Strand-seq enables reliable separation of long reads by chromosome via expectation maximization

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Abstract

Motivation: Current sequencing technologies are able to produce reads orders of magnitude longer than ever possible before. Such long reads have sparked a new interest in de novo genome assembly, which removes reference biases inherent to re-sequencing approaches and allows for a direct characterization of complex genomic variants. However, even with latest algorithmic advances, assembling a mammalian genome from long error-prone reads incurs a significant computational burden and does not preclude occasional misassemblies. Both problems could potentially be mitigated if assembly could commence for each chromosome separately. Results: To address this, we show how single-cell template strand sequencing (Strand-seq) data can be leveraged for this purpose. We introduce a novel latent variable model and a corresponding Expectation Maximization algorithm, termed SaaRclust, and demonstrates its ability to reliably cluster long reads by chromosome. For each long read, this approach produces a posterior probability distribution over all chromosomes of origin and read directionalities. In this way, it allows to assess the amount of uncertainty inherent to sparse Strand-seq data on the level of individual reads. Among the reads that our algorithm confidently assigns to a chromosome, we observed more than 99% correct assignments on a subset of Pacific Bioscience reads with 30.1×coverage. To our knowledge, SaaRclust is the first approach for the in silico separation of long reads by chromosome prior to assembly.

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Ghareghani, M., Porubska, D., Sanders, A. D., Meiers, S., Eichler, E. E., Korbel, J. O., & Marschall, T. (2018). Strand-seq enables reliable separation of long reads by chromosome via expectation maximization. In Bioinformatics (Vol. 34, pp. i115–i123). Oxford University Press. https://doi.org/10.1093/bioinformatics/bty290

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