Intron

An intron is a specific nucleotide sequence found within a gene. These sequences are not expressed or operative in the final RNA product. The term comes from "intragenic region," meaning a region located inside a gene.

While introns are part of the initial genetic code, they are removed during a process called splicing. The remaining sequences that are joined together to form mature RNA are called exons. Introns are common in most eukaryotes, which are complex organisms. They are also found in many eukaryotic viruses. However, they are quite rare in prokaryotes like Bacteria and Archaea.

To understand how this works, we must look at the process of RNA splicing. First, the cell transcribes a long RNA molecule known as a pre-mRNA. This precursor contains both the functional exons and the non-functional introns. During splicing, the cell must identify and remove the introns. Once the introns are gone, the exons are linked together to create a mature messenger RNA. This mature RNA is then ready for translation into proteins.

This mechanism ensures that only the correct instructions reach the protein-making machinery of the cell.

Scientists have identified at least four main types of introns based on how they are removed. Spliceosomal introns are found in nuclear protein-coding genes. These are removed by a large complex called a spliceosome, which uses specific RNA molecules to recognize boundaries. tRNA introns are found in transfer RNA genes. These require specific proteins, called endonucleases and ligases, to perform the removal. Group I and group II introns are unique because they are self-splicing. These introns fold into complex three-dimensional architectures that allow them to remove themselves through RNA catalysis.

Spliceosomal introns are particularly complex. They are characterized by specific sequences at the boundaries between introns and exons. These sequences allow the spliceosome to initiate the reaction. These introns also contain a branch point, which is a nucleotide sequence near the 3' end. During splicing, this sequence becomes covalently linked to the 5' end of the intron, creating a branched structure. While these specific elements are conserved, the rest of the nuclear pre-mRNA intron sequence is highly variable. These introns are often much longer than the exons that surround them.

The discovery of introns changed our understanding of genetics. In 1977, several laboratories independently discovered that genes were split by these intervening sequences. Phillip Allen Sharp and Richard J. Roberts led prominent labs that made these findings. Their work earned them the Nobel Prize in Physiology or Medicine in 1993. Other researchers, such as Louise Chow and Thomas Broker, also contributed to this discovery. Much of the research in the Sharp lab was conducted by postdoctoral fellow Susan Berget. The American biochemist Walter Gilbert introduced the official term "intron" in 1978.

Introns vary greatly in size and frequency across the biological spectrum. In the nuclear genome of jawed vertebrates, like humans and mice, introns are extremely common. For example, the human MST1L gene contains a very short intron of only 30 base pairs. In contrast, the Drosophila DhDhc7 gene in fruit flies contains an enormous intron. This single intron is 3.6 megabase long and takes roughly three days to transcribe.

Distribution also varies by cell type. While introns are common in vertebrate nuclei, they are absent in vertebrate mitochondrial genomes. In baker's yeast, introns are also quite rare.

Splicing is a highly precise but imperfect process. The spliceosome is a massive structure containing up to one hundred proteins and five different RNAs. Under ideal conditions, splicing is 99.999% accurate. However, real-world error rates can be much higher. Some studies suggest errors may occur at a rate of 0.1% per intron, or even 2% to 3% per gene. These errors often happen because of "cryptic" splice sites, which are accidental cutting points. Most incorrect transcripts are quickly destroyed by a process called nonsense-mediated decay.

When splicing errors occur due to genetic mutations, they can cause serious disease. A mutation in an intron can create a new, incorrect splice site. This happened in the descendants of Queen Victoria, leading to hemophilia. In that case, a mutation in a blood clotting factor gene created a cryptic 3' splice site. This resulted in aberrant splicing and a non-functional protein. Beyond disease, introns play a vital role in biology by helping to regulate gene expression. Some introns even encode their own functional RNAs through further processing.