Alternative splicing ( mechanism and its regulation )

Summary

This video explores the concept of alternative splicing, a mechanism that allows a single gene to produce multiple proteins, contributing to the complexity of the human proteome. It explains how alternative splicing can generate diversity in protein production through different methods, including exon skipping and intron retention. The video also delves into the regulatory mechanisms and tissue-specific factors influencing splicing. Furthermore, it highlights the evolutionary significance of a mutation in the human gene Arap11a, which led to the development of unique traits in humans, distinguishing us from other primates.

Takeaways

• 😀 Alternative splicing is a key mechanism explaining why the human genome with ~25,000 genes can produce around 500,000 different proteins.
• 😀 The concept of 'one gene, one protein' was challenged by the discovery of alternative splicing, which allows a single gene to code for multiple proteins.
• 😀 In addition to differential gene expression, alternative splicing also contributes to cell type specificity and the creation of unique proteins in different cells, such as hepatocytes, nerve cells, and muscle cells.
• 😀 Alternative splicing works through selective exon inclusion, where different combinations of exons are spliced together to produce unique mRNAs and proteins.
• 😀 There are various mechanisms for alternative splicing, including exon skipping, intron retention, and alternative exon selection, each leading to diverse protein products.
• 😀 The muscle protein troponin is an example of how alternative splicing generates isoforms like alpha and beta troponin from the same RNA transcript.
• 😀 The SV40 virus T antigen also undergoes alternative splicing, with different splice site selections producing full-length and truncated versions of the protein.
• 😀 Polyadenylation site choice can also lead to diversity, as different tissues may select different polyadenylation sites, generating distinct products like calcitonin in the thyroid and CGRP in the brain.
• 😀 Alternative splicing is regulated by activators and repressors, which interact with the splicing machinery to control which exons are included in the final mRNA transcript.
• 😀 A mutation in the human gene ARHGAP11A, which occurred 5 million years ago, led to the creation of a new splice variant, ARHGAP11B, contributing to human brain evolution by increasing cortical volume and neuron proliferation.

Q & A

What is alternative splicing, and why is it important?

Alternative splicing is a process by which a single gene can produce multiple protein variants. It allows cells to generate diversity in protein production, which is essential for different cell types and tissue-specific functions.

How many genes are in the human genome, and how does this relate to the large number of proteins produced?

The human genome contains around 20,000 to 25,000 genes. However, the human body produces approximately 500,000 proteins, which is much more than the number of genes, and this is explained by alternative splicing.

What is the hypothesis 'one gene = one protein,' and why doesn't it fully explain protein diversity?

'One gene = one protein' suggests that each gene codes for a single protein, but this doesn’t account for the large diversity of proteins produced in humans. Alternative splicing explains how a single gene can lead to the production of multiple proteins through various combinations of exons.

What are exons and introns, and how do they relate to alternative splicing?

Exons are the protein-coding regions of a gene, while introns are non-coding regions. During transcription, both exons and introns are copied into RNA, but during alternative splicing, the introns are removed, and different combinations of exons can be joined to produce varied protein products.

How does exon skipping contribute to alternative splicing?

Exon skipping occurs when the splicing machinery skips over one or more exons, leading to a different combination of exons being joined together. This results in a different protein product being produced.

What is intron retention, and how does it affect the final protein product?

Intron retention occurs when part or all of an intron is retained in the mature RNA transcript. This can disrupt the coding sequence, potentially changing the protein's function or rendering it nonfunctional.

What role do splicing activators and repressors play in alternative splicing?

Splicing activators promote the use of specific splice sites, while repressors inhibit the use of certain splice sites. These regulators ensure that splicing occurs correctly, and their presence or absence determines the diversity of proteins produced in different cell types.

Can you provide an example of alternative splicing in muscle cells?

In muscle cells, the troponin gene undergoes alternative splicing to produce two isoforms of troponin: alpha-troponin and beta-troponin. These different proteins contribute to muscle function and are produced in different tissues.

How does alternative splicing affect the production of proteins in viruses, such as the SV40 virus?

In the SV40 virus, alternative splicing of the T antigen gene leads to the production of different protein variants. Depending on which splice sites are selected, a full-length or truncated T antigen can be produced, affecting the virus’s virulence.

How did a mutation in the AGAP11A gene contribute to human evolution?

A mutation in the AGAP11A gene around 5 million years ago led to the creation of AGAP11B, a new protein with a different function. This protein plays a crucial role in regulating the development of neurons, contributing to the larger and more complex human brain.