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Exon

An exon is a segment of a gene's DNA sequence in eukaryotic organisms that is transcribed into RNA and retained in the mature messenger RNA (mRNA) after the removal of intervening non-coding sequences known as introns during the process of RNA splicing.^[1] These sequences typically encode portions of proteins but can also include untranslated regions (UTRs) at the 5' or 3' ends of the mRNA that influence stability, localization, and translation efficiency.^[2] The term "exon," short for "expressed region," was coined by biochemist Walter Gilbert in 1978 to describe these functional units of split genes.^[3] The discovery of exons and introns fundamentally reshaped molecular biology by revealing that most eukaryotic genes are discontinuous, consisting of coding exons separated by non-coding introns.^[4] This breakthrough was independently achieved in 1977 by Phillip Sharp at the Massachusetts Institute of Technology and Richard Roberts at Cold Spring Harbor Laboratory through experiments on adenovirus RNA, demonstrating that mRNA is assembled from non-contiguous gene segments.^[4] Their work earned them the 1993 Nobel Prize in Physiology or Medicine for elucidating the split structure of genes.^[5] Exons are recognized and joined by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs) that identifies exon-intron boundaries via conserved sequence motifs such as the 5' splice site (GU), branch point, and 3' splice site (AG).^[1] Exons play a pivotal role in generating proteomic diversity through alternative splicing, a regulated process where different exon combinations from the same pre-mRNA produce multiple mRNA isoforms and protein variants.^[6] In humans, approximately 95% of multi-exon genes undergo alternative splicing, enabling a single gene to encode numerous functional products essential for cellular differentiation, tissue specificity, and response to environmental cues.^[6] This mechanism not only amplifies the coding capacity of the genome but also contributes to disease when dysregulated, as seen in conditions like cancer and neurodegenerative disorders where aberrant exon inclusion or skipping alters protein function.^[6]

Definition and Basics

Definition

In eukaryotic genomes, genes are typically organized as interrupted sequences consisting of exons and introns, unlike prokaryotic genes which generally lack introns and are transcribed into continuous mRNA molecules.^[7] Exons represent the segments of DNA (or the corresponding RNA transcripts) that are retained in the mature messenger RNA (mRNA) following the removal of introns through RNA splicing.^[2] This process ensures that only exon sequences are incorporated into the final mRNA product exported from the nucleus for translation or other functions.^[8] Exons serve as the foundational units in gene expression, where they can encode amino acid sequences that form proteins in protein-coding genes or contribute to the structure of functional RNA molecules in non-coding genes, such as those producing ribosomal RNAs or microRNAs.^[2] Within protein-coding transcripts, exons are categorized into coding regions that directly translate into polypeptides and untranslated regions (UTRs), including the 5' UTR which regulates translation initiation and the 3' UTR which influences mRNA stability and localization.^[2] These UTR exons, while not translated, play essential regulatory roles in modulating gene expression efficiency.^[2]

