Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci

Victor Lopez Soriano, Alfredo Dueñas Rey, Rajarshi Mukherjee, Frauke Coppieters, Miriam Bauwens, Andy Willaert and Elfride De Baere ()
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Victor Lopez Soriano: Ghent University
Alfredo Dueñas Rey: Ghent University
Rajarshi Mukherjee: St James’s University Hospital
Frauke Coppieters: Ghent University
Miriam Bauwens: Ghent University
Andy Willaert: Ghent University
Elfride De Baere: Ghent University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specific cis-regulators of developmental gene expression. Here, we characterize a set of UCNEs as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data reveals 594 genes under potential cis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidate cis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England reveals 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.

Date: 2024
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DOI: 10.1038/s41467-024-45381-1

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