Kr. Wollenberg et Wr. Atchley, Separation of phylogenetic and functional associations in biological sequences by using the parametric bootstrap, P NAS US, 97(7), 2000, pp. 3288-3291
Citations number
25
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Quantitative analyses of biological sequences generally proceed under the a
ssumption that individual DNA or protein sequence elements vary independent
ly. However, this assumption is not biologically realistic because sequence
elements often vary in a concerted manner resulting from common ancestry a
nd structural or functional constraints. We calculated intersite associatio
ns among aligned protein sequences by using mutual information. To discrimi
nate associations resulting from common ancestry from those resulting from
structural or functional constraints, we used a parametric bootstrap algori
thm to construct replicate data sets. These data are expected to have inter
site associations resulting solely from phytogeny. By comparing the distrib
ution of our association statistic for the replicate data against that calc
ulated for empirical data, we were able to assign a probability that two si
tes covaried resulting from structural or functional constraint rather than
phylogeny. We tested our method by using an alignment of 237 basic helix-l
oop-helix (bHLH) protein domains. Comparison of our results against a solve
d three-dimensional structure confirmed the identification of several sites
important to function and structure of the bHLH domain. This analytical pr
ocedure has broad utility as a first step in the identification of sites th
at are important to biological macromolecular structure and function when a
solved structure is unavailable.