Peer-Reviewed Publication
Nat Commun2025;16(1):2648.March 18, 2025Journal Article
Diverse ancestral representation improves genetic intolerance metrics.
Alexander L Han1,2, Chloe F Sands1,2, Dorota Matelska3, Jessica C Butts4,5, Vida Ravanmehr1,2, Fengyuan Hu3, Esmeralda Villavicencio Gonzalez2,6, Nicholas Katsanis7, Carlos D Bustamante7, Quanli Wang8, Slavé Petrovski9,10, Dimitrios Vitsios3, Ryan S Dhindsa11,12,13
1Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
2Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
3Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
4Department of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, TX, USA.
5Rice Neuroengineering Initiative, George R. Brown School of Engineering, Rice University, Houston, TX, USA.
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
7Galatea Bio, Inc, Miami, FL, USA.
8Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA.
9Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. slav.petrovski@astrazeneca.com.
10Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia. slav.petrovski@astrazeneca.com.
11Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. ryan.dhindsa@bcm.edu.
12Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA. ryan.dhindsa@bcm.edu.
13Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. ryan.dhindsa@bcm.edu.
Abstract
The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation-regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple a…
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