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Science. 2014 Nov 21;346(6212):1007-12. doi: 10.1126/science.1246426.

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution.

Author information

1
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
2
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
4
Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
5
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Howard Hughes Medical Institute.
6
Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
7
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute.
8
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
9
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
10
Howard Hughes Medical Institute. Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
11
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
12
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
13
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
14
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Radiation Oncology, University of Washington, Seattle, WA 98109, USA.
15
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
16
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Division of Oncology, Department of Medicine, University of Washington, Seattle, WA 98195, USA. jstam@uw.edu.

Abstract

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.

PMID:
25411453
PMCID:
PMC4337786
DOI:
10.1126/science.1246426
[Indexed for MEDLINE]
Free PMC Article

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