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Assaying the regulatory potential of mammalian conserved non-coding sequences in human cells

Catia Attanasio16, Alexandre Reymond12, Richard Humbert3, Robert Lyle14, Michael S Kuehn3, Shane Neph3, Peter J Sabo3, Jeff Goldy3, Molly Weaver3, Andrew Haydock3, Kristin Lee3, Michael Dorschner3, Emmanouil T Dermitzakis5, Stylianos E Antonarakis1* and John A Stamatoyannopoulos3*

Author Affiliations

1 Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, 1211, Geneva 4, Switzerland

2 Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland

3 Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, USA

4 Department of Medical Genetics, Ullevål University Hospital, 0407 Oslo, Norway

5 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

6 Current address: Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA

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Genome Biology 2008, 9:R168  doi:10.1186/gb-2008-9-12-r168

Published: 2 December 2008

Abstract

Background

Conserved non-coding sequences in the human genome are approximately tenfold more abundant than known genes, and have been hypothesized to mark the locations of cis-regulatory elements. However, the global contribution of conserved non-coding sequences to the transcriptional regulation of human genes is currently unknown. Deeply conserved elements shared between humans and teleost fish predominantly flank genes active during morphogenesis and are enriched for positive transcriptional regulatory elements. However, such deeply conserved elements account for <1% of the conserved non-coding sequences in the human genome, which are predominantly mammalian.

Results

We explored the regulatory potential of a large sample of these 'common' conserved non-coding sequences using a variety of classic assays, including chromatin remodeling, and enhancer/repressor and promoter activity. When tested across diverse human model cell types, we find that the fraction of experimentally active conserved non-coding sequences within any given cell type is low (approximately 5%), and that this proportion increases only modestly when considered collectively across cell types.

Conclusions

The results suggest that classic assays of cis-regulatory potential are unlikely to expose the functional potential of the substantial majority of mammalian conserved non-coding sequences in the human genome.