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; National Centre for Indigenous Genomics; Hardip R Patel; Ira W Deveson

doi:10.1038/s41586-023-06842-7

The landscape of genomic structural variation in Indigenous Australians

Nature. 2023 Dec;624(7992):602-610. doi: 10.1038/s41586-023-06842-7. Epub 2023 Dec 13.

Authors

Andre L M Reis^{1

2

3}, Melissa Rapadas^{1

2}, Jillian M Hammond^{1

2}, Hasindu Gamaarachchi^{1

2

4}, Igor Stevanovski^{1

2}, Meutia Ayuputeri Kumaheri^{1

2}, Sanjog R Chintalaphani^{1

2

3}, Duminda S B Dissanayake^{5

6}, Owen M Siggs^{1

2

7}, Alex W Hewitt⁸, Bastien Llamas^{5

9

10

11}, Alex Brown^{5

11}, Gareth Baynam^{12

13

14}, Graham J Mann⁵, Brendan J McMorran⁵, Simon Easteal⁵, Azure Hermes⁵, Misty R Jenkins¹⁵; National Centre for Indigenous Genomics; Hardip R Patel¹⁶, Ira W Deveson^{17

18

19}

Collaborators

National Centre for Indigenous Genomics:
Glen Pearson, Yvette Roe, Janine Mohamed, Ben Murray, Lyndon Ormond-Parker, Erica Kneipp, Keith Nugent, Graham Mann

Affiliations

¹ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
² Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Darlinghurst, New South Wales, Australia.
³ Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁴ School of Computer Science and Engineering, University of New South Wales, Sydney, New South Wales, Australia.
⁵ National Centre for Indigenous Genomics, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
⁶ Institute for Applied Ecology, University of Canberra, Canberra, Australian Capital Territory, Australia.
⁷ Department of Ophthalmology, Flinders University, Bedford Park, South Australia, Australia.
⁸ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁹ Australian Centre for Ancient DNA, School of Biological Sciences and Environment Institute, University of Adelaide, Adelaide, South Australia, Australia.
¹⁰ ARC Centre of Excellence for Australian Biodiversity and Heritage, University of Adelaide, Adelaide, South Australia, Australia.
¹¹ Indigenous Genomics, Telethon Kids Institute, Adelaide, South Australia, Australia.
¹² Telethon Kids Institute and Division of Paediatrics, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.
¹³ Genetic Services of Western Australia, Western Australian Department of Health, Perth, Western Australia, Australia.
¹⁴ Western Australian Register of Developmental Anomalies, Western Australian Department of Health, Perth, Western Australia, Australia.
¹⁵ Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
¹⁶ National Centre for Indigenous Genomics, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. hardip.patel@anu.edu.au.
¹⁷ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. i.deveson@garvan.org.au.
¹⁸ Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Darlinghurst, New South Wales, Australia. i.deveson@garvan.org.au.
¹⁹ Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. i.deveson@garvan.org.au.

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 datasets^1-3. 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.

MeSH terms

Alleles
Australia / ethnology
Australian Aboriginal and Torres Strait Islander Peoples* / genetics
DNA Copy Number Variations / genetics
Datasets as Topic
Genetic Loci / genetics
Genetics, Medical
Genome, Human* / genetics
Genomic Structural Variation* / genetics
Genomics
Humans
INDEL Mutation / genetics
Interspersed Repetitive Sequences / genetics
Microsatellite Repeats / genetics

Supplementary concepts

Australians