Purifying selection on noncoding deletions of human regulatory loci detected using their cellular pleiotropy
- David W. Radke1,2,3,
- Jae Hoon Sul4,
- Daniel J. Balick1,2,3,
- Sebastian Akle1,2,3,
- Alzheimer's Disease Neuroimaging Initiative6,
- Robert C. Green2,3,5 and
- Shamil R. Sunyaev1,2,3
- 1Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA;
- 4Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California 90095, USA;
- 5Ariadne Labs, Boston, Massachusetts 02115, USA
Abstract
Genomic deletions provide a powerful loss-of-function model in noncoding regions to assess the role of purifying selection on genetic variation. Regulatory element function is characterized by nonuniform tissue and cell type activity, necessarily linking the study of fitness consequences from regulatory variants to their corresponding cellular activity. We generated a callset of deletions from genomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used deletions from The 1000 Genomes Project Consortium (1000GP) in order to examine whether purifying selection preserves noncoding sites of chromatin accessibility marked by DNase I hypersensitivity (DHS), histone modification (enhancer, transcribed, Polycomb-repressed, heterochromatin), and chromatin loop anchors. To examine this in a cellular activity-aware manner, we developed a statistical method, pleiotropy ratio score (PlyRS), which calculates a correlation-adjusted count of “cellular pleiotropy” for each noncoding base pair by analyzing shared regulatory annotations across tissues and cell types. By comparing real deletion PlyRS values to simulations in a length-matched framework and by using genomic covariates in analyses, we found that purifying selection acts to preserve both DHS and enhancer noncoding sites. However, we did not find evidence of purifying selection for noncoding transcribed, Polycomb-repressed, or heterochromatin sites beyond that of the noncoding background. Additionally, we found evidence that purifying selection is acting on chromatin loop integrity by preserving colocalized CTCF binding sites. At regions of DHS, enhancer, and CTCF within chromatin loop anchors, we found evidence that both sites of activity specific to a particular tissue or cell type and sites of cellularly pleiotropic activity are preserved by selection.
Footnotes
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↵6 Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275263.121.
- Received January 13, 2021.
- Accepted April 16, 2021.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.