different splicing patterns result in proteins with altered amino acid sequences, which can lead to changes in their shape, activity, cellular location, or ability to interact with other molecules.
Controlling Cellular Processes
Alternative splicing acts as a regulatory mechanism for gene expression and protein function within cells. This process enables cells to perform specialized functions by producing specific protein isoforms tailored to different tissues or developmental stages. For example, a protein variant needed in brain cells might be different from a variant of the same protein found in muscle cells, despite originating from the same gene.
This dynamic control allows cells to respond and adapt quickly to changing internal or external conditions. By switching which protein isoforms are produced, cells can alter their functions rapidly. For instance, the immune system utilizes alternative splicing to adapt its genes to recognize and combat new pathogens by creating tailored proteins.
The regulation of alternative splicing involves numerous components, including specific RNA sequences within the pre-mRNA (cis-acting elements) and various proteins (trans-acting factors) that bind to these sequences. These regulatory proteins, such as SR proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), either promote or inhibit the inclusion of certain exons, guiding the splicing machinery. External stimuli, like hormones or cellular signals, can influence these splicing factors, leading to changes in protein isoform production and allowing cells to fine-tune their responses.
Impact on Health and Disease
When alternative splicing malfunctions, it can have consequences for health, leading to the production of non-functional or harmful protein isoforms that contribute to various diseases. Errors in this process can arise from mutations in the DNA sequence that affect splice sites or regulatory elements, or from disruptions in the proteins that control splicing. These alterations can lead to exons being incorrectly included or excluded, resulting in aberrant proteins.
Such dysregulation of alternative splicing is implicated in a range of human diseases. For example, it plays a role in certain cancers, where altered splicing can lead to proteins that promote uncontrolled cell growth, inhibit programmed cell death (apoptosis), or enhance the spread of tumors. Specific examples include changes in the splicing of the FAS gene, which can produce a protein that blocks cell death, or the BCL-X gene, which generates isoforms with opposing effects on apoptosis.
Alternative splicing dysfunction is linked to neurological disorders, such as autism spectrum disorder and schizophrenia, where it can affect brain development and function. For instance, mutations in the MAPT gene, which encodes the tau protein, can alter its splicing and contribute to neurodegenerative conditions like frontotemporal dementia. Genetic conditions like spinal muscular atrophy are associated with reduced levels of a survival motor neuron (SMN) protein due to aberrant alternative splicing. Understanding these malfunctions opens avenues for therapeutic strategies, where targeting specific alternative splicing events could offer new approaches to disease treatment.