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Alternative Splicing

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Alternative splicing is a process that enables a messenger RNA (mRNA) to direct synthesis of different protein variants (isoforms) that may have different cellular functions or properties. It occurs by rearranging the pattern of intron and exon elements that are joined by splicing to change the mRNA coding sequence. Alternative splicing of RNA is a crucial process for changing the genomic instructions into functional proteins. It plays a critical role in the regulation of gene expression and protein diversity in a variety of eukaryotes. In humans, approximately 95% of multi-exon genes undergo alternative splicing.

It is a regulated process during gene expression that results in a single gene coding for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. Consequently, the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions. Notably, alternative splicing allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes.

Alternative splicing occurs as a normal phenomenon in eukaryotes, where it greatly increases the biodiversity of proteins that can be encoded by the genome. There are numerous modes of alternative splicing observed, of which the most common is exon skipping. In this mode, a particular exon may be included in mRNAs under some conditions or in particular tissues, and omitted from the mRNA in others. 

The production of alternatively spliced mRNAs is regulated by a system of trans-acting proteins that bind to cis-acting sites on the primary transcript itself. Such proteins include splicing activators that promote the usage of a particular splice site, and splicing repressors that reduce the usage of a particular site. Mechanisms of alternative splicing are highly variable, and new examples are constantly being found, particularly through the use of high-throughput techniques. Researchers hope to fully elucidate the regulatory systems involved in splicing, so that alternative splicing products from a given gene under particular conditions (“splicing variants”) could be predicted by a “splicing code”. 

Abnormal variations in splicing are also implicated in disease; a large proportion of human genetic disorders result from splicing variants. Abnormal splicing variants are also thought to contribute to the development of cancer and splicing factor genes are frequently mutated in different types of cancer. 

There is another form of alternative splicing, known as trans splicing, in which exons from two different genes get assembled together by a spliceosome. This genetic process has only been observed in a few single-celled organisms, but could help explain their genetic diversity without sexual reproduction. While sexually reproducing organisms must breed to mix their genetics and produce new varieties, these organisms can do it much faster. This form of alternative splicing can easily create entirely new functions in these organisms, which may prove to be beneficial.

During alternative splicing, cis-acting regulatory elements in the mRNA sequence determine which exons are retained and which exons are spliced out. These cis-acting regulatory elements alter splicing by binding different trans-acting protein factors, such as SR (Serine-Arginine rich) proteins that function as splicing facilitators, and heterogeneous nuclear ribonucleoproteins (hnRNPs) that suppress splicing. Inhibition of silencing could be achieved sterically, when binding of splicing inhibitors to splicing silencers located in close proximity to splicing enhancers blocks the binding of snRNPs and other activator proteins or prevents the spliceosome assembly. The final decision to include or splice an alternative exon is thus determined by combinatorial effects, cellular abundance, and competitive binding between SR activators and hnRNPs inhibitors. 

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