Types of Exons

Exons are broadly classified into coding and non-coding types based on their role in protein synthesis. Coding exons contain nucleotide sequences that are translated into amino acids to form part of a protein, forming the open reading frame (ORF) of messenger RNA (mRNA).^[2] In contrast, non-coding exons do not contribute to the protein-coding sequence; they include untranslated regions (UTRs) such as the 5' UTR, which precedes the start codon, and the 3' UTR, which follows the stop codon, as well as exons in non-coding RNA (ncRNA) genes like microRNAs or long non-coding RNAs that perform regulatory functions without translation.^[2] For instance, UTR exons regulate mRNA stability, localization, and translation efficiency through interactions with RNA-binding proteins and microRNAs.^[2] Exons are further categorized by their position within the transcript as initial (or first), internal, or terminal (or last) exons, each with distinct structural and functional features. Initial exons, located at the 5' end of the pre-mRNA, include the transcription start site and 5' UTR, and they acquire the 7-methylguanosine cap structure shortly after transcription initiation to protect the mRNA and facilitate ribosome binding.^[9] Internal exons are positioned between the initial and terminal exons, typically flanked by splice sites on both ends, and often contain coding sequences that are conserved across species due to their protein-coding roles.^[10] Terminal exons, at the 3' end, encompass the 3' UTR and the polyadenylation signal, which triggers cleavage and addition of the poly(A) tail to enhance mRNA stability and export.^[11] This positional classification influences splicing patterns and post-transcriptional modifications.^[10] In the context of alternative splicing, certain exons exhibit variable inclusion, leading to subtypes like cassette exons and mutually exclusive exons. Cassette exons are optional internal exons that can be included or skipped in the mature mRNA, allowing for isoform diversity; for example, in the Drosophila Dscam gene, multiple cassette exons generate thousands of neuronal isoforms for cell recognition.^[12] Mutually exclusive exons involve the selection of one exon from a pair or cluster, excluding the other, which is common in genes requiring precise functional variants, such as the Dscam gene in Drosophila where it supports neural wiring specificity.^[13] Additionally, intron retention can result in introns being retained in the mature transcript, effectively functioning as exons, though often introducing premature stop codons that lead to mRNA degradation or non-productive isoforms; this is sometimes initially annotated as novel exons in genomic studies.^[14] Exons also display functional diversity based on the genes they belong to, particularly in housekeeping versus tissue-specific contexts. Housekeeping genes, essential for basic cellular functions like metabolism and cytoskeletal maintenance, typically feature constitutive exons with low alternative splicing rates to ensure uniform expression across tissues.^[15] In contrast, tissue-specific genes, such as those involved in neural or muscle development, often incorporate alternative exons—especially initial or cassette types—to enable regulated, localized expression; for example, alternative first exons in the DLG1 gene drive brain-specific isoforms.^[16] This diversity allows exons to fine-tune protein function in response to cellular needs.^[16]

Historical Development

Discovery

The discovery of exons emerged from groundbreaking experiments in the mid-1970s that revealed eukaryotic genes are not continuous but composed of discontinuous coding segments separated by non-coding intervening sequences. In 1977, Phillip A. Sharp and his team at the Massachusetts Institute of Technology used RNA-DNA hybridization techniques on adenovirus 2 late mRNA, forming R-loop structures that were visualized via electron microscopy; these images showed the mRNA pairing with non-contiguous DNA regions, with unpaired DNA loops indicating intervening sequences later termed introns. Independently that same year, Richard J. Roberts and colleagues at Cold Spring Harbor Laboratory applied similar hybridization and electron microscopy methods to adenovirus 2, mapping mRNA to multiple separated DNA segments and confirming the split gene structure across several viral transcripts. Their parallel findings demonstrated that eukaryotic genes consist of expressed exons interspersed with introns that are removed during RNA processing, fundamentally altering the understanding of gene organization.^[17] Early evidence supporting this discontinuous architecture came from electron micrographs of these hybrids, where introns appeared as looped-out DNA segments excluded from mRNA pairing, a visual hallmark observed in eukaryotic genes like those in adenovirus.^[18] This looped-out pattern provided direct proof that coding sequences (exons) are not linearly contiguous in the genome, challenging the prevailing colinearity model of DNA to protein.^[19] Soon after, the split structure was extended to cellular genes, first in the chicken ovalbumin gene in November 1977, where two interruptions were detected in the coding sequences.^[20] This was confirmed in mammalian genes through hybridization studies on the beta-globin gene. In 1978, Shirley M. Tilghman and colleagues at the National Institutes of Health used restriction enzyme mapping and nucleic acid hybridization to analyze the mouse beta-globin gene, revealing two intervening sequences that interrupt the coding region into three non-contiguous exons; these findings confirmed the presence of introns in a well-studied mammalian gene essential for hemoglobin production.^[21] The term "exon" was coined in 1978 by biochemist Walter Gilbert to describe these expressed, conserved sequences that are spliced together to form mature mRNA, contrasting with introns as the removed intervening regions; Gilbert proposed this nomenclature in a seminal commentary on the implications of split genes for evolution and protein diversity. For their pioneering work on split genes and RNA splicing, Sharp and Roberts shared the 1993 Nobel Prize in Physiology or Medicine.^[17]

