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Ultraconservation identifies a small subset of extremely constrained developmental enhancers


Extended perfect human-rodent sequence identity of at least 200 base pairs (ultraconservation) is potentially indicative of evolutionary or functional uniqueness. We used a transgenic mouse assay to compare the embryonic enhancer activity of 231 noncoding ultraconserved human genome regions with that of 206 extremely conserved regions lacking ultraconservation. Developmental enhancers were equally prevalent in both populations, suggesting instead that ultraconservation identifies a small, functionally indistinct subset of similarly constrained cis-regulatory elements.

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Figure 1: Ultraconservation identifies a small fraction of elements that are under similar evolutionary constraint.
Figure 2: Highly constrained enhancers target expression to similar tissues independent of ultraconservation.


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We thank I. Dubchak, A. Poliakov and S. Minovitsky for help with genome alignments and database development; S. Bhardwaj and S. Phouanenavong for technical assistance; and N. Ahituv, M. Nobrega, J. Noonan and members of the Pennacchio and Rubin laboratories for discussion and critical comments on the manuscript. L.A.P. was supported by grant HL066681, Berkeley-Program for Genomic Applications, under the Programs for Genomic Applications, funded by National Heart, Lung, and Blood Institute, and HG003988 funded by National Human Genome Research Institute. Research was done under Department of Energy Contract DE-AC02-05CH11231, University of California, E.O. Lawrence Berkeley National Laboratory. A.V. was supported by an American Heart Association postdoctoral fellowship.

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Correspondence to Len A Pennacchio.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1,3 and 5, Supplementary Figures 1 and 2 (PDF 315 kb)

Supplementary Table 2

Genome-wide set of extremely human-rodent constrained non-coding sequences (XLS 284 kb)

Supplementary Table 4

Genome-wide enhancer testing of non-exonic ultraconserved elements (XLS 58 kb)

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Visel, A., Prabhakar, S., Akiyama, J. et al. Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Nat Genet 40, 158–160 (2008).

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