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The noncoding human genome and the future of personalised medicine

  • Philip Cowie (a1), Elizabeth A. Hay (a1) and Alasdair MacKenzie (a1)

Abstract

Non-coding cis-regulatory sequences act as the ‘eyes’ of the genome and their role is to perceive, organise and relay cellular communication information to RNA polymerase II at gene promoters. The evolution of these sequences, that include enhancers, silencers, insulators and promoters, has progressed in multicellular organisms to the extent that cis-regulatory sequences make up as much as 10% of the human genome. Parallel evidence suggests that 75% of polymorphisms associated with heritable disease occur within predicted cis-regulatory sequences that effectively alter the ‘perception’ of cis-regulatory sequences or render them blind to cell communication cues. Cis-regulatory sequences also act as major functional targets of epigenetic modification thus representing an important conduit through which changes in DNA-methylation affects disease susceptibility. The objectives of the current review are (1) to describe what has been learned about identifying and characterising cis-regulatory sequences since the sequencing of the human genome; (2) to discuss their role in interpreting cell signalling pathways pathways; and (3) outline how this role may be altered by polymorphisms and epigenetic changes. We argue that the importance of the cis-regulatory genome for the interpretation of cellular communication pathways cannot be overstated and understanding its role in health and disease will be critical for the future development of personalised medicine.

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Corresponding author

* Corresponding author: Alasdair MacKenzie, University of Aberdeen, School of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail alasdair.mackenzie@abdn.ac.uk

References

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Maurano, M. T., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099): 1190-5.
Graur, D., et al. (2013). On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol 5(3): 578-90.
Murgatroyd, C. and Spengler, D. (2012). Epigenetic programming of the HPA axis: early life decides. Stress 14(6): 581.
MacKenzie, A., Hing, B. and Davidson, S. (2013). Exploring the effects of polymorphisms on cis-regulatory signal transduction response. Trends Mol Med 19(2): 99-107.

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The noncoding human genome and the future of personalised medicine

  • Philip Cowie (a1), Elizabeth A. Hay (a1) and Alasdair MacKenzie (a1)

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