skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Progressive Loss of Function in a Limb Enhancer during Snake Evolution

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1400415
Grant/Contract Number:
AC02-05CH11231
Resource Type:
Journal Article: Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 167; Journal Issue: 3; Related Information: CHORUS Timestamp: 2017-10-19 21:01:30; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English

Citation Formats

Kvon, Evgeny Z., Kamneva, Olga K., Melo, Uirá S., Barozzi, Iros, Osterwalder, Marco, Mannion, Brandon J., Tissières, Virginie, Pickle, Catherine S., Plajzer-Frick, Ingrid, Lee, Elizabeth A., Kato, Momoe, Garvin, Tyler H., Akiyama, Jennifer A., Afzal, Veena, Lopez-Rios, Javier, Rubin, Edward M., Dickel, Diane E., Pennacchio, Len A., and Visel, Axel. Progressive Loss of Function in a Limb Enhancer during Snake Evolution. United States: N. p., 2016. Web. doi:10.1016/j.cell.2016.09.028.
Kvon, Evgeny Z., Kamneva, Olga K., Melo, Uirá S., Barozzi, Iros, Osterwalder, Marco, Mannion, Brandon J., Tissières, Virginie, Pickle, Catherine S., Plajzer-Frick, Ingrid, Lee, Elizabeth A., Kato, Momoe, Garvin, Tyler H., Akiyama, Jennifer A., Afzal, Veena, Lopez-Rios, Javier, Rubin, Edward M., Dickel, Diane E., Pennacchio, Len A., & Visel, Axel. Progressive Loss of Function in a Limb Enhancer during Snake Evolution. United States. doi:10.1016/j.cell.2016.09.028.
Kvon, Evgeny Z., Kamneva, Olga K., Melo, Uirá S., Barozzi, Iros, Osterwalder, Marco, Mannion, Brandon J., Tissières, Virginie, Pickle, Catherine S., Plajzer-Frick, Ingrid, Lee, Elizabeth A., Kato, Momoe, Garvin, Tyler H., Akiyama, Jennifer A., Afzal, Veena, Lopez-Rios, Javier, Rubin, Edward M., Dickel, Diane E., Pennacchio, Len A., and Visel, Axel. 2016. "Progressive Loss of Function in a Limb Enhancer during Snake Evolution". United States. doi:10.1016/j.cell.2016.09.028.
@article{osti_1400415,
title = {Progressive Loss of Function in a Limb Enhancer during Snake Evolution},
author = {Kvon, Evgeny Z. and Kamneva, Olga K. and Melo, Uirá S. and Barozzi, Iros and Osterwalder, Marco and Mannion, Brandon J. and Tissières, Virginie and Pickle, Catherine S. and Plajzer-Frick, Ingrid and Lee, Elizabeth A. and Kato, Momoe and Garvin, Tyler H. and Akiyama, Jennifer A. and Afzal, Veena and Lopez-Rios, Javier and Rubin, Edward M. and Dickel, Diane E. and Pennacchio, Len A. and Visel, Axel},
abstractNote = {},
doi = {10.1016/j.cell.2016.09.028},
journal = {Cell},
number = 3,
volume = 167,
place = {United States},
year = 2016,
month =
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.cell.2016.09.028

Save / Share:
  • The evolution of body shape is thought to be tightly coupled to changes in regulatory sequences, but specific molecular events associated with major morphological transitions in vertebrates have remained elusive. In this paper, we identified snake-specific sequence changes within an otherwise highly conserved long-range limb enhancer of Sonic hedgehog (Shh). Transgenic mouse reporter assays revealed that the in vivo activity pattern of the enhancer is conserved across a wide range of vertebrates, including fish, but not in snakes. Genomic substitution of the mouse enhancer with its human or fish ortholog results in normal limb development. In contrast, replacement with snake orthologsmore » caused severe limb reduction. Synthetic restoration of a single transcription factor binding site lost in the snake lineage reinstated full in vivo function to the snake enhancer. Our results demonstrate changes in a regulatory sequence associated with a major body plan transition and highlight the role of enhancers in morphological evolution.« less
  • Epigenomic mapping of enhancer-associated chromatin modifications facilitates the genome-wide discovery of tissue-specific enhancers in vivo. However, reliance on single chromatin marks leads to high rates of false-positive predictions. More sophisticated, integrative methods have been described, but commonly suffer from limited accessibility to the resulting predictions and reduced biological interpretability. Here we present the Limb-Enhancer Genie (LEG), a collection of highly accurate, genome-wide predictions of enhancers in the developing limb, available through a user-friendly online interface. We predict limb enhancers using a combination of > 50 published limb-specific datasets and clusters of evolutionarily conserved transcription factor binding sites, taking advantage ofmore » the patterns observed at previously in vivo validated elements. By combining different statistical models, our approach outperforms current state-of-the-art methods and provides interpretable measures of feature importance. Our results indicate that including a previously unappreciated score that quantifies tissue-specific nuclease accessibility significantly improves prediction performance. We demonstrate the utility of our approach through in vivo validation of newly predicted elements. Moreover, we describe general features that can guide the type of datasets to include when predicting tissue-specific enhancers genome-wide, while providing an accessible resource to the general biological community and facilitating the functional interpretation of genetic studies of limb malformations.« less
  • The evolution of polar ozone observed by the Upper Atmosphere Research Satellite (UARS) Microwave Limb Sounder (MLS) is described for the northern hemisphere (NH) winters of 1991/1992, 1992/1993, and 1993/1994 and the southern hemisphere (SH) winters of 1992 and 1993. Imterannual and interhemispheric variability in polar ozone evolution are closely related to differences in the polar vortex and to the frequency, duration and strength of stratospheric sudden warmings. Ozone in the midstratospheric vortices increases during the winter, with largest increases associated with stratospheric warmings and a much larger increase in the NH than in the SH. A smaller NH increasemore » was observed in 1993/1994, when the middle stratospheric vortex was stronger. During strong stratospheric warmings in the NH, the upper stratospheric vortex may be so much eroded that it presents little barrier to poleward transport; in contrast, the SH vortex remains strong throughout the stratosphere during wintertime warmings, and ozone increases only below the mixing ratio peak, due to enhanced diabatic descent. Ozone mixing ratios decrease rapidly in the lower stratosphere in both SH late winters, as expected from chemical destruction due to enhanced reactive chlorine. The interplay between dynamics and chemistry is more complex in the NH lower stratosphere and interannual variability is greater. Evidence has previously been shown for chemical ozone destruction in the 1991/1992 and 1992/1993 winters.« less
  • We have utilized a modification of the limb bud mesenchyme micromass culture system to screen compounds that might stimulate chondrogenesis. Two compounds in the sulfoxide family (methylphenylsulfoxide and p-chlorophenyl methyl sulfoxide) were stimulatory at 10(-2) M and 10(-3) M, respectively; whereas other sulfoxides and organic solvents were not active at these concentrations. In addition, specific growth factors (basic FGF, IGF-I, IGF-II) were not chondroinductive at concentrations that are active in other cell systems. Both sulfoxide compounds stimulated cartilage nodule formation, ({sup 35}S)sulfate incorporation, and activity of the regulatory sequences of the collagen II gene. In contrast, transforming growth factor beta-1more » (10 ng/ml) stimulated sulfate incorporation but produced only a diffuse deposition of cartilage matrix and reduced the ability of the cells to utilize the regulatory sequences of the collagen II gene. The sulfoxides appear to promote the differentiation of limb bud cells to chondrocytes and thus exhibit chondroinductive activity.« less