transposon

**Definition and structure** - Transposons (transposable elements) are DNA sequences that can change position within a genome. Movement is called transposition. - Simple transposons, called insertion sequences (IS), encode only the transposase and are flanked by inverted repeats. - Composite transposons (e.g., Tn5, Tn10) carry additional genes, often antibiotic resistance genes, between two IS elements. - Insertion creates short direct repeats of target DNA flanking the element.

**Mechanisms** 1. **Cut-and-paste (conservative):** Transposase excises the element and inserts it elsewhere. No replication of the element is needed. 2. **Replicative (copy-and-paste):** The element is copied, so one copy stays at the original site and one goes to the new site. This is common in bacterial transposons such as Tn3, which use resolvase. 3. **Retrotransposition:** DNA is transcribed to RNA, then reverse-transcribed to DNA and inserted at a new site. Reverse transcriptase is encoded by the element itself. The two types are: - LTR retrotransposons (similar to retroviruses). - Non-LTR retrotransposons: LINEs (e.g., LINE-1) and SINEs (e.g., Alu).

**Human genome** - About 45% of the human genome consists of transposon-derived sequences. - LINE-1 makes up about 17% of the genome and is the only autonomously active human transposon. It encodes reverse transcriptase and endonuclease. - Alu (a SINE) makes up about 10% of the genome. It is nonautonomous and uses LINE-1 machinery. - Most elements are inactive, and methylation silences them.

**Clinical significance** - **Antibiotic resistance spread:** Transposons let resistance genes move between chromosomes, plasmids, and bacteriophages. They are a key part of horizontal gene transfer alongside conjugation, transduction, and transformation. Examples include the vanA transposon Tn1546 in VRE, and the mec cassette and β-lactamase genes in staphylococci and gram-negative bacteria. They are also central to the spread of carbapenemases and ESBLs. - **Insertional mutagenesis:** New insertions can disrupt genes and cause disease. Examples: - LINE-1 insertion into the factor VIII gene causes hemophilia A. - Alu insertions have been reported in NF1 (neurofibromatosis type 1), BRCA1/2, and other genes. - Alu-Alu recombination can cause deletions or duplications. - **Cancer:** Somatic LINE-1 retrotransposition is common in epithelial cancers such as colorectal cancer. Hypomethylation reactivates elements and contributes to genomic instability. - **Relationship to retroviruses:** HIV and other retroviruses integrate through mechanisms similar to retrotransposons. The integrase of HIV is the target of integrase inhibitors (raltegravir, dolutegravir). Human endogenous retroviruses (HERVs) are ancient retroviral insertions. - **Genetic history:** Barbara McClintock discovered transposons in maize and won the 1983 Nobel Prize. - **Immunology:** The RAG1/RAG2 recombinase used in V(D)J recombination is thought to have evolved from an ancient transposase. This is a favorite conceptual link on exams.

**Board pearls** - Transposon = "jumping gene." Transposase is the enzyme for DNA transposons. Reverse transcriptase is the enzyme for retrotransposons. - Transposons are a key mechanism for spread of antibiotic resistance. Know the difference between the four ways bacteria gain DNA: - Conjugation: plasmid transfer through a pilus. - Transduction: phage-mediated. - Transformation: uptake of naked DNA. - Transposition: movement within or between DNA molecules in one cell. - Transposons are not infectious by themselves. They need a vehicle (plasmid or phage) to move between cells.