Chapter 3 Stability of TADs in evolution

Preamble

This chapter is submitted for publication and currently under peer-review. A preprint is available on bioRxiv:

Krefting J, Andrade-Navarro MA, Ibn-Salem J^#. Evolutionary stability of topologically associating domains is associated with conserved gene regulation. bioRxiv. 2017. doi:doi.org/10.1101/231431.

My contributions to this publication are indicated in Table E.1. The source code of the complete analysis is available at GitHub: https://github.com/Juppen/TAD-Evolution. Supplementary figures and links to supplementary tables are shown in Appendix B.

^#corresponding author

Abstract

Background: The human genome is highly organized in the three-dimensional nucleus. Chromosomes fold locally into topologically associating domains (TADs) defined by increased intra-domain chromatin contacts. TADs contribute to gene regulation by restricting chromatin interactions of regulatory sequences, such as enhancers, with their target genes. Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. However, it is not clear to which extent TAD regions are conserved in evolution and whether disruption of TADs by evolutionary rearrangements can alter gene expression.

Results: Here, we hypothesize that TADs represent essential functional units of genomes, which are selected against rearrangements during evolution. We investigate this using whole-genome alignments to identify evolutionary rearrangement breakpoints of different vertebrate species. Rearrangement breakpoints are strongly enriched at TAD boundaries and depleted within TADs across species. Furthermore, using gene expression data across many tissues in mouse and human, we show that genes within TADs have more conserved expression patterns. Disruption of TADs by evolutionary rearrangements is associated with changes in gene expression profiles, consistent with a functional role of TADs in gene expression regulation.

Conclusions: Together, these results indicate that TADs are conserved building blocks of genomes with regulatory functions that are often reshuffled as a whole instead of being disrupted by rearrangements.