Protein domain hierarchy Gibbs sampling strategies

Neuwald Andrew F. ()
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Neuwald Andrew F.: Institute for Genome Sciences and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, BioPark II, Room 617, 801 West Baltimore St., Baltimore, MD 21201, USA

Statistical Applications in Genetics and Molecular Biology, 2014, vol. 13, issue 4, 497-517

Abstract: Hierarchically-arranged multiple sequence alignment profiles are useful for modeling protein domains that have functionally diverged into evolutionarily-related subgroups. Currently such alignment hierarchies are largely constructed through manual curation, as for the NCBI Conserved Domain Database (CDD). Recently, however, I developed a Gibbs sampler that uses an approach termed statistical evolutionary dynamics analysis to accomplish this task automatically while, at the same time, identifying sequence determinants of protein function. Here I describe the statistical model and sampling strategies underlying this sampler. When implemented and applied to simulated protein sequences (which conform to the underlying statistical model precisely), these sampling strategies efficiently converge on the hierarchy used to generate the sequences. However, for real protein sequences the sampler finds alternative, nearly-optimal hierarchies for many domains, indicating a significant degree of ambiguity. I illustrate how both the nature of such ambiguities and the most robust (“consensus”) features of a hierarchy may be determined from an ensemble of independently generated hierarchies for the same domain. Such consensus hierarchies can provide reliably stable models of protein domain functional divergence.

Keywords: Markov chain Monte Carlo; computer algorithm; Bayesian statistics; protein sequence analysis (search for similar items in EconPapers)
Date: 2014
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DOI: 10.1515/sagmb-2014-0008

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