Regulators evolve faster than genes

Mutations in regulatory sequences may be the main drivers of species divergence

By | July 31, 2007

The DNA sequences that help regulate genes evolve far more quickly than the genes they control, according to a study published this week in Science. The findings suggest that evolutionary divergence between species may be driven mostly by mutations in these sequences. "You look at humans and chimps, and we're 98.5 percent identical in our gene sequences, for instance, but we're very different physically," Michael Snyder of Yale University, senior author of the study, told The Scientist. "We're suggesting that these differences between species -- and not just in mammals, but in general -- are due more to changes in gene regulation and not the genes themselves." Transcription factors turn genes on and off by binding to distinct regulatory sites along the genome. The researchers identified and compared the binding sites of two transcription factors in three closely related species of Saccharomyces yeast, using chromatin immunoprecipitation and microarray analysis. Although the three species had few differences between their gene sequences, "we found these huge differences between the gene regulatory sites," Snyder said. The two transcription factors bound to the same site in all three species just 20 and 21 percent of the time, respectively. Surprisingly, even when the DNA sequences of binding sites remained conserved across species, in many cases binding sites that worked with a transcription factor in one species did not work with that transcription factor in another. "In a sense, that's bad news" for researchers who compare conserved DNA sequences in functionally important genes between species to study evolution, Greg Wray at Duke University, who did not participate in this study, told The Scientist. Based on the current study, he said, "those approaches could miss a lot of differences between species when it comes to gene regulation." Similar findings have recently been published in mammals and in flies. "The nice thing about this study in yeast is that the environment is completely controlled," Ernest Fraenkel at the Massachusetts Institute of Technology, senior author on the work in mammals, told The Scientist. "Comparing mice and humans, there was always the question as to how much the very different environments they live in might have caused the differences in transcriptional regulation we saw." Altogether, these findings in yeast, mammals and flies "are pointing to a pretty widespread phenomenon," Leonid Kruglyak at Princeton University, who co-authored a commentary on the new findings, told The Scientist. Snyder estimated that these gene regulatory elements evolve roughly two orders of magnitude more quickly than gene sequences. That might be because mutations at those sites would likely only raise or lower gene expression, whereas mutations in genes would probably have more dramatic effects. The fact that some binding sites had conserved sequences between species but different functions could have a multitude of explanations, Kruglyak conjectured. For instance, he said, species differences in how the binding sites are folded up in the genome could make them accessible or inaccessible, or other proteins may interact with transcription factors in a sequence-specific manner. Also, Snyder noted, binding sites often work in combinations. So even if one site is conserved, if the other is lost, both no longer work. Although the current study focused on differences between species, said Snyder, these mutations could also lead to variation between individuals within a species, potentially broadening the results further to areas such as human disease. Charles Q. Choi Links within this article: A.R. Borneman et al. "Divergence of transcription factor binding sites across related yeast species." Science, published online August 10, 2007. K. Hopkin, "Think big, dress casual," The Scientist, November 8, 2004. M.L. Phillips, "Transcription factors help distinguish humans," The Scientist, March 9, 2006. J.M. Perkel, "Chromatin immunoprecipitation," The Scientist, May 1, 2006. J.M. Perkel, "In search of microarray standards," The Scientist, April 1, 2006. Greg Wray D.T. Odom et al., "Tissue-specific transcriptional regulation has diverged significantly between human and mouse," Nature Genetics, June 2007. A.M. Moses et al., "Large-scale turnover of functional transcription factor binding sites in Drosophila," PLoS Computational Biology, October 2006. Ernest Fraenkel
Leonid Kruglyak
L. Kruglyak and D.L. Stern, "An embarrassment of switches," Science, August 10, 2007.

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