An Alu insertion is the integration of a short DNA sequence, an Alu element, into a new genomic location. These common “jumping genes” copy and paste themselves into different chromosomal positions, contributing to the dynamic nature of our genetic material. Alu insertions influence genetic variation and can contribute to certain diseases.
Understanding Alu Elements
Alu elements are short interspersed nuclear elements (SINEs), a type of repetitive DNA sequence abundant in primate genomes. In humans, over one million copies make up approximately 10% of the total DNA. These elements originated from the 7SL RNA gene.
An Alu element is typically around 300 base pairs long, characterized by a dimeric arrangement of two similar “arms” joined by an A-rich linker. Each arm contains internal RNA polymerase III promoter elements, “A boxes” and “B boxes,” which are important for transcription into RNA. Alu elements also have an A-rich tail at their 3′ end, essential for their insertion.
How Alu Elements Insert
Alu elements insert into new genomic locations via retrotransposition, a process involving an RNA intermediate. This “copy-and-paste” mechanism starts with the transcription of the Alu element from DNA into an RNA molecule, driven by RNA polymerase III recognizing internal promoter sequences.
After transcription, the Alu RNA molecule utilizes the cellular machinery of LINE-1 (L1) retrotransposons. The L1-encoded protein ORF2p, with reverse transcriptase and endonuclease activities, is hijacked by Alu RNA. ORF2p endonuclease nicks the genomic DNA at a T-rich sequence, exposing a 3′-hydroxyl group. This 3′-OH end primes the reverse transcription of Alu RNA into a DNA copy, a process called target-primed reverse transcription (TPRT).
The newly synthesized Alu cDNA integrates into the target site. This often duplicates a short DNA sequence, creating target site duplications (TSDs) that flank the Alu element. Cellular DNA repair machinery may help resolve integration. This process allows Alu elements to alter the genomic landscape.
Impact on Genetic Variation and Disease
Alu insertions contribute to genetic variation among individuals and populations, influencing genome evolution and diversity. Their ongoing retrotransposition introduces new sequences, shaping human genome architecture. Most Alu insertions have little impact, but a small subset are polymorphic, varying in presence or absence among individuals. These polymorphic insertions serve as useful genetic markers for studying human population genetics and ancestry.
Beyond normal genetic variation, de novo (new) Alu insertions can have detrimental effects, leading to various human diseases. When an Alu element inserts into a gene’s coding region (exon) or interferes with mRNA splicing, it can disrupt gene function. Such disruptions are linked to conditions like neurofibromatosis type 1, hemophilia A and B, and Duchenne muscular dystrophy, where new Alu insertions interrupt genes.
Existing Alu elements can also mediate genomic rearrangements through non-allelic homologous recombination (NAHR). Their repetitive nature and high sequence similarity can cause Alu elements at different positions to misalign during cell division, especially meiosis. This misalignment leads to crossover events, resulting in large-scale genomic changes like deletions, duplications, or inversions. These rearrangements can disrupt gene dosage or structure, contributing to genetic disorders and certain cancers, such as hereditary nonpolyposis colorectal cancer and breast cancer.