This Article Full Text Full Text (PDF) Supplemental Research Data All Versions of this Article: gr.6929408v1 18/2/252    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by McGaughey, D. M. Articles by McCallion, A. S. PubMed PubMed Citation Articles by McGaughey, D. M. Articles by McCallion, A. S. Related Content Related Article Social Bookmarking                   What's this?

Letter

Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b

¹ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; ² Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; ³ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Despite its recognized utility, the extent to which evolutionary sequence conservation-based approaches may systematically overlook functional noncoding sequences remains unclear. We have tiled across sequence encompassing the zebrafish phox2b gene, ultimately evaluating 48 amplicons corresponding to all noncoding sequences therein for enhancer activity in zebrafish. Post hoc analyses of this interval utilizing five commonly used measures of evolutionary constraint (AVID, MLAGAN, SLAGAN, phastCons, WebMCS) demonstrate that each systematically overlooks regulatory sequences. These established algorithms detected only 29%–61% of our identified regulatory elements, consistent with the suggestion that many regulatory sequences may not be readily detected by metrics of sequence constraint. However, we were able to discriminate functional from nonfunctional sequences based upon GC composition and identified position weight matrices (PWM), demonstrating that, in at least one case, deleting sequences containing a subset of these PWMs from one identified regulatory element abrogated its regulatory function. Collectively, these data demonstrate that the noncoding functional component of vertebrate genomes may far exceed estimates predicated on evolutionary constraint.

E-mail amccall2{at}jhmi.edu; fax (410) 502-7544.

[Supplemental material is available online at www.genome.org.]

Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.6929408

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

Qualifying the relationship between sequence conservation and molecular function

Gregory M. Cooper and Christopher D. Brown
Genome Res. 2008 18: 201-205. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				A. Tsirigos and I. Rigoutsos Human and mouse introns are linked to the same processes and functions through each genome's most frequent non-conserved motifs Nucleic Acids Res., May 1, 2008; (2008) gkn155v1. [Abstract] [Full Text] [PDF]

				G. M. Cooper and C. D. Brown Qualifying the relationship between sequence conservation and molecular function Genome Res., February 1, 2008; 18(2): 201 - 205. [Abstract] [Full Text] [PDF]