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Hi-C: A Method to Study the Three-dimensional Architecture of Genomes.
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Studying 3D genome evolution using genomic sequence.

Raphaël Mourad1

  • 1LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France.

Bioinformatics (Oxford, England)
|October 13, 2019
PubMed
Summary

We developed a new method to study the evolution of the 3D genome using only DNA sequences. This approach, the 3D ratio (3DR), effectively detects CTCF looping and its evolution across vertebrate species without costly Hi-C data.

Area of Science:

  • Genomics
  • Evolutionary Biology
  • Bioinformatics

Background:

  • The three-dimensional (3D) genome architecture is crucial for gene regulation and replication timing.
  • Chromatin looping in vertebrates is frequently mediated by CTCF and characterized by convergent CTCF motifs.
  • While Hi-C reveals evolutionary changes in chromatin looping, its complexity and cost limit large-scale species comparisons.

Purpose of the Study:

  • To develop a novel, sequence-based method for studying 3D genome evolution in vertebrates.
  • To assess the utility of the proposed method for detecting evolutionary constraints on CTCF looping.
  • To infer the ancestral states of 3D genome organization.

Main Methods:

  • A new approach using only genomic sequence data, bypassing the need for Hi-C.

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  • Calculation of the '3D ratio' (3DR) by comparing distances between convergent and divergent CTCF motifs.
  • Application of ancestral character reconstruction to infer historical 3DR values.

    • Main Results:

    • The 3DR statistic effectively detects CTCF looping encoded in genomic sequences, indicating evolutionary constraints.
    • The 3DR, reflecting CTCF looping and topologically associating domain organization, shows evolutionary dynamics across vertebrate genomes.
    • Ancestral character reconstruction can successfully infer 3DR in ancestral genomes.

    Conclusions:

    • The novel 3DR method provides a cost-effective and scalable approach to study 3D genome evolution.
    • The 3DR is a robust indicator of evolutionary constraints on CTCF looping and genome organization.
    • This work opens new avenues for investigating the evolutionary history of the 3D genome across diverse species.