Key Milestones

In the 1980s, the development of cDNA cloning techniques enabled researchers to isolate and sequence messenger RNA-derived DNA copies, facilitating the precise mapping of exon boundaries by comparing cDNA sequences to genomic DNA.^[22] This approach was instrumental in elucidating gene structures, as demonstrated in early applications to eukaryotic genes where cDNA libraries revealed discontinuous exon arrangements.^[23] Concurrently, Northern blotting emerged as a key method for detecting RNA transcripts and confirming exon connectivity, allowing visualization of mature mRNA sizes and hybridization with exon-specific probes to delineate boundaries.^[24] The standardization of reverse transcription polymerase chain reaction (RT-PCR) during this decade further advanced exon validation, providing a sensitive tool to amplify and verify specific exon junctions from RNA templates, thus confirming splicing patterns in various genes.^[25] The 1990s marked significant progress through the initiation of the Human Genome Project in 1990, which spurred the creation of computational tools for exon prediction amid the growing need to annotate vast genomic sequences.^[26] A pivotal advancement was the development of GENSCAN in 1997, an algorithm that accurately predicted complete gene structures, including exon locations, by modeling splice site probabilities and coding potential, achieving 75-80% accuracy on human gene sets.^[27] Building on early discoveries such as the 1980 demonstration of exon skipping in immunoglobulin genes like the mu heavy chain, where differential inclusion of exons produced membrane-bound versus secreted isoforms to highlight splicing's role in immune diversity, studies on alternative splicing gained broader traction during this period with genomic-scale analyses.^[28] The release of the draft human genome sequence in 2001 represented a landmark achievement, revealing that exons constitute only about 1-2% of the genome—far lower than prior estimates of 5% or more—thus reshaping understandings of genomic organization and the prevalence of non-coding regions. This finding, derived from the International Human Genome Sequencing Consortium's efforts, underscored the challenges in exon annotation and catalyzed refinements in prediction algorithms.^[29]

Genomic Organization

Exon-Intron Architecture

In eukaryotic genes, the mature mRNA is derived from a primary transcript known as pre-mRNA, which consists of an alternating series of exons and introns. Exons represent the segments retained in the final mRNA, while introns are intervening sequences removed during splicing. This architecture typically features one or more exons at the 5' and 3' termini of the gene, with introns interspersed between them, allowing for the modular assembly of coding information.^[30] The boundaries defining exon-intron junctions are highly conserved and characterized by specific consensus motifs essential for spliceosome recognition. At the 5' splice site, the intron begins with the nearly invariant dinucleotide GU (or GT in DNA), often embedded in a broader sequence such as MAG|GURAGU, where M is A or C and R is a purine. The 3' splice site, marking the end of the intron, concludes with the dinucleotide AG, preceded by a polypyrimidine tract—a stretch of pyrimidine-rich nucleotides (primarily U and C)—and an upstream branch point sequence featuring a critical adenine (A) residue, typically within 20–50 nucleotides of the 3' splice site. These motifs, including the branch point A that forms a lariat intermediate during splicing, ensure precise cleavage and ligation.^[31] Splice site recognition operates through two primary models: the intron definition model and the exon definition model, which depend on the relative lengths of introns and exons. In the intron definition model, prevalent in organisms with short introns such as yeast (Saccharomyces cerevisiae, where average intron length is approximately 250 nucleotides), the spliceosome assembles across the intron by directly pairing the 5' and 3' splice sites. Conversely, in the exon definition model, common in vertebrates with longer introns (average ~3–7 kb in humans), recognition begins across the exon, involving interactions between the 3' splice site of the upstream intron and the 5' splice site of the downstream intron, facilitated by exon-binding factors like SR proteins. This exon-centric mechanism accommodates the challenges posed by expansive introns, promoting efficient splicing of small internal exons (often 50–300 nucleotides).^[32]

