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Adaptive evolution of non-coding DNA in Drosophila


A large fraction of eukaryotic genomes consists of DNA that is not translated into protein sequence, and little is known about its functional significance. Here I show that several classes of non-coding DNA in Drosophila are evolving considerably slower than synonymous sites, and yet show an excess of between-species divergence relative to polymorphism when compared with synonymous sites. The former is a hallmark of selective constraint, but the latter is a signature of adaptive evolution, resembling general patterns of protein evolution in Drosophila1,2. I estimate that about 40–70% of nucleotides in intergenic regions, untranslated portions of mature mRNAs (UTRs) and most intronic DNA are evolutionarily constrained relative to synonymous sites. However, I also use an extension to the McDonald–Kreitman test3 to show that a substantial fraction of the nucleotide divergence in these regions was driven to fixation by positive selection (about 20% for most intronic and intergenic DNA, and 60% for UTRs). On the basis of these observations, I suggest that a large fraction of the non-translated genome is functionally important and subject to both purifying selection and adaptive evolution. These results imply that, although positive selection is clearly an important facet of protein evolution, adaptive changes to non-coding DNA might have been considerably more common in the evolution of D. melanogaster.

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The author thanks D. Bachtrog for extensive comments on the manuscript and help with data quality issues, C. Bustamante and K. Thornton for providing code, and B. Ballard for Zimbabwe fly lines. P. Haddrill and K. Thornton assisted in designing primers for distal intergenic and coding regions, respectively. Thanks to B. Fischman for technical help, A. Betancourt, A. Kondrashov, A. Poon, D. Presgraves, M. Przeworski and S. Wright for critical comments on the manuscript, and L. Chao and J. Huelsenbeck for advice. Thanks also to the Washington University Genome Sequencing Center for providing unpublished D. simulans sequences. This work was funded in part by a research grant from the Biotechnology and Biological Sciences Research Council (UK) to P.A. The author is supported by an Alfred P. Sloan Fellowship in Molecular and Computational Biology.

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Correspondence to Peter Andolfatto.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The author declares no competing financial interests.

Supplementary information

Supplementary Notes S1

Regions surveyed in this study. (PDF 157 kb)

Supplementary Notes S2

Assumptions of the McDonald-Kreitman test. (PDF 229 kb)

Supplementary Notes S3

Estimates and confidence limits of α and 2Nes. (PDF 91 kb)

Supplementary Notes S4

Estimating the rate of adaptation. (PDF 84 kb)

Supplementary Notes S5

Adjacent base contexts and rates of divergence. (PDF 45 kb)

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Further reading

Figure 1: Mean Tajima's D values for coding and non-coding DNA.
Figure 2: Quantifying adaptive divergence and selection intensity.


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