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Published online on April 26, 2007, 10.1073/pnas.0611223104

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Evolution
Thousands of human mobile element fragments undergo strong purifying selection near developmental genes

( exaptation | genome evolution | transposon | vertebrate cis-regulation )

Craig B. Lowe *, Gill Bejerano {dagger}{ddagger}, and David Haussler *{sect}

*Center for Biomolecular Science and Engineering and {sect}Howard Hughes Medical Institute, University of California, Santa Cruz, CA 95064; and {dagger}Departments of Developmental Biology and Computer Science, Stanford University, Stanford, CA 94305

Edited by Susan R. Wessler, University of Georgia, Athens, GA, and approved March 20, 2007 (received for review December 18, 2006)

At least 5% of the human genome predating the mammalian radiation is thought to have evolved under purifying selection, yet protein-coding and related untranslated exons occupy at most 2% of the genome. Thus, the majority of conserved and, by extension, functional sequence in the human genome seems to be nonexonic. Recent work has highlighted a handful of cases where mobile element insertions have resulted in the introduction of novel conserved nonexonic elements. Here, we present a genome-wide survey of 10,402 constrained nonexonic elements in the human genome that have all been deposited by characterized mobile elements. These repeat instances have been under strong purifying selection since at least the boreoeutherian ancestor (100 Mya). They are most often located in gene deserts and show a strong preference for residing closest to genes involved in development and transcription regulation. In particular, constrained nonexonic elements with clear repetitive origins are located near genes involved in cell adhesion, including all characterized cellular members of the reelin-signaling pathway. Overall, we find that mobile elements have contributed at least 5.5% of all constrained nonexonic elements unique to mammals, suggesting that mobile elements may have played a larger role than previously recognized in shaping and specializing the landscape of gene regulation during mammalian evolution.

Author contributions: C.B.L., G.B., and D.H. designed research; C.B.L. and G.B. performed research; C.B.L. and G.B. analyzed data; and C.B.L., G.B., and D.H. wrote the paper.

The authors declare no conflict of interest.

{ddagger}To whom correspondence should be addressed.

Gill Bejerano, E-mail: bejerano{at}stanford.edu

www.pnas.org/cgi/doi/10.1073/pnas.0611223104
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