Abstract
Our genomes influence nearly every aspect of human biology—from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations.
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Acknowledgements
This work was supported by the NIH NHGRI IGVF Program (UM1HG011966, UM1HG011969, UM1HG011972, UM1HG011989, UM1HG011996, UM1HG012003, UM1HG012010, UM1HG012053, UM1HG011986, UM1HG012076, UM1HG012077, U01HG011952, U01HG011967, U01HG012009, U01HG012022, U01HG012039, U01HG012064, U01HG012069, U01HG012041, U01HG012047, U01HG012051, U01HG012059, U01HG012079, U01HG012103, U24HG012012, U24HG012070), NIH NCI (R01CA197774), and the Novo Nordisk Foundation (NNF21SA0072102). Artwork in Figs. 1–3 were created by SciStories and V. Yeaung. We thank members of the IGVF External Consultants Panel (G. Bourque, P. Mali, J. Cho, B. Engelhardt and O. Troyanskaya) for critical feedback on the manuscript.
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J.M.E., H.A.L. and H. Singh co-led the Writing Group. J.M.E., H.A.L., H. Singh, L. M. Starita, G.C.H., H. Carter, N. Sahni, T.E.R., X. Lin, Y. Li, N.V.M., M.H.C., B.C.H. and A.M. wrote initial text based on input from principal investigators, the Writing Group, and Working Group and Focus Group co-chairs. J.M.E., A.P.B. and J. Ryu developed figures. All authors contributed to developing the vision and goals of the IGVF Consortium, outlining the project, and editing the manuscript. The role of the NHGRI Program Management in the preparation of this paper was limited to coordination and scientific management of the IGVF Consortium.
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R.D.S. has been a consultant for Leadiant Biosciences, Mirum Pharmaceuticals, PTC Therapeutics and Travere. He has received honoraria from Medscape and is an employee and shareholder of PreventionGenetics, part of Exact Sciences. B.P.K. is a co-inventor on patents and patent applications that describe genome engineering technologies, and is on the scientific advisory board of Acrigen Biosciences, Life Edit Therapeutics and Prime Medicine. The other authors declare no competing interests.
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IGVF Consortium. Deciphering the impact of genomic variation on function. Nature 633, 47–57 (2024). https://doi.org/10.1038/s41586-024-07510-0
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DOI: https://doi.org/10.1038/s41586-024-07510-0
