Regulatory divergence modifies limb length between mammals

  1. Chris J. Cretekos1,2,
  2. Ying Wang1,
  3. Eric D. Green3,
  4. NISC Comparative Sequencing Program3,
  5. James F. Martin4,
  6. John J. Rasweiler IV5, and
  7. Richard R. Behringer1,6
  1. 1 Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston 77030, Texas, USA;
  2. 2 Department of Biological Sciences, Idaho State University, Pocatello, Idaho 83209, USA;
  3. 3 Genome Technology Branch and National Institutes of Health Intramural Sequencing Center (NISC), National Human Genome Research Institute, Bethesda, Maryland 20892, USA;
  4. 4 Alkek Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA;
  5. 5 Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA

Abstract

Natural selection acts on variation within populations, resulting in modified organ morphology, physiology, and ultimately the formation of new species. Although variation in orthologous proteins can contribute to these modifications, differences in DNA sequences regulating gene expression may be a primary source of variation. We replaced a limb-specific transcriptional enhancer of the mouse Prx1 locus with the orthologous sequence from a bat. Prx1 expression directed by the bat enhancer results in elevated transcript levels in developing forelimb bones and forelimbs that are significantly longer than controls because of endochondral bone formation alterations. Surprisingly, deletion of the mouse Prx1 limb enhancer results in normal forelimb length and Prx1 expression, revealing regulatory redundancy. These findings suggest that mutations accumulating in pre-existing noncoding regulatory sequences within a population are a source of variation for the evolution of morphological differences between species and that cis-regulatory redundancy may facilitate accumulation of such mutations.

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