Exploring single-sample SNP and INDEL calling with whole-genome de novo assembly

Motivation: Eugene Myers in his string graph paper (Myers, 2005) suggested that in a string graph or equivalently a unitig graph, any path spells a valid assembly. As a string/unitig graph also encodes every valid assembly of reads, such a graph, provided that it can be constructed correctly, is in fact a lossless representation of reads. In principle, every analysis based on whole-genome shotgun sequencing (WGS) data, such as SNP and insertion/deletion (INDEL) calling, can also be achieved with unitigs. Results: To explore the feasibility of using de novo assembly in the context of resequencing, we developed a de novo assembler, fermi, that assembles Illumina short reads into unitigs while preserving most of information of the input reads. SNPs and INDELs can be called by mapping the unitigs against a reference genome. By applying the method on 35-fold human resequencing data, we showed that in comparison to the standard pipeline, our approach yields similar accuracy for SNP calling and better results for INDEL calling. It has higher sensitivity than other de novo assembly based methods for variant calling. Our work suggests that variant calling with de novo assembly be a beneficial complement to the standard variant calling pipeline for whole-genome resequencing. In the methodological aspects, we proposed FMD-index for forward-backward extension of DNA sequences, a fast algorithm for finding all super-maximal exact matches and one-pass construction of unitigs from an FMD-index. Availability: http://github.com/lh3/fermi Contact: [email protected]: Rev2: submitted version with minor improvements; 7 page

Reverse-Safe Data Structures for Text Indexing

We introduce the notion of reverse-safe data structures. These are data structures that prevent the reconstruction of the data they encode (i.e., they cannot be easily reversed). A data structure D is called z-reverse-safe when there exist at least z datasets with the same set of answers as the ones stored by D. The main challenge is to ensure that D stores as many answers to useful queries as possible, is constructed efficiently, and has size close to the size of the original dataset it encodes. Given a text of length n and an integer z, we propose an algorithm which constructs a z-reverse-safe data structure that has size O(n) and answers pattern matching queries of length at most d optimally, where d is maximal for any such z-reverse-safe data structure. The construction algorithm takes O(n ω log d) time, where ω is the matrix multiplication exponent. We show that, despite the n ω factor, our engineered implementation takes only a few minutes to finish for million-letter texts. We further show that plugging our method in data analysis applications gives insignificant or no data utility loss. Finally, we show how our technique can be extended to support applications under a realistic adversary model