Size Distribution and Genomic Contribution

In humans, the average length of internal exons is approximately 147 nucleotides (nt), with most exons falling between 50 and 300 nt.^[33] Exon sizes exhibit a broad range, from as short as 1 base pair (bp) to over 90,000 bp in extreme cases across eukaryotic genes including humans, though the majority are under 500 bp.^[34] In contrast, introns are significantly larger, with an average length of about 3,356 bp.^[35] The distribution of exon numbers per gene typically ranges from 5 to 10 in human protein-coding genes, with an average of 8.8 exons per gene.^[36] This pattern reflects a higher exon density in more complex organisms, where genes often contain multiple exons to support diverse splicing outcomes. Exons constitute only 1-1.1% of the total human genome, despite encoding 100% of the protein-coding sequences.^[37]^[38] This small proportion underscores the compact nature of coding regions relative to non-coding DNA. Comparative analyses across species reveal that invertebrates generally feature fewer but longer exons per gene compared to vertebrates, which exhibit more numerous, shorter exons.^[39]^[40] This shift correlates with increasing organismal complexity, as seen in the expansion of exon counts during vertebrate evolution from invertebrate ancestors.^[40]

Recent Discoveries in Exon Annotation

In 2024, researchers at the University of Toronto utilized exon trapping to identify approximately one million previously unannotated exons in the human genome, significantly expanding the known transcriptomic landscape beyond initial post-genome sequencing annotations.^[41] This discovery, derived from analyzing diverse human samples, revealed novel isoforms and regulatory elements that were missed by short-read technologies, highlighting the limitations of earlier annotation efforts.^[42] Advancements in cryptic exon detection have further illuminated hidden splicing events, particularly those regulated by RNA-binding proteins. A 2025 study employing long-read RNA sequencing uncovered a TDP-43-dependent cryptic exon in the MNAT1 gene, whose inclusion disrupts normal splicing and is associated with neurodegeneration in conditions like amyotrophic lateral sclerosis.^[43] This finding underscores how proteinopathies can activate latent exons within introns, altering gene function in neuronal contexts.^[44] Similarly, investigations into hybrid exons—formed through coordinated transcription initiation and splicing—have revealed evolutionary mechanisms for generating novel transcript structures. In 2024, genomic analyses demonstrated that hybrid exons arise from nucleotide-level coupling of promoter activity and splice site selection, enabling adaptive isoform diversity across species.^[10] These exons often integrate upstream transcriptional starts with downstream splicing, contributing to regulatory flexibility in gene expression. Recent multi-species annotation efforts have enhanced comparative genomics resources for exon-intron structures. A 2024 phylogenetic study across 590 eukaryotic species updated intron-exon architecture data using existing genome annotations, revealing conserved patterns in splicing evolution.^[45] Such database expansions facilitate cross-species analyses of alternative splicing mechanisms. These discoveries collectively revise prior estimates, indicating that alternative splicing affects more than 90% of human multi-exon genes, thereby amplifying proteomic complexity and underscoring the genome's untapped regulatory potential.^[46]

Structure and Function

Molecular Structure

Exons are characterized by distinct nucleotide compositions that differentiate them from intronic sequences. Notably, exons display a higher GC content, averaging approximately 7% greater than that of flanking introns, which contributes to increased nucleosome occupancy and chromatin packaging in coding regions.^[47] This bias arises from evolutionary pressures favoring stable secondary structures and efficient transcription in protein-coding areas. Additionally, codon usage within exons exhibits patterns of bias, particularly near exon-intron boundaries, where synonymous codons are selected to minimize disruption of splice site recognition while optimizing translation efficiency.^[48] At the biophysical level, exons often harbor secondary structural elements such as stem-loops or hairpins formed by base-pairing within the RNA sequence. These structures can modulate splicing efficiency by influencing the accessibility of regulatory motifs, with certain hairpins repressing inclusion of specific exons in a tissue-dependent manner.^[49] Embedded within these sequences are short cis-regulatory motifs known as exonic splicing enhancers (ESEs) and silencers (ESSs). ESEs, typically 6-8 nucleotides long, serve as binding sites for serine/arginine-rich (SR) proteins that promote exon recognition by the spliceosome, whereas ESSs recruit repressive factors like hnRNP proteins to inhibit splicing.^[50] Functional exons demonstrate high sequence conservation across diverse species, reflecting their critical role in encoding conserved protein domains and regulatory elements. This evolutionary stability is evident in orthologous exons shared among mammals, where nucleotide identity often exceeds 80% due to purifying selection against deleterious mutations.^[51] Exons are delimited by conserved splice site sequences at their boundaries, ensuring precise intron removal during RNA processing.

