L1 recombination-associated deletions generate human genomic variation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 49; pp. 19366 - 19371
• Main Authors: Han, Kyudong, Lee, Jungnam, Meyer, Thomas J, Remedios, Paul, Goodwin, Lindsey, Batzer, Mark A
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.12.2008; National Acad Sciences
• Subjects: 3' Flanking Region - genetics; Animals; Biological Sciences; Biological variation; Chimpanzees; Chromosomes; Comparative analysis; copy number; DNA; Evolution, Molecular; Gene Deletion; Genetic loci; Genetic Variation; Genome, Human - genetics; Genomes; Genomics; Homologous recombination; Human genome; Humans; Insertion; Interspersed Repetitive Sequences - genetics; Long Interspersed Nucleotide Elements - genetics; Molecular Sequence Data; Monkeys & apes; Monomers; Nucleotide sequence; Pan troglodytes; Polymorphism, Genetic - genetics; Recombination, Genetic - genetics; Retroelements - genetics; Retrotransposons
• DOI: 10.1073/pnas.0807866105
• ISSN: 0027-8424

Mobile elements have created structural variation in the human genome through their de novo insertions and post-insertional genomic rearrangements. L1 elements are a type of long interspersed element (LINE) that is dispersed at high copy numbers within most mammalian genomes. To determine the magnitude of L1 recombination-associated deletions (L1RADs), we computationally extracted L1RAD candidates by comparing the human and chimpanzee genomes and verified each of the L1RAD events by using wet-bench analyses. Through these analyses, we identified 73 human-specific L1RAD events that occurred subsequent to the divergence of the human and chimpanzee lineages. Despite their low frequency, the L1RAD events deleted [almost equal to]450 kb of the human genome. One L1RAD event generated a large deletion of [almost equal to]64 kb. Multiple alignments of prerecombination and postrecombination L1 elements suggested that two different deletion mechanisms generated the L1RADs: nonallelic homologous recombination (55 events) and nonhomologous end joining between two L1s (18 events). In addition, the position of L1RADs throughout the genome does not correlate with local chromosomal recombination rates. This process may be implicated in the partial regulation of L1 copy numbers by the finding that [almost equal to]60% of the DNA sequences deleted by the L1RADs consist of L1 sequences that were either directly involved in the recombination events or located in the intervening sequence between recombining L1s. Overall, there is increasing evidence that L1RADs have played an important role in creating structural variation.