SP Transcription Factor Paralogs and DNA-Binding Sites Coevolve and Adaptively Converge in Mammals and Birds

Abstract

Functional modification of regulatory proteins can affect hundreds of genes throughout the genome, and is therefore thought to be almost universally deleterious. This belief, however, has recently been challenged. A potential example comes from transcription factor SP1, for which statistical evidence indicates that motif preferences were altered in eutherian mammals. Here, we set out to discover possible structural and theoretical explanations, evaluate the role of selection in SP1 evolution, and discover effects on coregulatory proteins. We show that SP1 motif preferences were convergently altered in birds as well as mammals, inducing coevolutionary changes in over 800 regulatory regions. Structural and phylogenic evidence implicates a single causative amino acid replacement at the same SP1 position along both lineages. Furthermore, paralogs SP3 and SP4, which coregulate SP1 target genes through competitive binding to the same sites, have accumulated convergent replacements at the homologous position multiple times during eutherian and bird evolution, presumably to preserve competitive binding. To determine plausibility, we developed and implemented a simple model of transcription factor and binding site coevolution. This model predicts that, in contrast to prevailing beliefs, even small selective benefits per locus can drive concurrent fixation of transcription factor and binding site mutants under a broad range of conditions. Novel binding sites tend to arise de novo, rather than by mutation from ancestral sites, a prediction substantiated by SP1-binding site alignments. Thus, multiple lines of evidence indicate that selection has driven convergent evolution of transcription factors along with their binding sites and coregulatory proteins.

Tracing the Evolution of Lineage-Specific Transcription Factor Binding Sites in a Birth-Death Framework

“…For densely sampled phylogenies containing relatively short branch lengths, such turnover events can be inferred as long as the gain and loss occur on different branches. This is usually the case, since old binding sites are seldom lost through selection and are generally lost slowly, following a nearly-neutral rate of decay [29] , [30] . Many neutrally (or near-neutrally) evolving sites are still present after relatively long periods of mammalian evolution [29] .…”

“…Our approach is designed to estimate genome-wide rates of evolution for a given motif according to a birth-death framework (formally, a quasi birth-death process [69] ), similar to that used to measure the timing of accelerated motif evolution as in [29] . The birth rate ( ) represents the rate at which a new motif occurrence appears at any unoccupied site per year, while the death rate ( ) represents the rate at which an existing site is lost per year.…”

“…Gains and losses of TFBS have been explicitly used both to improve cross-species sequence comparisons and to detect cis-regulatory modules, although such models are usually framed within the context of an alignment [21] , [28] . A more similar alignment-free model was previously used to measure the overall rate of TFBS creation along different lineages [29] . In this work, we instead applied our framework to infer lineage-specific TFBS, estimating the branch of origin of each individual TFBS for six TFs.…”

Increased Expression of Colonic Wnt9A through Sp1-mediated Transcriptional Effects involving Arylsulfatase B, Chondroitin 4-Sulfate, and Galectin-3

“…These and other reports caused low molecular weight carrageenan to be identified as a class IIB agent by the International Agency for Research on Cancer (40). In rats, a lifetime exposure level of 2310 mg/kg body weight of degraded carrageenan was implicated in development of large intestinal malignancies in half of the exposed animals (TD 50 ) by the Carcinogenic Potency Database (44). This corresponds to a lifetime exposure of ϳ138 g in a 60-kg person.…”

Nonadaptive Amino Acid Convergence Rates Decrease over Time

“…Although evolution mostly proceeds by accumulation of differences between groups, numerous examples of convergent evolution exist, where similar solutions are found to similar evolutionary problems. Well-known morphological examples include eyes and wings, but an increasing number of examples are known at the molecular level, including proteins involved in echolocation in bats and cetaceans ( Liu et al 2010 ; Shen et al 2012 ; Parker et al 2013 ), foregut fermentation proteins in monkeys and cows ( Stewart et al 1987 ), transcription factors in mammals and birds ( Yokoyama and Pollock 2012 ), and mitochondrial proteins among different snakes ( Castoe et al 2008 ), and mitochondrial proteins between snakes and agamid lizards ( Castoe et al 2009 ).…”