The landscape of genomic structural variation in Indigenous Australians

Andre L. M. Reis, Melissa Rapadas, Jillian M. Hammond, Hasindu Gamaarachchi, Igor Stevanovski, Meutia Ayuputeri Kumaheri, Sanjog R. Chintalaphani, Duminda S. B. Dissanayake, Owen M. Siggs, Alex W. Hewitt, Bastien Llamas, Alex Brown, Gareth Baynam, Graham J. Mann, Brendan J. McMorran, Simon Easteal, Azure Hermes, Misty R. Jenkins, Hardip R. Patel () and Ira W. Deveson ()
Additional contact information
Andre L. M. Reis: Garvan Institute of Medical Research
Melissa Rapadas: Garvan Institute of Medical Research
Jillian M. Hammond: Garvan Institute of Medical Research
Hasindu Gamaarachchi: Garvan Institute of Medical Research
Igor Stevanovski: Garvan Institute of Medical Research
Meutia Ayuputeri Kumaheri: Garvan Institute of Medical Research
Sanjog R. Chintalaphani: Garvan Institute of Medical Research
Duminda S. B. Dissanayake: Australian National University
Owen M. Siggs: Garvan Institute of Medical Research
Alex W. Hewitt: University of Tasmania
Bastien Llamas: Australian National University
Alex Brown: Australian National University
Gareth Baynam: University of Western Australia
Graham J. Mann: Australian National University
Brendan J. McMorran: Australian National University
Simon Easteal: Australian National University
Azure Hermes: Australian National University
Misty R. Jenkins: The Walter and Eliza Hall Institute of Medical Research
Hardip R. Patel: Australian National University
Ira W. Deveson: Garvan Institute of Medical Research

Nature, 2023, vol. 624, issue 7992, 602-610

Abstract: Abstract Indigenous 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.

Date: 2023
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DOI: 10.1038/s41586-023-06842-7

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