Abstract
Circular consensus sequencing with Pacific Biosciences (PacBio) technology generates long (10–25 kilobases), accurate ‘HiFi’ reads by combining serial observations of a DNA molecule into a consensus sequence. The standard approach to consensus generation, pbccs, uses a hidden Markov model. We introduce DeepConsensus, which uses an alignment-based loss to train a gap-aware transformer–encoder for sequence correction. Compared to pbccs, DeepConsensus reduces read errors by 42%. This increases the yield of PacBio HiFi reads at Q20 by 9%, at Q30 by 27% and at Q40 by 90%. With two SMRT Cells of HG003, reads from DeepConsensus improve hifiasm assembly contiguity (NG50 4.9 megabases (Mb) to 17.2 Mb), increase gene completeness (94% to 97%), reduce the false gene duplication rate (1.1% to 0.5%), improve assembly base accuracy (Q43 to Q45) and reduce variant-calling errors by 24%. DeepConsensus models could be trained to the general problem of analyzing the alignment of other types of sequences, such as unique molecular identifiers or genome assemblies.
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Data availability
Sequencing data, predictions and analysis files are available at https://console.cloud.google.com/storage/browser/brain-genomics-public/research/deepconsensus/publication.
Code availability
Code and pretrained models are available at https://github.com/google/deepconsensus. Sequencing data are available from the following sources:
∙ Sequel II data from Novogene42 at https://console.cloud.google.com/storage/browser/brain-genomics-public/research/sequencing
∙ 15-kb HG002 and 24-kb HG002 reads from PacBio at https://console.cloud.google.com/storage/browser/brain-genomics-public/research/deepconsensus/publication/sequencing
∙ Sequel II data from PacBio at https://downloads.pacbcloud.com/public/dataset/HG002_SV_and_SNV_CCS/
∙ HG002 diploid assembly at https://obj.umiacs.umd.edu/marbl_publications/hicanu/hg002_hifi_hicanu_combined.fasta.gz
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Acknowledgements
We thank F. Liu of the Google TensorFlow Model Garden team for improving our use of open-source implementation of the transformer architecture.
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Authors and Affiliations
Contributions
G.B., P.-C.C. and A.C. conceived the study. G.B. and D.E.C. wrote DeepConsensus and trained models. G.B., D.E.C., K.S., T.Y., M.N. and A.B. performed experiments with DeepConsensus reads and made figures and documentation. F.L.-L., Q.B. and J.-P.V. conceived and implemented the alignment loss strategy, which D.E.C. integrated into DeepConsensus. A.M.W., W.J.R. and A.T. provided insight into PacBio data, identified areas for improvement, suggested informative features and provided code for preprocessing and evaluation. W.A. experimented with embedding strategies. A.K. and A.T. contributed to efficient processing of PacBio reads. H.Y. coordinated data acquisition and research agreements. J.-P.V., A.V., C.Y.M., M.N., P.-C.C. and A.C. provided guidance on experimental design, architecture and code review. G.B., D.E.C., K.S., T.Y., F.L.-L., Q.B., A.M.W., W.J.R., M.N., J.-P.V., A.V., C.Y.M., P.-C.C. and A.C. wrote the paper.
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Competing interests
G.B., D.E.C., K.S., T.Y., F.L.-L., Q.B., A.B., M.N., H.Y., A.K., W.A., J.-P.V., A.V., C.Y.M., P.-C.C. and A.C. are employees of Google LLC and own Alphabet stock as part of the standard compensation package. A.M.W., A.T. and W.J.R. are full-time employees and shareholders of Pacific Biosciences. This study was funded by Google LLC.
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Nature Biotechnology thanks Justin Zook, Andrey Bzikadze and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data
Extended Data Fig. 1 DeepConsensus with longer reads improves genome assembly contiguity.
(a) HG002 read length distribution for 15kb and 24kb DeepConsensus reads from two SMRT Cells. (b) Contiguity of the HG002 hifiasm assembly with 15kb and 24kb DeepConsensus reads from two SMRT Cells. (c) HG002 variant calling performance for 15kb and 24kb reads from DeepConsensus for two SMRT Cells.
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Supplementary Information
Supplementary Figs. 1–11, Supplementary Tables 1–29 and documentation of software commands used.
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Baid, G., Cook, D.E., Shafin, K. et al. DeepConsensus improves the accuracy of sequences with a gap-aware sequence transformer. Nat Biotechnol 41, 232–238 (2023). https://doi.org/10.1038/s41587-022-01435-7
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DOI: https://doi.org/10.1038/s41587-022-01435-7
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