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Accurate in vivo population sequencing uncovers drivers of within-host genetic diversity in viruses

By Maoz Gelbart, Sheri Harari, Ya’ara Ben-Ari, Talia Kustin, Dana Wolf, Michal Mandelboim, Orna Mor, Pleuni Pennings, Adi Stern

Posted 18 Jun 2018
bioRxiv DOI: 10.1101/349498

Mutations fuel evolution and facilitate adaptation to novel environments. However, characterizing the spectrum of mutations in a population is obscured by high error rates of next generation sequencing. Here, we present AccuNGS, a novel in vivo sequencing approach that detects variants as rare as 1:10,000. Applying it to 46 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV, revealed large differences in within-host genetic diversity among virus populations. Haplotype reconstruction revealed that increased diversity was mostly driven by multiple transmitted/founder viruses in HIV and CMV samples. Conversely, we detected an abundance of defective virus genomes (DVGs) in RSV samples, including hyper-edited genomes, nonsense mutations and single point deletions. Higher proportions of DVGs correlated with increased viral loads, suggesting increased cellular co-infection rates, which enable DVG persistence. AccuNGS establishes a general platform that allows detecting DVGs, and in general, rare variants that drive evolution.

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