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Natural selection on human microRNA binding sites inferred from SNP data

Abstract

A fundamental problem in biology is understanding how natural selection has shaped the evolution of gene regulation. Here we use SNP genotype data and techniques from population genetics to study an entire layer of short, cis-regulatory sites in the human genome. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally repress mRNA through cis-regulatory sites in 3′ UTRs. We show that negative selection in humans is stronger on computationally predicted conserved miRNA binding sites than on other conserved sequence motifs in 3′ UTRs, thus providing independent support for the target prediction model and explicitly demonstrating the contribution of miRNAs to darwinian fitness. Our techniques extend to nonconserved miRNA binding sites, and we estimate that 30%–50% of these are functional when the mRNA and miRNA are endogenously coexpressed. As we show that polymorphisms in predicted miRNA binding sites are likely to be deleterious, they are candidates for causal variants of human disease. We believe that our approach can be extended to studying other classes of cis-regulatory sites.

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Figure 1: SNP density in conserved miRNA sites.
Figure 2: DAF distributions in conserved miRNA sites suggests stronger negative selection compared with other conserved 7-mers in 3′ UTRs.
Figure 3: DAF distributions in nonconserved miRNA sites coexpressed with the miRNAs.

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Acknowledgements

We thank P. Andolfatto, R. Borowsky, E. Halperin, N. Hübner and M. Siegal for helpful discussions. We also thank E. van Nimwegen and R. Nielsen for critical readings of a preliminary version of the manuscript. This research was supported in part by the Howard Hughes Medical Institute grant through the Undergraduate Biological Sciences Education Program to New York University.

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Correspondence to Nikolaus Rajewsky.

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Supplementary information

Supplementary Fig. 1

Derived allele frequency distributions of Perlegen SNPs in conserved miRNA sites. (PDF 171 kb)

Supplementary Fig. 2

Derived allele frequency distributions of Perlegen SNPs in coexpressed miRNA sites. (PDF 172 kb)

Supplementary Table 1

List of conserved miRNA sites. (XLS 2778 kb)

Supplementary Table 2

List of coexpressed miRNA sites. (XLS 1851 kb)

Supplementary Table 3

List of all SNPs used in the analysis. (XLS 157 kb)

Supplementary Table 4

microRNA expression data. (PDF 202 kb)

Supplementary Methods (PDF 25 kb)

Supplementary Note (PDF 63 kb)

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Chen, K., Rajewsky, N. Natural selection on human microRNA binding sites inferred from SNP data. Nat Genet 38, 1452–1456 (2006). https://doi.org/10.1038/ng1910

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