Maximum Likelihood de novo reconstruction of viral populations using paired end sequencing data

We present MLEHaplo, a maximum likelihood de novo assembly algorithm for reconstructing viral haplotypes in a virus population from paired-end next generation sequencing (NGS) data. Using the pairing information of reads in our proposed Viral Path Reconstruction Algorithm (ViPRA), we generate a small subset of paths from a De Bruijn graph of reads that serve as candidate paths for true viral haplotypes. Our proposed method MLEHaplo then generates a maximum likelihood estimate of the viral population using the paths reconstructed by ViPRA. We evaluate and compare MLEHaplo on simulated datasets of 1200 base pairs at different sequence coverage, on HCV strains with sequencing errors, and on a lab mixture of five HIV-1 strains. MLEHaplo reconstructs full length viral haplotypes having a 100% sequence identity to the true viral haplotypes in most of the small genome simulated viral populations at 250x sequencing coverage. While reference based methods either under-estimate or over-estimate the viral haplotypes, MLEHaplo limits the over-estimation to 3 times the size of true viral haplotypes, reconstructs the full phylogeny in the HCV to greater than 99% sequencing identity and captures more sequencing variation for the HIV-1 strains dataset compared to their known consensus sequences.