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Study could help scientists understand how gene regulation differs from one person to the next

A study of led by scientists at the EMBL-European Bioinformatics Institute (EMBL-EBI) and the University of Cambridge has revealed the first steps of evolution in in mice. Published in the journal Cell, the research has implications for the study of differences in gene regulation between people.

  • Over the course of evolution in closely related mammals, certain clusters of transcription factors continue to work in concert, which is important for both genetic and evolutionary stability.
  • For the first time, this study shows the full extent of this cooperative stabilization in five mouse species.
  • The evolution of gene regulation is more flexible in mammals than in .

“We found an impressive amount of variation between these apparently very similar mice in terms of transcription-factor binding, which is an important indicator of gene-regulation activity,” says Paul Flicek of EMBL-EBI. “Often you’ll see a specific combination of these transcription factors acting in concert – and it was fascinating for us to see just how important these combinations are. They’re much more likely to be conserved over the course of evolution than whatever DNA sequence they might be binding to.”

The team studied gene expression in five very closely related mouse species in order to pinpoint changes at the very earliest stages of evolution. To do this, they compared the way that three transcription factors (TFs) bind to genes to control if they’re turned on or off in liver cells in the different mouse species.

“By looking at mice that are very closely related to each other, we were able to capture a snapshot of what regulatory evolution is happening,” explains Duncan Odom of the University of Cambridge. “That’s important because it’s much harder to see how something has evolved when you don’t have a clear picture of the starting point.”

Say you wanted to know how an orange tree evolved, but you could only compare it to an elm or oak. You’d have greater insight into how an orange tree evolved if you could compare it to much more closely related plants like grapefruit and lemons, which could give insight into how each came from an ancestral citrus plant. In this study, instead of comparing leaf and fruit shapes, the team looked at gene regulation in mice that had only recently diverged from one another. They demonstrated that TFs work in clusters that are conserved in order to ensure genetic and evolutionary stability.

The researchers contrasted their findings with gene-regulation data from another model organism, Drosophila, to see where the similarities lay. They found that there were a lot more differences between closely related mouse strains than there are between distantly related fruit-fly strains.

“Mammals have lots of DNA kicking around that doesn’t code for proteins, while fruit flies have relatively little. So a mouse’s regulatory wiring will just have a lot more wiggle room than a fruit fly’s,” says Paul. “That gives us a clearer picture of what we can expect to learn about mammalian genetic regulation from fruit flies.”

The study could help scientists understand how gene regulation differs from one person to the next, explaining why genes that cause disease in some people don’t have that effect in others.


Cooperativity and Rapid Evolution of Cobound Transcription Factors in Closely Related Mammals

Cell, Volume 154, Issue 3, 530-540, 1 August 2013; Copyright © 2013 Elsevier Inc. All rights reserved; 10.1016/j.cell.2013.07.007

Authors: Klara Stefflova, David Thybert, Michael D. Wilson, Ian Streeter, Jelena Aleksic, Panagiota Karagianni, Alvis Brazma, David J. Adams, Iannis Talianidis, John C. Marioni, Paul Fliceksend email, Duncan T. Odomsend

Summary: To mechanistically characterize the microevolutionary processes active in altering transcription factor (TF) binding among closely related mammals, we compared the genome-wide binding of three tissue-specific TFs that control liver gene expression in six rodents. Despite an overall fast turnover of TF binding locations between species, we identified thousands of TF regions of highly constrained TF binding intensity. Although individual mutations in bound sequence motifs can influence TF binding, most binding differences occur in the absence of nearby sequence variations. Instead, combinatorial binding was found to be significant for genetic and evolutionary stability; cobound TFs tend to disappear in concert and were sensitive to genetic knockout of partner TFs. The large, qualitative differences in genomic regions bound between closely related mammals, when contrasted with the smaller, quantitative TF binding differences among Drosophila species, illustrate how genome structure and population genetics together shape regulatory evolution.

European Molecular Biology Laboratory