Predicting the impact of noncoding genetic variation requires interpreting it in the context of three-dimensional genome architecture. We have developed deepC, a transfer-learning-based deep neural network that accurately predicts genome folding from megabase-scale DNA sequence. DeepC predicts domain boundaries at high resolution, learns the sequence determinants of genome folding and predicts the impact of both large-scale structural and single base-pair variations.
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Hi-C data from Rao et al. is available under GSE63525. Chromatin feature data from ENCODE, Roadmap and other publicly available data are listed in detail with accession numbers in Supplementary Table 1. Additional ENCODE data used for chromatin segmentation and visualization are listed with accession numbers in Supplementary Table 5. Tiled-C and NG Capture-C validation data are available under the Gene Expression Omnibus superseries GSE137437. Source data are provided with this paper.
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We thank R. Beagrie for help in refining the manuscript. This work was supported by the MRC (grant no. MC_UU_00016/14 to J.R.H.) and the Wellcome Trust via Strategic Award (no. 106130/Z/14/Z to J.R.H.) and Institutional Strategic Support Fund (reference no. 105605/Z/14/Z to J.R.H.). The Wellcome Trust Genomic Medicine and Statistics PhD Program (grant nos. 203728/Z/16/Z to R.S. and 203141/Z/16/Z to R.C.B.). The Stevenson Junior Research Fellowship at University College, Oxford (to A.M.O). G.L. is supported by the Wellcome Trust supporting award (no. 090532/Z/09/Z). Y.W.T. is supported by the European Research Council under the European Union’s Seventh Framework Program (grant no. FP7/2007-2013) ERC grant agreement no. 617071. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS.
The authors declare no competing interests.
Peer review information Lin Tang was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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The Hi-C interactions are percentile-binned in a distance-stratified manner. For every genomic distance, in steps equal to the bin size, the Hi-C signal is split into unequal percentiles ranging from 20 % bottom to 5 % top. The percentiles are attributed the values 1 to 10 yielding the Hi-C skeleton. The unequal percentile sizes ensure a finer distinction of the differences at the high Hi-C interaction value range, while minor differences in the low interaction value range are squished. Effectively, this procedure reduces the proximity signal and enhances domains and domain boundaries.
Training a deepC model with the same architecture but without pre-seeding the lower convolutional layers with the chromatin feature model weights results in the emergence of triangular structures. Their positioning however does not match with the Hi-C structures. In contrast, with pre-seeding the predicted domains overlap well with the Hi-C skeleton.
Shown is a region on chromosome 2 around the MEIS1 locus. DeepC predicts a small domain with insulation to the upstream regions (black arrow) in a tissue specific manner. The domain is only visible in K562 Hi-C data and matches with tissue-specific CTCF binding. Tiled-C confirms the tissue-specific domain. For contrast, Tiled-C data were bounded between the 5 and 95 percentiles.
a) Example region with overlap of GM12878: Hi-C, skeleton and deepC prediction; NG Capture-C tracks, distance-normalized NG Capture-C tracks and CTCF ChIP-seq track (red). Shown is a CTCF viewpoint (purple triangle) and an intra domain viewpoint (blue triangle) not overlapping with any active elements. Dashed lines in the distance-normalized NG Capture-C tracks indicate the expected interaction value. Dotted black lines highlight deepC prediction details that correspond to boundaries in the NG Capture-C tracks. b) K562 data of the same region.
Shown are GM12878 deepC predictions over the IKZF2 locus (a) on chromosome 2 and focused on the IKZF2 promoter (b). Aligned are DHS as well as ChIP-seq tracks for CTCF and histone modifications. Shown in green is the saliency score which is a proxy for the importance every base has in predicting the chromatin interactions of that region. The saliency score shows sharp peaks overlapping CTCF binding sites and broader peaks overlapping active gene promoters. Resolving the saliency score at base-pair resolution (b) highlights CTCF and general transcription factor binding motifs.
Distance-stratified Pearson correlation between prediction and Hi-C skeleton across chromosomes in cross-validation scheme. Smoothed and unsmoothed (M0–M2).
a, Pearson correlation between NG Capture-C profiles and virtual4C profiles from the Hi-C skeleton and predictions respectively. b1, Average distance-normalized NG Capture-C signal over insulation-score called boundaries in GM12878. b2, Average distance-normalized NG Capture-C signal over insulation-score called boundaries in GM12878.
a, Meta-profiles of saliency over stratified genomic elements. b, Predicted effects of genomic element deletion screen. c, Predicted effect of 1,000 randomly sampled SNPs within CTCF sites.
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Schwessinger, R., Gosden, M., Downes, D. et al. DeepC: predicting 3D genome folding using megabase-scale transfer learning. Nat Methods 17, 1118–1124 (2020). https://doi.org/10.1038/s41592-020-0960-3