Three linked variants have opposing regulatory effects on isovaleryl-CoA dehydrogenase gene expression.

Autor:	Brown EA; The Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, United States.; Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, United States., Kales S; The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, United States., Boyle MJ; The Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, United States., Vitti J; The Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, United States.; Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, United States., Kotliar D; The Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, United States.; Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, United States., Schaffner S; Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, United States., Tewhey R; The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, United States., Sabeti PC; The Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, United States.; Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, United States.; Howard Hughes Medical Institute, Harvard University, 26 Oxford Street, Cambridge, MA 02138, United States.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Jan 20; Vol. 33 (3), pp. 270-283.
DOI:	10.1093/hmg/ddad177
Abstrakt:	While genome-wide association studies (GWAS) and positive selection scans identify genomic loci driving human phenotypic diversity, functional validation is required to discover the variant(s) responsible. We dissected the IVD gene locus-which encodes the isovaleryl-CoA dehydrogenase enzyme-implicated by selection statistics, multiple GWAS, and clinical genetics as important to function and fitness. We combined luciferase assays, CRISPR/Cas9 genome-editing, massively parallel reporter assays (MPRA), and a deletion tiling MPRA strategy across regulatory loci. We identified three regulatory variants, including an indel, that may underpin GWAS signals for pulmonary fibrosis and testosterone, and that are linked on a positively selected haplotype in the Japanese population. These regulatory variants exhibit synergistic and opposing effects on IVD expression experimentally. Alleles at these variants lie on a haplotype tagged by the variant most strongly associated with IVD expression and metabolites, but with no functional evidence itself. This work demonstrates how comprehensive functional investigation and multiple technologies are needed to discover the true genetic drivers of phenotypic diversity. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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