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PMID: 16904011 Published · epublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Detecting the limits of regulatory element conservation and divergence estimation using pairwise and multiple alignments.

BMC bioinformatics ·Vol. 7 ·2006-08-14 ·Pages 376

Pollard DA, Moses AM, Iyer VN, Eisen MB

Abstract

Molecular evolutionary studies of noncoding sequences rely on multiple alignments. Yet how multiple alignment accuracy varies across sequence types, tree topologies, divergences and tools, and further how this variation impacts specific inferences, remains unclear. Here we develop a molecular evolution simulation platform, CisEvolver, with models of background noncoding and transcription factor binding site evolution, and use simulated alignments to systematically examine multiple alignment accuracy and its impact on two key molecular evolutionary inferences: transcription factor binding site conservation and divergence estimation. We find that the accuracy of multiple alignments is determined almost exclusively by the pairwise divergence distance of the two most diverged species and that additional species have a negligible influence on alignment accuracy. Conserved transcription factor binding sites align better than surrounding noncoding DNA yet are often found to be misaligned at relatively short divergence distances, such that studies of binding site gain and loss could easily be confounded by alignment error. Divergence estimates from multiple alignments tend to be overestimated at short divergence distances but reach a tool specific divergence at which they cease to increase, leading to underestimation at long divergences. Our most striking finding was that overall alignment accuracy, binding site alignment accuracy and divergence estimation accuracy vary greatly across branches in a tree and are most accurate for terminal branches connecting sister taxa and least accurate for internal branches connecting sub-alignments. Our results suggest that variation in alignment accuracy can lead to errors in molecular evolutionary inferences that could be construed as biological variation. These findings have implications for which species to choose for analyses, what kind of errors would be expected for a given set of species and how multiple alignment tools and phylogenetic inference methods might be improved to minimize or control for alignment errors.

MeSH Terms
Binding Sites/genetics Evolution, Molecular Models, Genetic Regulatory Elements, Transcriptional/genetics Sequence Alignment/methods Sequence Analysis, DNA/methods Species Specificity
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Pollard Daniel A
Graduate Group in Biophysics, University of California, Berkeley, CA 94720, USA. [email protected]
Moses Alan M
Iyer Venky N
Eisen Michael B
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Article Info
Journal
BMC bioinformatics
Abbr.
BMC Bioinformatics
ISSN
1471-2105
DOI
10.1186/1471-2105-7-376
Email
[email protected]
Published
2006-08-14
Epub
2006-00-14
Pages
376
Language
English
Region
England
NLM ID
100965194
PMCID
PMC1613255
Subset
IM
Grants
NHGRI NIH HHS · R01 HG002779-01 · United States
NHGRI NIH HHS · R01 HG002779-04 · United States
NHGRI NIH HHS · R01 HG002779 · United States
NHGRI NIH HHS · R01-HG002779-02 · United States
NHGRI NIH HHS · R01 HG002779-03 · United States
NHGRI NIH HHS · R01 HG002779-02 · United States
External Links
PubMed source DOI: 10.1186/1471-2105-7-376 PMC Full Text View journal details
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