Genome-wide identification of conserved regulatory function in diverged sequences.

Abstract:

:Plasticity of gene regulatory encryption can permit DNA sequence divergence without loss of function. Functional information is preserved through conservation of the composition of transcription factor binding sites (TFBS) in a regulatory element. We have developed a method that can accurately identify pairs of functional noncoding orthologs at evolutionarily diverged loci by searching for conserved TFBS arrangements. With an estimated 5% false-positive rate (FPR) in approximately 3000 human and zebrafish syntenic loci, we detected approximately 300 pairs of diverged elements that are likely to share common ancestry and have similar regulatory activity. By analyzing a pool of experimentally validated human enhancers, we demonstrated that 7/8 (88%) of their predicted functional orthologs retained in vivo regulatory control. Moreover, in 5/7 (71%) of assayed enhancer pairs, we observed concordant expression patterns. We argue that TFBS composition is often necessary to retain and sufficient to predict regulatory function in the absence of overt sequence conservation, revealing an entire class of functionally conserved, evolutionarily diverged regulatory elements that we term "covert."

journal_name

Genome Res

journal_title

Genome research

authors

Taher L,McGaughey DM,Maragh S,Aneas I,Bessling SL,Miller W,Nobrega MA,McCallion AS,Ovcharenko I

doi

10.1101/gr.119016.110

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

1139-49

issue

7

eissn

1088-9051

issn

1549-5469

pii

gr.119016.110

journal_volume

21

pub_type

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