Role in RNA Processing

Exons play a central role in the maturation of pre-messenger RNA (pre-mRNA) through the splicing process, where they are precisely joined together after the removal of intervening introns. The spliceosome, a large ribonucleoprotein complex composed of five small nuclear ribonucleoproteins (snRNPs) and over 150 proteins, catalyzes this process via two sequential transesterification reactions. In the first step, the 2'-OH group of an adenosine at the intron's branch point attacks the 5' splice site, leading to cleavage at the exon-intron boundary and formation of a lariat intermediate containing the intron. The second step involves the 3'-OH of the upstream exon attacking the 3' splice site, resulting in intron release and ligation of the adjacent exons to form mature mRNA.^[52] Exon sequences at the intron boundaries serve as critical scaffolds for spliceosome assembly and recognition. The 5' splice site, typically marked by a GU dinucleotide at the end of the upstream exon, is recognized by the U1 snRNP through base-pairing with its 5' stem-loop, initiating spliceosome recruitment. Similarly, the 3' splice site, ending with an AG dinucleotide at the start of the downstream exon, interacts with U2 auxiliary factor (U2AF) and U2 snRNP to stabilize binding near the branch point sequence within the intron. These exon-flanking motifs ensure accurate definition of exon boundaries, with disruptions often leading to splicing errors.^[53] Following successful splicing, the exon junction complex (EJC) is deposited approximately 20-24 nucleotides upstream of each exon-exon junction on the mature mRNA. Composed of core proteins eIF4A3, MAGOH, Y14, and MLN51, the EJC marks the splicing event and facilitates downstream processes such as nuclear export by interacting with export factors like TAP/p15, enhancing mRNA transport to the cytoplasm. Additionally, the EJC contributes to quality control by promoting nonsense-mediated decay (NMD) of mRNAs with premature termination codons located more than 50 nucleotides upstream of an exon junction, thereby preventing the production of truncated proteins.^[54] Aberrant splicing, such as exon skipping or intron retention, can arise from mutations in exon boundary sequences or spliceosome components, leading to disease. For instance, a mutation in the 5' splice site of exon 20 in the IKBKAP gene causes skipping of that exon in familial dysautonomia, resulting in a truncated IKAP protein and autonomic nervous system dysfunction. Similarly, exon skipping in the SMN1 gene due to splice site variants is a primary cause of spinal muscular atrophy, highlighting the pathological consequences of disrupted exon processing.^[55]

Alternative Splicing Mechanisms

Alternative splicing mechanisms allow exons to be variably included or excluded in mature mRNA transcripts, thereby generating multiple protein isoforms from a single gene and expanding proteomic diversity.^[56] These processes are tightly regulated and can involve several distinct patterns, including exon skipping, where one or more exons are omitted from the final mRNA; intron retention, in which introns are retained alongside exons; mutually exclusive exons, where only one of two or more exons is included; and poison exons, which introduce premature termination codons (PTCs) that trigger nonsense-mediated decay (NMD) to regulate gene expression.^[57] Exon skipping is the most prevalent mechanism, accounting for a significant portion of splicing events in humans, while intron retention often occurs in specific cellular contexts like neuronal differentiation.^[58] Regulation of these mechanisms relies on cis-acting elements within pre-mRNA, such as exonic splicing enhancers (ESEs) and silencers (ESSs), which interact with trans-acting factors including SR proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs).^[59] SR proteins typically bind ESEs to promote exon inclusion by recruiting the spliceosome, whereas hnRNPs often bind ESSs or intronic splicing silencers (ISSs) to repress splicing and favor exon skipping or intron retention.^[60] This antagonism enables tissue-specific splicing patterns; for instance, in brain tissue, hnRNP A1 promotes skipping of certain neural exons, while SR protein SRSF1 enhances inclusion of muscle-specific isoforms.^[61] Such regulation is crucial for developmental processes, where alternative splicing adjusts isoform ratios in response to cellular signals.^[58] Through these mechanisms, a single gene can produce thousands of isoforms, dramatically increasing functional diversity; a prime example is the Drosophila DSCAM gene, which generates over 38,000 protein variants via mutually exclusive splicing of four exon clusters, aiding neuronal self-avoidance and wiring specificity.^[62] In humans, similar complexity occurs in genes like fibronectin, where variable exon inclusion modulates extracellular matrix interactions.^[56] Aberrant alternative splicing contributes to pathologies, particularly cancer, where dysregulated exon inclusion promotes tumor progression. For example, in breast and colon cancers, increased inclusion of CD44 variable exon v6 (CD44v6) enhances cell migration and metastasis by altering hyaluronan binding and signaling.^[63] This shift often results from overexpression of splicing factors like Tra2β, which favors v6 inclusion, underscoring how splicing dysregulation can drive oncogenic phenotypes.^[64] Poison exons also play a role in disease, as their aberrant inclusion can silence tumor suppressor genes via NMD.^[65]

