Year: 2026
Type: preprint
Abstract: Understanding the functional impact of archaic hominin introgression remains challenging due to the poor representation of global introgression in publicly available genomics resources. Sequence-to-function models can predict the effects of any possible variant in the human genome and may fill this gap. Here, we used AlphaGenome to predict the effects of 144,139 introgressed SNPs segregating in present-day individuals of Papuan genetic ancestry. AlphaGenome’s chromatin accessibility predictions recapitulate experimentally observed effects, but gene expression performs no better than chance. Predictions correlate more strongly with an independent reporter assay of single-variant activity than with the same variants’ effects in live cells, indicating that AlphaGenome captures the regulatory potential of individual variants more reliably. Predictions carry tissue specificity, allowing us to predict specific tissues potentially impacted by introgressed haplotypes. We identify genes, including JAK1 and TAB2, that are associated with haplotypes that contain an excess of variants predicted by AlphaGenome to have large impacts on chromatin accessibility. Finally, we highlight the challenges and limitations associated with using sequence-to-function models for introgressed variant effect prediction, and show that while AlphaGenome’s chromatin accessibility predictions can aid in prioritising candidate functional regions, expression predictions and the assignment of variants to target genes remain as open challenges.
Institutions: The University of Melbourne, St Vincents Institute of Medical Research, Walter and Eliza Hall Institute of Medical Research, University of Tartu, University of Papua New Guinea, The University of Queensland, Centre National de la Recherche Scientifique, Université Toulouse III - Paul Sabatier, Institut National Polytechnique de Toulouse, Institut de Recherche pour le Développement, Centre de Recherche sur la Biodiversité et l'Environnement, Université de Toulouse, University of Auckland
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Royal Society, Royal Society Te Apārangi, Agence Nationale de la Recherche, Eesti Teadusagentuur, State Government of Victoria, Région Occitanie Pyrénées-Méditerranée, Medical Research Council, Australian Research Council, National Health and Medical Research Council, European Regional Development Fund, Marsden Fund
Awards: G1190173965, G1901855984, Toulouse Initiative for Research’s Impact on Society, Impact of change in diet on the coevolution genome-microbiome in Oceanians, G400255850, G4008762420, Using the 3D genome to predict and treat leukaemia, G6857983970, The genetic and phenotypic impact of archaic introgression in the Major Histocompatibility Complex, Unravelling the contributions of Denisovan DNA to the peoples of Oceania, G8951737883
OpenAlex ID: W7204990137