by Bin Z. He, Alisha K. Holloway, Sebastian J. Maerkl, Martin Kreitman
Transcription factor binding site(s) (TFBS) gain and loss (i.e., turnover) is a
well-documented feature of cis-regulatory module (CRM) evolution, yet little
attention has been paid to the evolutionary force(s) driving this turnover
process. The predominant view, motivated by its widespread occurrence,
emphasizes the importance of compensatory mutation and genetic drift. Positive
selection, in contrast, although it has been invoked in specific instances of
adaptive gene expression evolution, has not been considered as a general
alternative to neutral compensatory evolution. In this study we evaluate the two
hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS
of well-characterized CRM in two closely related Drosophila species,
Drosophila melanogaster and Drosophila
simulans. An important feature of the analysis is classification of
TFBS mutations according to the direction of their predicted effect on binding
affinity, which allows gains and losses to be evaluated independently along the
two phylogenetic lineages. The observed patterns of polymorphism and divergence
are not compatible with neutral evolution for either class of mutations.
Instead, multiple lines of evidence are consistent with contributions of
positive selection to TFBS gain and loss as well as purifying selection in its
maintenance. In discussion, we propose a model to reconcile the finding of
selection driving TFBS turnover with constrained CRM function over long
evolutionary time.
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