Applications and Techniques

Experimental Identification Methods

Classical methods for identifying exons relied on techniques that detect and map specific RNA transcripts. Northern blotting involves hybridizing labeled probes to RNA separated by electrophoresis, allowing visualization of transcript sizes and confirmation of exon presence in mature mRNAs. This method was instrumental in early exon characterization by distinguishing full-length transcripts from potential splicing variants based on size differences. Similarly, the S1 nuclease protection assay uses single-stranded DNA probes complementary to target RNAs; unprotected regions are digested by S1 nuclease, protecting only hybridized exon sequences for quantification and precise boundary mapping. These assays provided high sensitivity for low-abundance transcripts but were limited to predefined probes and labor-intensive for genome-wide analysis. Sequencing-based approaches revolutionized exon detection by enabling transcriptome-wide profiling. Expressed Sequence Tags (ESTs), short partial sequences from cDNA clones, were among the first to systematically identify exons by aligning them to genomic DNA, revealing splicing patterns and novel transcripts. ESTs facilitated the identification of thousands of expressed genes and mRNA abundance patterns in model organisms through large-scale sequencing efforts, contributing significantly to early transcriptome annotation. RNA-Seq, utilizing high-throughput short-read sequencing of cDNA, quantifies exon usage across the transcriptome by mapping reads to reference genomes, detecting differential splicing and novel exons with high resolution. This method outperforms microarrays in sensitivity and dynamic range, capturing rare isoforms and tissue-specific exon inclusion. Advanced sequencing technologies have enhanced exon characterization by resolving complex isoforms. Long-read platforms like PacBio generate full-length transcripts, accurately assembling multi-exon structures and identifying alternative splicing events that short reads fragment. For instance, PacBio Iso-Seq has revealed novel isoforms in disease-associated genes by spanning entire coding regions without assembly errors. Oxford Nanopore sequencing similarly provides direct RNA reads, enabling detection of full isoforms and splice variants in single cells, with applications in mapping alternative splicing in neural tissues. Complementing these, Crosslinking and Immunoprecipitation sequencing (CLIP-seq) identifies splicing factor binding sites near exons, elucidating regulatory interactions that influence exon inclusion. CLIP-seq data integration with RNA-Seq has pinpointed context-specific splicing factors, improving predictions of exon functionality. Emerging single-cell techniques, such as single-cell RNA sequencing (scRNA-seq) variants including scSplice and targeted assays like Nanostring, enable exon-level resolution of alternative splicing in heterogeneous cell populations, revealing cell-type-specific exon usage in diseases like cancer and neurodegeneration as of 2025. Computational methods complement experimental data for ab initio exon prediction. Tools like AUGUSTUS employ hidden Markov models to scan genomic sequences for exon-intron boundaries based on statistical patterns, achieving high accuracy in eukaryotic gene annotation. AUGUSTUS integrates splice site motifs, such as GT-AG rules, to delineate exons without prior transcript evidence. Recent advancements incorporate machine learning, with deep neural networks like Pangolin predicting splice sites and exon structures from DNA sequences alone, outperforming traditional models in variant effect assessment. These tools benchmark favorably on diverse genomes, enhancing annotation of short or atypical exons.

