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Nunez-Iglesias J.,FlyEM Project | Nunez-Iglesias J.,Life science Computation Center | Kennedy R.,FlyEM Project | Kennedy R.,University of Pennsylvania | And 3 more authors.
Frontiers in Neuroinformatics | Year: 2014

The aim in high-resolution connectomics is to reconstruct complete neuronal connectivity in a tissue. Currently, the only technology capable of resolving the smallest neuronal processes is electron microscopy (EM). Thus, a common approach to network reconstruction is to perform (error-prone) automatic segmentation of EM images, followed by manual proofreading by experts to fix errors. We have developed an algorithm and software library to not only improve the accuracy of the initial automatic segmentation, but also point out the image coordinates where it is likely to have made errors. Our software, called gala (graph-based active learning of agglomeration), improves the state of the art in agglomerative image segmentation. It is implemented in Python and makes extensive use of the scientific Python stack (numpy, scipy, networkx, scikit-learn, scikit-image, and others). We present here the software architecture of the gala library, and discuss several designs that we consider would be generally useful for other segmentation packages. We also discuss the current limitations of the gala library and how we intend to address them. © 2014 Nunez-Iglesias, Kennedy, Plaza, Chakraborty and Katz.


Thompson E.R.,Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory | Doyle M.A.,Peter MacCallum Cancer Center | Ryland G.L.,Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory | Ryland G.L.,Monash Institute of Medical Research | And 17 more authors.
PLoS Genetics | Year: 2012

Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families. © 2012 Thompson et al.


Powell D.R.,Monash University | Powell D.R.,Life science Computation Center | Seemann T.,Monash University | Seemann T.,Life science Computation Center
Bioinformatics | Year: 2013

Velvet is a popular open-source de novo genome assembly software tool, which is run from the Unix command line. Most of the problems experienced by new users of Velvet revolve around constructing syntactically and semantically correct command lines, getting input files into acceptable formats and assessing the output. Here, we present Velvet Assembler Graphical User Environment (VAGUE), a multi-platform graphical front-end for Velvet. VAGUE aims to make sequence assembly accessible to a wider audience and to facilitate better usage amongst existing users of Velvet. © 2012 The Author. Published by Oxford University Press. All rights reserved.


Dominguez D J.F.,Monash University | Egan G.F.,Monash University | Egan G.F.,Life science Computation Center | Egan G.F.,University of Melbourne | And 8 more authors.
PLoS ONE | Year: 2013

IMAGE-HD is an Australian based multi-modal longitudinal magnetic resonance imaging (MRI) study in premanifest and early symptomatic Huntington's disease (pre-HD and symp-HD, respectively). In this investigation we sought to determine the sensitivity of imaging methods to detect macrostructural (volume) and microstructural (diffusivity) longitudinal change in HD. We used a 3T MRI scanner to acquire T1 and diffusion weighted images at baseline and 18 months in 31 pre-HD, 31 symp-HD and 29 controls. Volume was measured across the whole brain, and volume and diffusion measures were ascertained for caudate and putamen. We observed a range of significant volumetric and, for the first time, diffusion changes over 18 months in both pre-HD and symp-HD, relative to controls, detectable at the brain-wide level (volume change in grey and white matter) and in caudate and putamen (volume and diffusivity change). Importantly, longitudinal volume change in the caudate was the only measure that discriminated between groups across all stages of disease: far from diagnosis (>15 years), close to diagnosis (<15 years) and after diagnosis. Of the two diffusion metrics (mean diffusivity, MD; fractional anisotropy, FA), only longitudinal FA change was sensitive to group differences, but only after diagnosis. These findings further confirm caudate atrophy as one of the most sensitive and early biomarkers of neurodegeneration in HD. They also highlight that different tissue properties have varying schedules in their ability to discriminate between groups along disease progression and may therefore inform biomarker selection for future therapeutic interventions. © 2013 Domínguez D et al.


