dc.contributor |
Háskóli Íslands |
dc.contributor |
University of Iceland |
dc.contributor.author |
Boukas, Leandros |
dc.contributor.author |
Havrilla, James M. |
dc.contributor.author |
Hickey, Peter F. |
dc.contributor.author |
Quinlan, Aaron R. |
dc.contributor.author |
Bjornsson, Hans |
dc.contributor.author |
Hansen, Kasper D. |
dc.date.accessioned |
2020-05-08T10:08:56Z |
dc.date.available |
2020-05-08T10:08:56Z |
dc.date.issued |
2019-03-11 |
dc.identifier.citation |
Boukas, L. T., Bjornsson, H. D., Hansen, K. M., Havrilla, J. R., Quinlan, A. F., & Hickey, P. (2019). Coexpression patterns define epigenetic regulators associated with neurological dysfunction. Genome Research, 29(4), 532-542. |
dc.identifier.issn |
1088-9051 |
dc.identifier.issn |
1549-5469 (eISSN) |
dc.identifier.uri |
https://hdl.handle.net/20.500.11815/1787 |
dc.description |
Publisher's version (útgefin grein) |
dc.description.abstract |
Coding variants in epigenetic regulators are emerging as causes of neurological dysfunction and cancer. However, a comprehensive effort to identify disease candidates within the human epigenetic machinery (EM) has not been performed; it is unclear whether features exist that distinguish between variation-intolerant and variation-tolerant EM genes, and between EM genes associated with neurological dysfunction versus cancer. Here, we rigorously define 295 genes with a direct role in epigenetic regulation (writers, erasers, remodelers, readers). Systematic exploration of these genes reveals that although individual enzymatic functions are always mutually exclusive, readers often also exhibit enzymatic activity (dual-function EM genes). We find that the majority of EM genes are very intolerant to loss-of-function variation, even when compared to the dosage sensitive transcription factors, and we identify 102 novel EM disease candidates. We show that this variation intolerance is driven by the protein domains encoding the epigenetic function, suggesting that disease is caused by a perturbed chromatin state. We then describe a large subset of EM genes that are coexpressed within multiple tissues. This subset is almost exclusively populated by extremely variation-intolerant genes and shows enrichment for dual-function EM genes. It is also highly enriched for genes associated with neurological dysfunction, even when accounting for dosage sensitivity, but not for cancer-associated EM genes. Finally, we show that regulatory regions near epigenetic regulators are genetically important for common neurological traits. These findings prioritize novel disease candidate EM genes and suggest that this coexpression plays a functional role in normal neurological homeostasis. |
dc.description.sponsorship |
This research was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award numbers R01GM121459 and DP5OD017877. L.B. was supported by the Maryland Genetics, Epidemiology and Medicine (MD-GEM) training program, funded by the Burroughs-Wellcome Fund. H.T.B. received support from the Louma G. Foundation. L.B., H.T.B., and K.D.H. received support from a Discovery Award from Johns Hopkins University. J.M.H. and A.R.Q. were supported by National Institutes of Health awards from the National Human Genome Research Institute (R01HG006693 and R01HG009141) and the National Institute of General Medical Sciences (R01GM124355). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. |
dc.format.extent |
532-542 |
dc.language.iso |
en |
dc.publisher |
Cold Spring Harbor Laboratory |
dc.relation.ispartofseries |
Genome Research;29(4) |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Genetics |
dc.subject |
Neurological dysfunction |
dc.subject |
Cancer |
dc.subject |
Erfðafræði |
dc.subject |
Krabbamein |
dc.subject |
Erfðarannsóknir |
dc.subject |
Taugasjúkdómar |
dc.title |
Coexpression patterns define epigenetic regulators associated with neurological dysfunction |
dc.type |
info:eu-repo/semantics/article |
dcterms.license |
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
dc.description.version |
Peer Reviewed |
dc.identifier.journal |
Genome Research |
dc.identifier.doi |
10.1101/gr.239442.118 |
dc.relation.url |
https://syndication.highwire.org/content/doi/10.1101/gr.239442.118 |
dc.contributor.department |
Læknadeild (HÍ) |
dc.contributor.department |
Faculty of Medicine (UI) |
dc.contributor.school |
Heilbrigðisvísindasvið (HÍ) |
dc.contributor.school |
School of Health Sciences (UI) |