Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci
Lopez Soriano, V.; Duenas Rey, A.; Mukherjee, R.; Genomics England Research Consortium, ; Coppieters, F.; Bauwens, M.; Willaert, A.; De Baere, E.
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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 characterized a set of UCNEs as candidate CREs (cCREs) during retinal development and evaluated 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 revealed 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 revealed 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.
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