Therapeutic Applications

One prominent therapeutic strategy targeting exons is exon skipping, which uses antisense oligonucleotides (AONs) to modulate splicing and bypass defective exons in genetic disorders. In Duchenne muscular dystrophy (DMD), eteplirsen (Exondys 51), a phosphorodiamidate morpholino oligomer, induces skipping of exon 51 in the DMD gene, restoring the reading frame and enabling partial dystrophin production in approximately 13-14% of patients with amenable mutations. The U.S. Food and Drug Administration granted accelerated approval to eteplirsen on September 19, 2016, marking the first oligonucleotide therapy for splicing modulation in DMD, though confirmatory trials are required to verify clinical benefits like improved motor function. CRISPR-Cas9 has emerged as a precise tool for exon excision or insertion in genetic diseases, with advances in specificity enhancing its therapeutic potential from 2023 to 2025. By directing Cas9 to target specific exons, this approach enables reframing or replacement of mutated sequences, as demonstrated in DMD models where variant Cas9 enzymes like SpCas9-LRVQR restored dystrophin expression through exon 53 reframing in patient-derived cells. Recent innovations, including improved prime editing and base editing variants, allow kilobase-scale insertions of functional exons without off-target effects, supporting applications in muscular dystrophies, collagen disorders, and other monogenic conditions. RNA exon editing via trans-splicing represents a non-DNA-altering method for mutation correction, where synthetic RNAs replace defective exons in pre-mRNA to produce functional proteins. This strategy is particularly suited for large genes exceeding 5 kb, as it facilitates replacement of entire exons or multi-exon segments using a single adeno-associated virus vector, addressing diverse mutations with broad applicability. In 2024 developments, enhanced trans-splicing efficiencies through optimized synthetic biology and bioinformatics enabled a phase 1/2 clinical trial (NCT06467344) for Stargardt disease, using ACDN-01 to correct multiple ABCA4 exons and potentially benefit up to 70% of patients. Poison exons, cryptic or cassette exons that trigger nonsense-mediated decay (NMD) upon inclusion, are being harnessed for targeted mRNA degradation in cancer therapies through splice modulation. In SF3B1-mutant tumors, antisense oligonucleotides promote inclusion of a poison exon in BRD9, leading to its mRNA degradation and suppression of oncogenic activity. Similarly, in 2025 studies, TRA2β poison exon inclusion via AONs regulated protein expression and acted as a long non-coding RNA to inhibit cancer cell growth. For amyotrophic lateral sclerosis (ALS), splice modulation targets cryptic poison exons arising from TDP-43 dysfunction; a novel MNAT1 cryptic exon, identified via long-read sequencing, induces NMD-mediated degradation and was confirmed in ALS/FTD patient tissues, offering potential for therapeutic intervention to mitigate neurotoxicity.

