Repair-Mediated Duplication by Capture of Proximal Chromosomal DNA Has Shaped Vertebrate Genome Evolution

DNA double-strand breaks (DSBs) are a common form of cellular damage that can lead to cell death if not repaired promptly. Experimental systems have shown that DSB repair in eukaryotic cells is often imperfect and may result in the insertion of extra chromosomal DNA or the duplication of existing DNA at the breakpoint. These events are thought to be a source of genomic instability and human diseases, but it is unclear whether they have contributed significantly to genome evolution. Here we developed an innovative computational pipeline that takes advantage of the repetitive structure of genomes to detect repair-mediated duplication events (RDs) that occurred in the germline and created insertions of at least 50 bp of genomic DNA. Using this pipeline we identified over 1,000 probable RDs in the human genome. Of these, 824 were intra-chromosomal, closely linked duplications of up to 619 bp bearing the hallmarks of the synthesis-dependent strand-annealing repair pathway. This mechanism has duplicated hundreds of sequences predicted to be functional in the human genome, including exons, UTRs, intron splice sites and transcription factor binding sites. Dating of the duplication events using comparative genomics and experimental validation revealed that the mechanism has operated continuously but with decreasing intensity throughout primate evolution. The mechanism has produced species-specific duplications in all primate species surveyed and is contributing to genomic variation among humans. Finally, we show that RDs have also occurred, albeit at a lower frequency, in non-primate mammals and other vertebrates, indicating that this mechanism has been an important force shaping vertebrate genome evolution

The diagnostic role of high-speed vocal fold vibratory imaging

Objective: Although high-speed imaging (HSI) has been identified as a valuable tool in phonatory biomechanics research, to date, there have only been a selected number of reports investigating the clinical utility of HSI. We aim to elucidate the role of HSI in the diagnosis of the dysphonic patient. Methods: The video files from 28 consecutive dysphonic patients with concurrently acquired videostroboscopy and HSI were retrospectively collected. Stroboscopy video files were edited to include vibratory motion only. Videos were then anonymously and randomly presented to four academic laryngologists. Experts were asked to assign a single best diagnosis for each video file. Assigned diagnoses were then compared with treatment diagnoses conferred based on medical history, phonatory evaluation, laryngeal examination, and response to treatment. Results: Interrater analysis for the four laryngologists demonstrated significant and meaningful correlations for the diagnoses of polyps, cysts, nodules, and normal examination using stroboscopy (kappa > 0.40, P 0.40, P < 0.001). Combined intrarater analysis performed by comparing single rater's diagnosis for single patient across both modalities resulted in poor correlation without statistical significance (kappa = 0.30, P = 0.07). Both stroboscopy- and HSI-assigned diagnoses matched the treatment diagnoses at equal predicted frequencies (32.3%), as demonstrated through multivariate logistic regression analysis (P < 0.001). Conclusion: Overall, HSI did not improve the diagnostic accuracy above stroboscopy alone. Although specific laryngeal states such as presbyphonia may be better diagnosed with HSI, further studies are required to define HSI's precise role in the clinical setting. © 2013 The Voice Foundation