Abstract
Changes in regulatory DNA contribute to phenotypic differences within and between taxa. Comparative studies show that many transcription factor binding sites (TFBS) are conserved between species whereas functional studies reveal that some mutations segregating within species alter TFBS function. Consistently, in this analysis of 13 regulatory elements in Drosophila melanogaster populations, single base and insertion/deletion polymorphism are rare in characterized regulatory elements. Experimentally defined TFBS are nearly devoid of segregating mutations and, as has been shown before, are quite conserved. For instance 8 of 11 Hunchback binding sites in the stripe 3+7 enhancer of even-skipped are conserved between D. melanogaster and Drosophila virilis. Oddly, we found a 72 bp deletion that removes one of these binding sites (Hb8), segregating within D. melanogaster. Furthermore, a 45 bp deletion polymorphism in the spacer between the stripe 3+7 and stripe 2 enhancers, removes another predicted Hunchback site. These two deletions are separated by ∼250 bp, sit on distinct haplotypes, and segregate at appreciable frequency. The Hb8Δ is at 5 to 35% frequency in the new world, but also shows cosmopolitan distribution. There is depletion of sequence variation on the Hb8Δ-carrying haplotype. Quantitative genetic tests indicate that Hb8Δ affects developmental time, but not viability of offspring. The Eve expression pattern differs between inbred lines, but the stripe 3 and 7 boundaries seem unaffected by Hb8Δ. The data reveal segregating variation in regulatory elements, which may reflect evolutionary turnover of characterized TFBS due to drift or co-evolution.
Highlights
Evolution of Transcriptional Regulatory Sequences The molecular basis for phenotypic divergence and standing variation is often attributed to differences in the regulation of transcription[1,2,3]
Purifying selection seems to affect both single nucleotide polymorphism (SNPs) and indel polymorphism, as there is a significant correlation between h for SNPs and indels (r = 0.48, p = 0.03, Figure S1A)
The genome comparisons confirm that both Hb binding sites in eve affected by these two deletions have been protected by purifying selection. This prompts the question, why do these deletions of conserved transcription factor binding sites (TFBS) occur at such high frequencies in populations? Here we focus mainly on studying the population genetics of Hb8D and assess its potential impact on development and fitness
Summary
Evolution of Transcriptional Regulatory Sequences The molecular basis for phenotypic divergence and standing variation is often attributed to differences in the regulation of transcription[1,2,3]. Changes in TFBS and even losses are permitted, if the transcriptional output is preserved Such models of stabilizing selection acting on transcriptional output can account for both loss of functional binding sites and evolutionary fine-tuning of regulatory elements [12]. They suggest that positive selection may sometimes play a role, acting on compensatory mutations in cis or trans. From first principles one would predict both co-evolution in cis (promoters, regulatory modules, more distantly located signals like insulators) and co-evolution of sequence elements with the trans environment (abundance of transcription factor, mediator or holenzyme components). Functional polymorphism (both single nucleotide polymorphism: SNPs or insertion/deletion polymorphism: indels) in human enhancers, are shaped by positive selection [21]
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