Below are some examples of computational projects that are part supported by the VLSCI
1. Dr Alicia Oshlack - formerly Walter and Eliza Hall Institute, now Murdoch Childrens Research Institute
New high throughput technologies have become available in the last few years that are revolutionising biology by allowing labs to routinely sequence billions of bases of DNA in a single experiment. These next-generation sequencing technologies are not only being applied to sequence genomes but also transcriptomes.
Our work focuses on using sequencing data to understand gene regulation and functional genetics. In particular we have been modelling biases in the data and proposing new analysis techniques to take these biases into account. We have discovered that the ability to detect differential expression between samples depends on the length of a gene. We have developed a statistical and computational approach to take this into account when performing gene set testing. However we have evidence that this is not the only bias present in the data.
2. Professor Ray Norton - Monash Institute of Pharmaceutical Sciences, Monash University
Merozoite surface protein 2 (MSP2) is an integral membrane protein anchored by a C-terminal GPI moiety to the surface of the P. falciparum merozoite. MSP2 appears to be essential for parasite viability, and a vaccine containing two allelic forms of MSP2 is being developed.
Although MSP2 is highly disordered in solution, its conformation on the merozoite surface has not been determined. Knowledge of this structure will provide insight into which regions of the protein are accessible to the immune system. As these regions are likely to be disordered, they have the potential to adopt different conformations bound to different antibodies; many of these interactions are likely to be low affinity, and thus less effective against the parasite. Determining the structures of key epitopes bound to different antibodies, and correlating bound conformation with affinity, will provide a basis for engineering analogues of MSP2 that favour the tightly binding conformations and thus represent better vaccine candidates.
Key aims are to:
1. Determine the structures of the N-terminal region and full-length MSP2 in a membrane environment.
2. Use this structural knowledge to clarify the state of MSP2 on the surface of the merozoite, including whether it forms oligomers stabilized by intermolecular beta-strand interactions, similar to those that stabilize amyloid-like fibrils formed by recombinant MSP2.
3. Define the implications of the disordered structure of MSP2 for its interaction with the host immune system and for possible mechanisms of immune evasion.
The project will involve computer simulation of proteins using high-performance, parallel computing systems (eg VLSCI, VPAC, NCI). The project will provide training in parallel computing and molecular modelling, as well as drug design methods. The students will carry out molecular dynamics simulations using Gromacs or Namd. Molecular docking studies will be performed using Glide.
3. Professor Ian Campbell & Dr Jason Li - VBCRC Cancer Genetics Laboratory and Bioinformatics Core - Peter MacCallum Cancer Centre
The VBCRC Cancer Genetics laboratory is undertaking full exome (coding regions of genes) sequencing of individuals who have had breast cancer and who have a strong family history suggesting they carry a gene variant that predisposes them to the disease.
While many of these individuals are likely to carry small base-pair variants that current algorithms are able to detect, it is likely that some will carry larger insertions or deletions of genetic material. There are currently no good methods to identify these from the sequencing data at present. Therefore we would like to develop a methodology for finding these “indels” using our data.
4.Dr Hamish Meffin & Dr Chi Luu- National ICT Australia, VIC Lab
The University of Melbourne is part of an Australian consortium building a high resolution bionic eye. Bionic eyes are capable of restoring partial vision to the blind by electrically stimulating surviving neurons in the retina. In order to optimize the visual resolution provided by the device, it is critical that the array of stimulating electrodes is in close contact with surface of the retina. This requires knowing how the retinal surface is shaped. However the precise shape of the retina and its inter-patient variability have not been systematically measured and characterised.
In this project the student will use optical coherence tomography (a standard, non-invasive and painless technique) to obtain retinal images for patients with retinal pathologies. These images will allow the student to analyse the shape of the retinal surface at a resolution of around a 10μm. A large cohort of patients will be examined to determine the inter-patient variability in retinal shape. The outcomes of the study will guide the design of the electrode array to ensure it lies in close contact with the retina.
