Reis, A.L.M.Rapadas, M.Hammond, J.M.Gamaarachchi, H.Stevanovski, I.Ayuputeri Kumaheri, M.Chintalaphani, S.R.Dissanayake, D.S.B.Siggs, O.M.Hewitt, A.W.Llamas, B.Brown, A.Baynam, G.Mann, G.J.McMorran, B.J.Easteal, S.Hermes, A.Jenkins, M.R.National Centre for Indigenous Genomics,Patel, H.R.et al.2024-04-082024-04-082023Nature, 2023; 624(7992):602-6100028-08361476-4687https://hdl.handle.net/2440/140525Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets1-3. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50  b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.en© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Genetic variation; Medical genomics; Next-generation sequencing; Structural variationHumansGenetics, MedicalGenomicsInterspersed Repetitive SequencesMicrosatellite RepeatsAllelesGenome, HumanAustraliaINDEL MutationGenetic LociGenomic Structural VariationDNA Copy Number VariationsDatasets as TopicAustralian Aboriginal and Torres Strait Islander PeoplesJournal article10.1038/s41586-023-06842-72024-04-08678814Llamas, B. [0000-0002-5550-9176]Brown, A. [0000-0003-2112-3918]