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Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution

Olgert Denas, View ORCID ProfileRichard Sandstrom, View ORCID ProfileYong Cheng, View ORCID ProfileKathryn Beal, View ORCID ProfileJavier Herrero, View ORCID ProfileRoss C. Hardison, View ORCID ProfileJames Taylor
doi: https://doi.org/10.1101/010926
Olgert Denas
1Department of Mathematics and Computer Science, Emory University, Atlanta, GA 30322;
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Richard Sandstrom
4Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
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Yong Cheng
3Department of Genetics, Stanford University, Stanford, CA 94305, USA;
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Kathryn Beal
7European Bioinformatics Institute (EMBL-EBI)
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Javier Herrero
5The Genome Analysis Centre, Norwich Research Park, Norwich, UK;
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Ross C. Hardison
6Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA 16802, USA;
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James Taylor
1Department of Mathematics and Computer Science, Emory University, Atlanta, GA 30322;
2Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA;
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Abstract

Background Because species-specific gene expression is driven by species-specific regulation, understanding the relationship between sequence and function of the regulatory regions in different species will help elucidate how differences among species arise. Despite active experimental and computational research, the relationships among sequence, conservation, and function are still poorly understood.

Results We compared transcription factor occupied segments (TFos) for 116 human and 35 mouse TFs in 546 human and 125 mouse cell types and tissues from the Human and the Mouse ENCODE projects. We based the map between human and mouse TFos on a one-to-one nucleotide cross-species mapper, bnMapper, that utilizes whole genome alignments (WGA).

Our analysis shows that TFos are under evolutionary constraint, but a substantial portion (25.1% of mouse and 25.85% of human on average) of the TFos does not have a homologous sequence on the other species; this portion varies among cell types and TFs. Furthermore, 47.67% and 57.01% of the homologous TFos sequence shows binding activity on the other species for human and mouse respectively. However, 79.87% and 69.22% is repurposed such that it binds the same TF in different cells or different TFs in the same cells. Remarkably, within the set of TFos not showing conservation of occupancy, the corresponding genome regions in the other species are preferred locations of novel TFos. These events suggest that a substantial amount of functional regulatory sequences is exapted from other biochemically active genomic material.

Despite substantial repurposing of TFos, we did not find substantial changes in their predicted target genes, suggesting that CRMs buffer evolutionary events allowing little or no change in the TF – target gene associations. Thus, the small portion of TFos with strictly conserved occupancy underestimates the degree of conservation of regulatory interactions.

Conclusion We mapped regulatory sequences from an extensive number of TFs and cell types between human and mouse. A comparative analysis of this correspondence unveiled the extent of the shared regulatory sequence across TFs and cell types under study. Importantly, a large part of the shared regulatory sequence repurposed on the other species. This sequence, fueled by turnover events, provides a strong case for exaptation in regulatory elements.

Footnotes

  • Olgert Denas denas{at}adobe.com

  • Richard Sandstrom sull{at}uw.edu

  • Yong Cheng yongc{at}stanford.edu

  • Kathryn Beal kathryn.beal{at}eaglegenomics.com

  • Javier Herrero javier.herrero{at}ucl.ac.uk

  • Ross C. Hardison rch8{at}psu.edu

  • James Taylor james{at}taylorlab.org

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 30, 2014.
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Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution
Olgert Denas, Richard Sandstrom, Yong Cheng, Kathryn Beal, Javier Herrero, Ross C. Hardison, James Taylor
bioRxiv 010926; doi: https://doi.org/10.1101/010926
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Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution
Olgert Denas, Richard Sandstrom, Yong Cheng, Kathryn Beal, Javier Herrero, Ross C. Hardison, James Taylor
bioRxiv 010926; doi: https://doi.org/10.1101/010926

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