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MBE Advance Access published online on December 3, 2007
Molecular Biology and Evolution, doi:10.1093/molbev/msm268
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© The Author 2007. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Large-scale Appearance of Ultraconserved Elements in Tetrapod Genomes and Slowdown of the Molecular Clock

Stuart Stephen*, Michael Pheasant*, Igor V. Makunin* and John S. Mattick

ARC Special Research Centre for Functional and Applied Genomics and ARC Centre of Excellence in Bioinformatics, Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia

Corresponding author: John S. Mattick, Telephone: 61 7 3346 2079, Fax: 61 7 3346 2111, Email: j.mattick{at}imb.uq.edu.au

Received for publication July 3, 2007. Revision received November 1, 2007. Accepted for publication November 28, 2007.

Mammalian genomes contain millions of highly conserved non-coding sequences, many of which are regulatory. The most extreme examples are the 481 ultraconserved elements (UCEs) which are identical over at least 200 bp in human, mouse and rat and show 96% identity with chicken, which diverged ~310 Myr ago. If the substitution rate in UCEs remained constant, these elements should also be present with a high level of identity in fish (~450 Myr), but this is not the case, suggesting that many appeared in the amniotes or tetrapods, or that the molecular clock has slowed down in these lineages, or both. Taking advantage of the availability of multiple genomes, we identified 13,736 UCEs in the human genome that are identical over at least 100 bp in at least 3 out of 5 placental mammals, including 2,189 sequences over at least 200bp, thereby greatly expanding the repertoire of known UCEs, and investigated the evolution of these sequences in opossum, chicken, frog, and fish. We conclude that there was a massive genome-wide acquisition and expansion of UCEs during tetrapod and then amniote evolution, accompanied by a slowdown of the molecular clock, particularly in the amniotes, a process consistent with their functional exaptation in these lineages. The majority of tetrapod-specific UCEs are non-coding and associated with genes involved in regulation of transcription and development. In contrast, fish genomes contain relatively few UCEs, the majority of which are common to all bony vertebrates. These elements are different from other conserved non-coding elements, and appear to be important regulatory innovations that became fixed following the emergence of vertebrates from the sea to the land.

Key Words: ultraconserved elements • exaptation • molecular clock

* These authors contributed equally to this work.


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