Names of investigators
Jenefer M Blackwell, Timo Lassmann, Sarra E Jamieson, Denise Anderson
Project information
In this project we are using whole exome sequencing (WES) (i.e. protein coding and adjacent regulatory sequences) to identify novel variants that may be associated with severe ear and renal disease phenotypes in Aboriginal Australians. The data from this whole exome sequencing also provided the first reference panel of genetic variation in an Australian Aboriginal population that can be used to support other health-based research projects, as well as the diagnosis of rare diseases in Aboriginal children. We originally provided a catalogue of variants called after sequencing the exomes of 72 Aboriginal individuals to a depth of 20X coverage in ~80% of the sequenced nucleotides. In that catalogue we determined 320,976 single nucleotide variants (SNVs) and 47,313 insertions/deletions using the Genome Analysis Toolkit. We had previously genotyped a subset of the Aboriginal individuals (70/72) using the Illumina Omni2.5 BeadChip platform and found ~99% concordance at overlapping sites, which suggests high quality variant detection. We compared our SNVs to six publicly available variant databases, such as the 1000 genomes and the ExAC project databases, and 70,115 of our SNVs did not overlap any of the single nucleotide polymorphic sites in all the databases. That is, these variants are novel in this Australian Aboriginal population. This data set, which is deposited in the European Genome Phenome Archive and available for health-based studies through application to a Data Access Committee, provides a useful reference for genomic studies on Aboriginal Australians. Note: as part of further analysis of Aboriginal Australian WES data we have updated this original catalogue of variants
In 2016 we focused on using this dataset to identify variants associated with both severe otitis media in Aboriginal children, and with type 2 diabetes and end stage renal disease in Aboriginal adults. In children with severe otitis media we have observed enrichment of rare functional variants in genes that encode proteins that make up primary cilia. Malfunction of ciliated epithelium lining the upper respiratory tract leads to persistent secretion retention and suppurative infection in the middle ear, nose and facial sinuses. Publication of this work is in preparation. In adults with type 2 diabetes and end stage renal disease, we have identified a rare functional variant in the ARSA (aryl sulphatase A) gene that is at higher frequency in the Aboriginal population and is associated with higher creatinine estimated glomerular filtration rates (eGFR).
Plain language summary
Extreme susceptibility to runny ears in children and end stage renal disease in adults are major health issues for Australian Aboriginal communities. Our research is designed to determine whether these extreme manifestations of disease are associated with rare or novel genetic variants in a Western Australian Aboriginal population, in the hope that this might provide leads for improved therapeutic interventions.
Funders of the project
NHMRC
External collaborators
Prof Heather Cordell, Newcastle University, UK
Clinical Prof Harvey L Coates, SPACH, PMH and UWA
Dr Michaela Fakiola, Institute of Molecular Genetics, Milan, Italy