GoKawiilReal-world impact: From rare diseases to population genetics and molecular biology
AlphaGenome Atlas provides a high-resolution, global view of the genome. These large-scale predictions become most useful when applied to targeted research questions. By translating this data into actionable biological insights, our academic partners are already uncovering links between genetic variation and disease.
Understanding unsolved rare diseases. A major hurdle in understanding rare diseases is the daunting task of pinpointing the few causal variants hidden among thousands of candidates. In collaboration with the GREGoR Consortium, researchers applied the AVI score to prioritize these needle-in-a-haystack genetic variants for unsolved rare disease research. When Laura Covill and Anne O’Donnell-Luria from the Broad Institute and their colleagues used the AVI score to prioritize variants, driving a rare disease, that were overlooked in previous research, the team discovered a variant affecting a gene called DNM1, which is strongly linked to epileptic encephalopathy.
Crucially, the AlphaGenome predictions underlying the AVI score showed exactly how the variant functioned: it created an incorrect splice site (a mistake in the cell’s genetic instructions) that led to an abnormal extension of the resulting protein. Experimental screens validated the research prediction and found nearby variants with similar effects, showing that Atlas is a powerful tool for understanding impactful genomic variation.
Mapping rare variants associated with protein levels and complex traits. Moving beyond individual rare disease research, AlphaGenome Atlas can help uncover the genetic architecture of common traits in the general population. Identifying which rare, non-coding variants are associated with a specific trait or disease is notoriously difficult because the sheer volume of harmless genetic changes creates a statistical 'background noise'.
To test how AlphaGenome Atlas can improve our ability to find non-coding variants affecting human traits, Gareth Hawkes, a Medical Research Council fellow at the University of Exeter, applied AlphaGenome Atlas to whole-genome data from over 54,000 UK Biobank participants, which made these elusive signals more obvious. By grouping rare variants based on their predicted molecular effects, Hawkes uncovered 22% more non-coding genetic associations, which would otherwise have not been detectable in the statistical noise. This let Hawkes pinpoint specific regulatory variants driving the abundance of critical proteins circulating in the human body, including PLA2G7 (linked to aging) and EGLN1 (a vital cellular oxygen sensor).
Taking this approach even further, Hawkes used AlphaGenome Atlas to look at how hundreds of millions of non-coding variants in the UK Biobank might be linked to body mass index. By focusing on the 1% of non-coding variants which Atlas predicts to be most impactful, he identified 19 genetic regions, which could help direct the next stage of targeted research into this trait.
Identifying the regulatory ‘words’ of the genome. Atlas can also be used to identify which recurring short sequences, or motifs, are driving different molecular processes in different cell types for different genes. These motifs can provide key clues, such as locating binding sites of transcription factors (proteins that turn genes on or off) and providing additional interpretation of non-coding variants. Julia Zeitlinger and Melanie Weilert at the Stowers Institute for Medical Research used this resource, for example, to categorize which transcription factors only affect the accessibility of DNA versus which ones are also able to turn genes on and off.
Accelerating genomic discovery
With AlphaGenome Atlas we are creating new layers of information that will help further our understanding of the human genetic code. We hope that this will be a valuable resource for scientists, but we also view it as a baseline rather than an endpoint. As our AI models like AlphaGenome improve, our maps of the entire human genome will become increasingly comprehensive and precise.
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