Abstract
It is a long-held belief in evolutionary biology that the rate of molecular evolution for a given DNA sequence is inversely related to the level of functional constraint. This belief holds true for the protein-coding homeotic (Hox) genes originally discovered in Drosophila melanogaster. Expression of the Hox genes in Drosophila embryos is essential for body patterning and is controlled by an extensive array of cis-regulatory modules (CRMs). How the regulatory modules functionally evolve in different species is not clear. A comparison of the CRMs for the Abdominal-B gene from different Drosophila species reveals relatively low levels of overall sequence conservation. However, embryonic enhancer CRMs from other Drosophila species direct transgenic reporter gene expression in the same spatial and temporal patterns during development as their D. melanogaster orthologs. Bioinformatic analysis reveals the presence of short conserved sequences within defined CRMs, representing gap and pair-rule transcription factor binding sites. One predicted binding site for the gap transcription factor KRUPPEL in the IAB5 CRM was found to be altered in Superabdominal (Sab) mutations. In Sab mutant flies, the third abdominal segment is transformed into a copy of the fifth abdominal segment. A model for KRUPPEL-mediated repression at this binding site is presented. These findings challenge our current understanding of the relationship between sequence evolution at the molecular level and functional activity of a CRM. While the overall sequence conservation at Drosophila CRMs is not distinctive from neighboring genomic regions, functionally critical transcription factor binding sites within embryonic enhancer CRMs are highly conserved. These results have implications for understanding mechanisms of gene expression during embryonic development, enhancer function, and the molecular evolution of eukaryotic regulatory modules.
Highlights
The Drosophila bithorax complex (BX-C) is over 300 kb in size [1], but contains only three homeotic (Hox) genes, Ultrabithorax (Ubx), abdominal-A, and Abdominal-B (Abd-B) [2]
We have examined critical DNA sequence modules which regulate genes that pattern the early embryo in different species of the fruit fly
Our experiments demonstrate that despite a distinctive lack of sequence conservation when compared to neighboring genomic regions, the experimentally well-defined IAB5 and IAB8 enhancer cisregulatory modules (CRMs) are functionally conserved across the Drosophila genus
Summary
The Drosophila bithorax complex (BX-C) is over 300 kb in size [1], but contains only three homeotic (Hox) genes, Ultrabithorax (Ubx), abdominal-A (abd-A), and Abdominal-B (Abd-B) [2] These genes control the identity of ten parasegments (PS5-14) in the posterior thorax and abdomen of the developing fly and are important in the evolution of animal morphology [3]. The iab-5 to iab-8 genomic regions each harbor at least one embryonic enhancer CRM which is responsible for driving Abd-B expression in specific segments (Figure 1A) [4,11]. The IAB5 enhancer CRM in the iab genomic region is capable of driving Abd-B expression in the presumptive fifth, seventh, and ninth abdominal segments of Drosophila melanogaster [12]. Enhancer CRMs usually contain a high number of transcription factor binding sites
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