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Letter

Evolutionary turnover of mammalian transcription start sites

¹ Genome Exploration Research Group, RIKEN Genomic Sciences Centre (GSC), RIKEN Yokohama Institute, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan; ² Genome Science Laboratory, Discovery and Research Institute, RIKEN Wako Institute, Wako, Saitama, 351-0198, Japan; ³ Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia; ⁴ Computational Biology Unit, Bergen Center for Computational Science, University of Bergen, HIB, N-5008 Bergen, Norway

Alignments of homologous genomic sequences are widely used to identify functional genetic elements and study their evolution. Most studies tacitly equate homology of functional elements with sequence homology. This assumption is violated by the phenomenon of turnover, in which functionally equivalent elements reside at locations that are nonorthologous at the sequence level. Turnover has been demonstrated previously for transcriptionfactor-binding sites. Here, we show that transcription start sites of equivalent genes do not always reside at equivalent locations in the human and mouse genomes. We also identify two types of partial turnover, illustrating evolutionary pathways that could lead to complete turnover. These findings suggest that the signals encoding transcription start sites are highly flexible and evolvable, and have cautionary implications for the use of sequence-level conservation to detect gene regulatory elements.

⁶ Corresponding author.

E-mail rgscerg{at}gsc.riken.jp; fax 81-45-5039216.

[Supplemental material is available online at www.genome.org.]

Article published online before print. Article is online at http://www.genome. org/cgi/doi/10.1101/gr.5031006

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