BackgroundTypical human genome differs from the reference genome at 4-5 million sites. This diversity is increasingly catalogued in repositories such as ExAC/gnomAD, consisting of >15,000 whole-genomes and >126,000 exome sequences from different individuals. Despite this enormous diversity, resequencing data workflows are still based on a single human reference genome. Identification and genotyping of genetic variants is typically carried out on short-read data aligned to a single reference, disregarding the underlying variation.ResultsWe propose a new unified framework for variant calling with short-read data utilizing a representation of human genetic variation – a pan-genomic reference. We provide a modular pipeline that can be seamlessly incorporated into existing sequencing data analysis workflows. Our tool is open source and available online: https://gitlab.com/dvalenzu/PanVC.ConclusionsOur experiments show that by replacing a standard human reference with a pan-genomic one we achieve an improvement in single-nucleotide variant calling accuracy and in short indel calling accuracy over the widely adopted Genome Analysis Toolkit (GATK) in difficult genomic regions.
Background We study a preprocessing routine relevant in pan-genomic analyses: consider a set of aligned haplotype sequences of complete human chromosomes. Due to the enormous size of such data, one would like to represent this input set with a few founder sequences that retain as well as possible the contiguities of the original sequences. Such a smaller set gives a scalable way to exploit pan-genomic information in further analyses (e.g. read alignment and variant calling). Optimizing the founder set is an NP-hard problem, but there is a segmentation formulation that can be solved in polynomial time, defined as follows. Given a threshold L and a set of m strings (haplotype sequences), each having length n , the minimum segmentation problem for founder reconstruction is to partition [1, n ] into set P of disjoint segments such that each segment has length at least L and the number of distinct substrings at segment [ a , b ] is minimized over . The distinct substrings in the segments represent founder blocks that can be concatenated to form founder sequences representing the original such that crossovers happen only at segment boundaries. Results We give an O ( mn ) time (i.e. linear time in the input size) algorithm to solve the minimum segmentation problem for founder reconstruction, improving over an earlier . Conclusions Our improvement enables to apply the formulation on an input of thousands of complete human chromosomes. We implemented the new algorithm and give experimental evidence on its practicality. The implementation is available in https://github.com/tsnorri/founder-sequences .
We study the problem of matching a string in a labeled graph. Previous research has shown that unless the Orthogonal Vectors Hypothesis (OVH) is false, one cannot solve this problem in strongly sub-quadratic time, nor index the graph in polynomial time to answer queries efficiently (Equi et al. ICALP 2019, SOFSEM 2021). These conditional lower-bounds cover even deterministic graphs with binary alphabet, but there naturally exist also graph classes that are easy to index: For example, Wheeler graphs (Gagie et al. Theor. Comp. Sci. 2017) cover graphs admitting a Burrows-Wheeler transform -based indexing scheme. However, it is NP-complete to recognize if a graph is a Wheeler graph (Gibney, Thankachan, ESA 2019). We propose an approach to alleviate the construction bottleneck of Wheeler graphs. Rather than starting from an arbitrary graph, we study graphs induced from multiple sequence alignments (). Elastic degenerate strings (Bernadini et al. SPIRE 2017, ICALP 2019) can be seen as such graphs, and we introduce here their generalization: elastic founder graphs. We first prove that even such induced graphs are hard to index under OVH. Then we introduce two subclasses, repeat-free and semi-repeat-free graphs, that are easy to index. We give a linear time algorithm to construct a repeat-free (non-elastic) founder graph from a gapless , and (parameterized) near-linear time algorithms to construct a semi-repeat-free (repeat-free, respectively) elastic founder graph from general . Finally, we show that repeat-free founder graphs admit a reduction to Wheeler graphs in polynomial time.
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