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

Pollard, Daniel A.; Moses, Alan M.; Iyer, Venky N.; Eisen, Michael B.

doi:10.1186/1471-2105-7-376

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

Journal Article · Mon Aug 14 00:00:00 EDT 2006 · BMC Bioinformatics

DOI:https://doi.org/10.1186/1471-2105-7-376· OSTI ID:1626325

Pollard, Daniel A. ^[1]; Moses, Alan M. ^[1]; Iyer, Venky N. ^[2]; Eisen, Michael B. ^[3]

Univ. of California, Berkeley, CA (United States). Graduate Group in Biophysics
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology
Univ. of California, Berkeley, CA (United States). Graduate Group in Biophysics; Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Dicision. Dept. of Genome Sciences; Univ. of California, Berkeley, CA (United States). Center for Integrative Genomics

Background: 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. Results: 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. Conclusion: 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1626325

Journal Information:: BMC Bioinformatics, Vol. 7, Issue 1; ISSN 1471-2105

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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