Variant calling, the problem of estimating whether a position in a DNA sequence differs from a reference sequence, given noisy, redundant, overlapping short sequences that cover that position, is fundamental to genomics. We propose a deep averaging network designed specifically for variant calling. Our model takes into account the independence of each short input read sequence by transforming individual reads through a series of convolutional layers, limiting the communication between individual reads to averaging and concatenating operations. Training and testing on the precisionFDA Truth Challenge (pFDA), we match state of the art overall 99.89 F1 score. Genome datasets exhibit extreme skew between easy examples and those on the decision boundary. We take advantage of this property to converge models at 5x the speed of standard epoch-based training by skipping easy examples during training. To facilitate future work, we release our code, trained models and pre-processed public domain datasets.
With recent advances in sequencing technology it has become affordable and practical to sequence genomes to very high depth-of-coverage, allowing researchers to discover low-frequency variants in the genome. However, due to the errors in sequencing it is an active area of research to develop algorithms that can separate noise from the true variants. LoFreq is a state of the art algorithm for low-frequency variant detection but has a relatively long runtime compared to other tools. In addition to this, the interface for running in parallel could be simplified, allowing for multithreading as wel…
Next Generation Sequencing can sample the whole genome (WGS) or the 1-2% of the genome that codes for proteins called the whole exome (WES). Machine learning approaches to variant calling achieve high accuracy in WGS data, but the reduced number of training examples causes training with WES data alone to achieve lower accuracy. We propose and compare three different data augmentation strategies for improving performance on WES data: 1) joint training with WES and WGS data, 2) warmstarting the WES model from a WGS model, and 3) joint training with the sequencing type specified. All three approa…
Motivation: The MinION device by Oxford Nanopore is the first portable sequencing device. MinION is able to produce very long reads (reads over 100~kBp were reported), however it suffers from high sequencing error rate. In this paper, we show that the error rate can be reduced by improving the base calling process. Results: We present the first open-source DNA base caller for the MinION sequencing platform by Oxford Nanopore. By employing carefully crafted recurrent neural networks, our tool improves the base calling accuracy compared to the default base caller supplied by the manufacturer. Th…
Genomics has become an essential technology for surveilling emerging infectious disease outbreaks. A wide range of technologies and strategies for pathogen genome enrichment and sequencing are being used by laboratories worldwide, together with different, and sometimes ad hoc, analytical procedures for generating genome sequences. As a result, public repositories now contain non-standard entries of varying quality. A standardized analytical process for consensus genome sequence determination, particularly for outbreaks such as the ongoing COVID-19 pandemic, is critical to provide a solid genom…
With the booming of next generation sequencing technology and its implementation in clinical practice and life science research, the need for faster and more efficient data analysis methods becomes pressing in the field of sequencing. Here we report on the evaluation of an optimized germline mutation calling pipeline, HummingBird, by assessing its performance against the widely accepted BWA-GATK pipeline. We found that the HummingBird pipeline can significantly reduce the running time of the primary data analysis for whole genome sequencing and whole exome sequencing while without significantl…
Cambridge Cancer Genomics（剑桥癌症基因组学）；University of Cambridge（剑桥大学）；University College London（伦敦大学学院）
DNA sequencing to identify genetic variants is becoming increasingly valuable in clinical settings. Assessment of variants in such sequencing data is commonly implemented through Bayesian heuristic algorithms. Machine learning has shown great promise in improving on these variant calls, but the input for these is still a standardized "pile-up" image, which is not always best suited. In this paper, we present a novel method for generating images from DNA sequencing data, which interlaces the human reference genome with personalized sequencing output, to maximize usage of sequencing reads and im…
SVPLEX: A Nextflow Pipeline for Cohort-level Structural Variant Calling
Walter and Eliza Hall Institute of Medical Research（沃尔特和伊尔莎霍尔医学研究所）；University of Melbourne（墨尔本大学）；Epilepsy Research Centre, Department of Medicine (Austin Health), University of Melbourne（墨尔本大学医学部癫痫研究中心（奥斯汀健康））
In recent years, aligning a sequence to a pangenome has become a central problem in genomics and pangenomics. A fast and accurate solution to this problem can serve as a toolkit to many crucial tasks such as read-correction, Multiple Sequences Alignment (MSA), genome assemblies, variant calling, just to name a few. In this paper we propose a new, fast and exact method to align a string to a D-string, the latter possibly representing an MSA, a pan-genome or a partial assembly. An implementation of our tool dsa is publicly available at https://github.com/urbanslug/dsa
We propose a frame-based representation of k-mers for detecting sequencing errors and rare variants in next generation sequencing data obtained from populations of closely related genomes. Frames are sets of non-orthogonal basis functions, traditionally used in signal processing for noise removal. We define a frame for genomes and sequenced reads to consist of discrete spatial signals of every k-mer of a given size. We show that each k-mer in the sequenced data can be projected onto multiple frames and these projections are maximized for spatial signals corresponding to the k-mer's substrings.…
Google Research（谷歌研究院）；Verily Life Sciences（Verily生命科学公司）；Pacific Biosciences（太平洋生物科学公司）
Accurate genome sequencing can improve our understanding of biology and the genetic basis of disease. The standard approach for generating DNA sequences from PacBio instruments relies on HMM-based models. Here, we introduce Distilled DeepConsensus - a distilled transformer-encoder model for sequence correction, which improves upon the HMM-based methods with runtime constraints in mind. Distilled DeepConsensus is 1.3x faster and 1.5x smaller than its larger counterpart while improving the yield of high quality reads (Q30) over the HMM-based method by 1.69x (vs. 1.73x for larger model). With imp…
