Functional Evolution of cis-Regulatory Modules at a Homeotic Gene in Drosophila

Ho, Margaret C.  W.; Johnsen, Holly; Goetz, Sara E.; Schiller, Benjamin J.; Bae, Esther; Tran, Diana A.; Shur, Andrey S.; Allen, John M.; Rau, Christoph; Bender, Welcome; Fisher, William W.; Celniker, Susan E.; Drewell, Robert A.

doi:10.1371/journal.pgen.1000709

Title: Functional Evolution of cis-Regulatory Modules at a Homeotic Gene in Drosophila

Journal Article · Fri Nov 06 00:00:00 EST 2009 · PLoS Genetics

DOI:https://doi.org/10.1371/journal.pgen.1000709· OSTI ID:1627279

Ho, Margaret C. W. ^[1]; Johnsen, Holly ^[1]; Goetz, Sara E. ^[1]; Schiller, Benjamin J. ^[1]; Bae, Esther ^[2]; Tran, Diana A. ^[1]; Shur, Andrey S. ^[1]; Allen, John M. ^[1]; Rau, Christoph ^[1]; Bender, Welcome ^[3]; Fisher, William W. ^[4]; Celniker, Susan E. ^[4]; Drewell, Robert A. ^[1]

Harvey Mudd College, Claremont, CA (United States). Biology Dept.
Western Univ. of Health Sciences, Pomona, CA (United States). College of Osteopathic Medicine of the Pacific
Harvard Medical School, Boston, MA (United States). Dept. of Biological Chemistry and Molecular Pharmacology
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Drosophila Genome Project

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH); National Science Foundation (NSF); Howard Hughes Medical Institute

Grant/Contract Number:: AC02-05CH11231; NIH-GM28630; NIH-HD54977; IOS-0845103; 520051213

OSTI ID:: 1627279

Journal Information:: PLoS Genetics, Vol. 5, Issue 11; ISSN 1553-7404

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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