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"The technology has increased the speed for causal gene ID by 10-fold and that’s significant. It’s really been a huge success for us."
Belinda Whittle
Head of Genomics Research, Australian Phenomics Facility (APF)
Belinda Whittle is Head of Genomics Research at the Australian Phenomics Facility (APF) located at the Australian National University in Canberra.
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Can you tell us about the APF?
The APF is a federally funded initiative established in 2004. We are a world leader in using ENU mutagenesis for discovering causative gene linkages between the mammalian genome and phenome. We are developing infrastructure that provides collections of mice with point mutations with the aim of perturbing every gene in the mouse genome. ENU, or Ethylnitrosourea, mutagenesis incorporates random point mutations, genome wide. This allows for the production of a number of genetically unique offspring from a single mutagenised male . These libraries of ENU mutagenised mice are then subjected to phenotypic screens by researchers for their key area of interest. We work with researchers from a diverse range of medical research fields ranging from early development to cancer, who have their own phenotype screen for the mice. When they find a phenovariant with a key difference, we can actually map the mutation that causes that phenotype. This is known as a forward genetics approach rather than the reverse genetics approach of producing a knockout. The ENU strategy is a much faster method and in addition, rather than knocking out the whole gene it might just disrupt a domain of a particular protein, providing a more accurate representation of human conditions.
How do you use Illumina Sequencing in this service model?
Supported by the Government Education Investment fund (EIF), the APF have developed a Next-Generation Sequencing pipeline for identification of causal mutations in mouse variant strains. Because ENU induces mutations predominantly in coding regions or splice sites, we have designed our pipeline around sequencing the exome rather than the whole genome. Since only human exome capture kits were available at the onset of this project, we collaborated with two companies to produce and test mouse exome kits that we are now running on the Illumina platform. By only sequencing the exome, we can run a lot more samples, approximately 10 times more than with the whole genome.What effect has Illumina sequencing had on your research?
We have been very happy with the Illumina technology and sequencing instruments. When we started, we chose Illumina because we had access to several machines and we had heard that they were producing quality data. We were not disappointed by the results we initially obtained and hence have continued to use Illumina as our technology of choice for our service. The use of Next-Generation Sequencing has greatly accelerated our ability to produce mouse models for human disease. Prior to next-gen sequencing, we mapped the causal mutations by traditional methods by outcrossing to a second inbred strain and then used a genome wide set of SNP markers to find linkage in the ENU variant strains. We would then Sanger sequence either candidate genes or all genes within the mapped interval. This process would take two to four years, from finding a phenotypic mutant through to identification of the causal gene. With Next Gen Seq it now takes two to four months. So the technology has increased the speed for causal gene ID by 10-fold and that's significant. It's really been a huge success for us.
Researcher Bio
At Illumina, our goal is to apply innovative technologies and revolutionary assays to the analysis of genetic variation and function, making studies possible that were not even imaginable just a few years ago. These studies will help make the realization of personalized medicine possible. With such rapid advances in technology taking place, it is mission critical to have solutions that are not only innovative, but flexible, scalable, and complete with industry-leading support and service. As a global company that places high value on collaborative interactions, rapid delivery of solutions, and prioritizing the needs of its customers, we strive to meet this challenge. Illumina's innovative, array-based solutions for DNA, RNA, and protein analysis serve as tools for disease research, drug development, and the development of molecular tests in the clinic.