1. Computational and Systems Biology
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Generative modeling of multi-mapping reads with mHi-C advances analysis of Hi-C studies

  1. Ye Zheng
  2. Ferhat Ay
  3. Sunduz Keles  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. La Jolla Institute for Allergy and Immunology, United States
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Cite this article as: eLife 2019;8:e38070 doi: 10.7554/eLife.38070


Current Hi-C analysis approaches are unable to account for reads that align to multiple locations, and hence underestimate biological signal from repetitive regions of genomes. We developed and validated mHi-C, a multi-read mapping strategy to probabilistically allocate Hi-C multi-reads. mHi-C exhibited superior performance over utilizing only uni-reads and heuristic approaches aimed at rescuing multi-reads on benchmarks. Specifically, mHi-C increased the sequencing depth by an average of 20% resulting in higher reproducibility of contact matrices and detected interactions across biological replicates. The impact of the multi-reads on the detection of significant interactions is influenced marginally by the relative contribution of multi-reads to the sequencing depth compared to uni-reads, cis-to-trans ratio of contacts, and the broad data quality as reflected by the proportion of mappable reads of datasets. Computational experiments highlighted that in Hi-C studies with short read lengths, mHi-C rescued multi-reads can emulate the effect of longer reads. mHi-C also revealed biologically supported bona fide promoter-enhancer interactions and topologically associating domains involving repetitive genomic regions, thereby unlocking a previously masked portion of the genome for conformation capture studies.

Data availability

GEO and ENCODE accession codes for all the data analyzed in this manuscript are provided in the manuscript.Source data files have been provided for Figures 1, 3, 4, and 5 (some via Dryad http://dx.doi.org/10.5061/dryad.v7k3140).The mHiC software is made available on github https://github.com/keleslab/mHiC with proper documentation.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ye Zheng

    Department of Statistics, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8806-2761
  2. Ferhat Ay

    La Jolla Institute for Allergy and Immunology, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sunduz Keles

    Department of Statistics, University of Wisconsin-Madison, Madison, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9048-0922


National Human Genome Research Institute (HG009744)

  • Sunduz Keles

La Jolla Institute for Allergy and Immunology (Institute Leadership Funds)

  • Ferhat Ay

National Human Genome Research Institute (HG007019)

  • Sunduz Keles

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Bing Ren, University of California, San Diego School of Medicine, United States

Publication history

  1. Received: May 3, 2018
  2. Accepted: January 30, 2019
  3. Accepted Manuscript published: January 31, 2019 (version 1)
  4. Version of Record published: April 5, 2019 (version 2)


© 2019, Zheng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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