Misconceptions and Terminology

Common Misuses of the Term

One common misuse of the term "exon" involves equating it directly with the entire gene or assuming that all exons exclusively encode proteins, thereby overlooking the presence of untranslated regions (UTRs) and exons in non-coding RNAs. Exons are defined as DNA sequences that are transcribed into RNA and retained in the mature transcript after splicing, but only a subset—less than 30% in humans—actually code for amino acids, with the remainder contributing to regulatory elements like UTRs or non-coding RNAs such as microRNAs and long non-coding RNAs. This misconception persists in some scientific literature, textbooks, and technologies like whole-exome sequencing, which primarily targets protein-coding regions and thus captures less than 25% of the total exome, leading to an incomplete representation of exonic diversity.^[2] Another frequent error is applying the concept of exons to prokaryotic genes, which generally lack introns and thus do not undergo the splicing process that defines exons in eukaryotes. In prokaryotes, such as bacteria, genes are typically continuous coding sequences without the interspersed non-coding introns found in eukaryotic genomes, making the distinction between exons and introns irrelevant; the entire transcribed region functions analogously to a single exon, but the terminology is eukaryotic-specific and arises from the evolutionary absence of spliceosomal introns in prokaryotes. This misuse can confuse comparative genomics discussions by imposing eukaryotic frameworks on prokaryotic systems, where no splicing occurs due to coupled transcription-translation mechanisms.^[66] A related overgeneralization stems from extrapolating exon characteristics from model organisms, such as assuming uniform exon sizes across species, which ignores significant variation in exon length and structure. For instance, average internal exon lengths vary across species, being around 147 base pairs in humans, approximately 200 base pairs in nematodes like Caenorhabditis elegans, and 179 base pairs in plants like Arabidopsis thaliana, decreasing further with increasing intron numbers within genes; this variability reflects evolutionary adaptations and cannot be uniformly applied without species-specific context. Such assumptions can lead to errors in annotating genomes from non-model organisms or predicting splicing patterns.^[67]^[33]^[68]^[69] In popular media and simplified educational materials, exons are often portrayed as straightforward "building blocks" of genes that directly assemble into proteins, neglecting the essential role of splicing and the modular nature of pre-mRNA processing. This oversimplification, echoed in some broader genetics communications, reinforces the protein-coding bias and underemphasizes how exons contribute to RNA stability, localization, and regulation beyond mere translation.^[2] Exons are fundamentally distinguished from introns in eukaryotic genes, as exons represent the transcribed sequences that are retained and joined together in the mature messenger RNA (mRNA) after splicing, whereas introns are the intervening non-coding sequences that are excised during RNA processing.^[70]^[71] This retention of exons ensures they contribute to the final coding or regulatory elements of the mRNA, while introns are degraded post-removal to prevent interference with translation.^[72] Unlike codons, which are specific triplets of nucleotides in the mRNA that directly encode individual amino acids during protein translation, exons are larger genomic segments that encompass multiple codons and may include untranslated regions.^[73] An exon typically spans dozens to hundreds of nucleotides, allowing it to contain several codons, but it is not equivalent to a single codon unit; instead, exons serve as modular blocks in pre-mRNA that are processed to form the continuous coding sequence.^[74] Protein domains, as functional and structural modules within the folded polypeptide chain, differ from exons in that domains operate at the level of protein architecture and often span portions of one or multiple exons, reflecting an evolutionary correlation rather than a one-to-one equivalence.^[75] While exon-intron boundaries can align with domain edges in some genes, promoting modular evolution through exon shuffling, domains are defined by their biochemical roles, such as enzymatic activity, independent of the underlying genomic exon structure.^[76] Exons must also be differentiated from isoforms, which are variant forms of mRNA or proteins arising from alternative splicing events that selectively include or exclude specific exons from the same gene.^[56] A single exon is a fixed genomic element, but isoforms represent the diverse products generated by combinatorial use of exons, enabling functional diversity without altering the exon sequences themselves.^[77]

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The term Southern blotting led to a “geographic” naming tradition, with RNA blotting bearing the name Northern blotting and protein transfer to membranes ...
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NHGRI History and Timeline of Events
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Pre-mRNA splicing is catalyzed by the spliceosome, a multimegadalton ribonucleoprotein (RNP) complex comprised of five snRNPs and numerous proteins.
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Regulation of alternative splicing by the core spliceosomal machinery
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Exploring the Diverse Functional and Regulatory Consequences of ...
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The elucidation of the largely unknown transcriptome of small RNAs is crucial for the understanding of genome and cellular function.
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Expressed Sequence Tags and Human Genome Project - Science
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Long-read RNA sequencing unveils a novel cryptic exon in MNAT1 ...
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Intron and exon length variation in Arabidopsis, rice, nematode, and ...
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Exon - National Human Genome Research Institute
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Intron - National Human Genome Research Institute
The protein coding sequences for many genes are broken into smaller pieces of coding sequences called exons separated by non-coding sequences called introns.
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Transcription/translation - Exons and introns - DNA Learning Center
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Exons, Introns & Codons
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Anatomy of a Gene - Learn Genetics Utah
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Protein domains correlate strongly with exons in multiple eukaryotic ...
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Exon–domain correlation and its corollaries | Bioinformatics
When the exon–intron split structure of genes correlates with the organization of protein domains, i.e. the exons match the domains, then duplication, ...
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All About Alternative Splicing | The Scientist
Sep 27, 2024 · Unlike constitutive splicing, where exons are joined in a fixed order, alternative splicing selectively includes or excludes certain coding ...