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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It is very likely that most miRNAs have many, perhaps as many as a few thousand, mRNA targets.
“We also find that neurons express multiple miRNAs and it is very likely that most miRNAs have many, perhaps as many as a few thousand, mRNA targets [1,2,6,56].”
From MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system (2007) · cites this paper as [56]
Cites
The International HapMap Project
†The International HapMap Consortium, Genotyping centres: Baylor College of Medicine and ParAllele BioScience, Gibbs, R. A., Belmont, J. W., Hardenbol, P., Willis, T. D., Yu, F., Chinese HapMap Consortium, Yang, H., Ch'ang, L.-Y., et al. (2003) · Nature · doi:10.1038/nature02168 · Cited by 6,057 · see citing works
Silencing of microRNAs in vivo with ‘antagomirs’
Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K. G., Tuschl, T., Manoharan, M., & Stoffel, M. (2005) · Nature · doi:10.1038/nature04303 · Cited by 3,949 · see citing works
Self-citationThe Widespread Impact of Mammalian MicroRNAs on mRNA Repression and Evolution
Farh, K. K.-H., Grimson, A., Jan, C., Lewis, B. P., Johnston, W. K., Lim, L. P., Burge, C. B., & Bartel, D. P. (2005) · Science · doi:10.1126/science.1121158 · Cited by 1,484 · see citing works
Clop, A., Marcq, F., Takeda, H., Pirottin, D., Tordoir, X., Bibé, B., Bouix, J., Caiment, F., Elsen, J.-M., Eychenne, F., et al. (2006) · Nature Genetics · doi:10.1038/ng1810 · Cited by 1,260 · see citing works
Stark, A., Brennecke, J., Bushati, N., Russell, R. B., & Cohen, S. M. (2005) · Cell · doi:10.1016/j.cell.2005.11.023 · Cited by 1,080 · see citing works
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Brennan, C. W., Verhaak, R. G. W., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., Zheng, S., Chakravarty, D., Sanborn, J. Z., Berman, S. H., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.034 · Cited by 5,016 · see citing works
Self-citationThe evolution of gene regulation by transcription factors and microRNAs
Chen, K., & Rajewsky, N. (2007) · Nature Reviews Genetics · doi:10.1038/nrg1990 · Cited by 1,547 · see citing works
Self-citationKapsimali, M., Kloosterman, W. P., de Bruijn, E., Rosa, F., Plasterk, R. H., & Wilson, S. W. (2007) · Genome Biology · doi:10.1186/gb-2007-8-8-r173 · Cited by 376 · see citing works
MicroRNAs targeting Nicastrin regulate Aβ production and are affected by target site polymorphisms
Delay, C., Dorval, V., Fok, A., Grenier-Boley, B., Lambert, J.-C., Hsiung, G.-Y., & Hébert, S. S. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00067 · Cited by 28 · see citing works
- Authors
- Chen, K., & Rajewsky, N.
- Venue
- Nature Genetics
- Published
- 2006-10-29
- Volume
- 38
- Issue
- 12
- Pages
- 1452-1456
- ISSN
- 1061-4036
- 1546-1718
- Cited by
- 391
- References
- 5
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
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