Poudel G.R.,Monash University | Poudel G.R.,Life science Computation Center | Stout J.C.,Monash University | Dominguez D. J.F.,Monash University | And 7 more authors.
Neurobiology of Disease | Year: 2015

Objective: To quantify 18-month changes in white matter microstructure in premanifest (pre-HD) and symptomatic Huntington's disease (symp-HD). To investigate baseline clinical, cognitive and motor symptoms that are predictive of white matter microstructural change over 18. months. Method: Diffusion tensor imaging (DTI) data were analyzed for 28 pre-HD, 25 symp-HD, and 27 controls scanned at baseline and after 18. months. Unbiased tract-based spatial statistics (TBSS) methods were used to identify longitudinal changes in fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) of white matter. Stepwise linear regression models were used to identify baseline clinical, cognitive, and motor measures that are predictive of longitudinal diffusion changes. Results: Symp-HD compared to controls showed 18-month reductions in FA in the corpus callosum and cingulum white matter. Symp-HD compared to pre-HD showed increased RD in the corpus callosum and striatal projection pathways. FA in the body, genu, and splenium of the corpus callosum was significantly associated with a baseline clinical motor measure (Unified Huntington's Disease Rating Scale: total motor scores: UHDRS-TMS) across both HD groups. This measure was also the only independent predictor of longitudinal decline in FA in all parts of the corpus callosum across both HD groups. Conclusions: We provide direct evidence of longitudinal decline in white matter microstructure in symp-HD. Although pre-HD did not show longitudinal change, clinical symptoms and motor function predicted white matter microstructural changes for all gene positive subjects. These findings suggest that loss of axonal integrity is an early hallmark of neurodegenerative changes which are clinically relevant. © 2014 Elsevier Inc.


Seemann T.,Monash University | Seemann T.,Life science Computation Center
Bioinformatics | Year: 2014

The multiplex capability and high yield of current day DNA-sequencing instruments has made bacterial whole genome sequencing a routine affair. The subsequent de novo assembly of reads into contigs has been well addressed. The final step of annotating all relevant genomic features on those contigs can be achieved slowly using existing web- and email-based systems, but these are not applicable for sensitive data or integrating into computational pipelines. Here we introduce Prokka, a command line software tool to fully annotate a draft bacterial genome in about 10 min on a typical desktop computer. It produces standards-compliant output files for further analysis or viewing in genome browsers. © 2014 The Author 2014.


Poudel G.R.,Monash University | Poudel G.R.,Life science Computation Center | Egan G.F.,Monash University | Egan G.F.,Life science Computation Center | And 4 more authors.
Journal of Psychiatry and Neuroscience | Year: 2014

Background: Functional neural impairments have been documented in people with symptomatic Huntington disease (symp-HD) and in premanifest gene carriers (pre-HD). This study aimed to characterize synchrony in resting state cerebral networks in both pre-HD and symp-HD populations and to determine its association with disease burden and neurocognitive functions. Methods: We acquired functional magnetic resonance imaging (fMRI) data from pre-HD, symp-HD and healthy control participants. The fMRI data were analyzed using multisubject independent component analysis and dual regression. We compared networks of interest among the groups using a nonparametric permutation method and correcting for multiple comparisons. Results: Our study included 25 people in the pre-HD, 23 in the symp-HD and 18 in the healthy control groups. Compared with the control group, the pre-HD group showed decreased synchrony in the sensorimotor and dorsal attention networks; decreased level of synchrony in the sensorimotor network was associated with poorer motor performance. Compared with the control group, the symp-HD group showed widespread reduction in synchrony in the dorsal attention network, which was associated with poorer cognitive performance. The posterior putamen and superior parietal cortex were functionally disconnected from the frontal executive network in the symp-HD compared with control and pre-HD groups. Furthermore, the left frontoparietal network showed areas of increased synchrony in the symp-HD compared with the pre-HD group. Limitations: We could not directly correct for influence of autonomic changes (e.g., heart rate) and respiration on resting state synchronization. Conclusion: Our findings suggest that aberrant synchrony in the sensorimotor and dorsal attention networks may serve as an early signature of neural change in pre-HD individuals. The altered synchrony in dorsal attention, frontoparietal and corticostriatal networks may contribute to the development of clinical symptoms in people with Huntington disease. © 2014 Canadian Medical Association.


Spitz G.,Monash University | Spitz G.,Epworth Hospital | Maller J.J.,Monash University | Maller J.J.,Alfred Hospital | And 6 more authors.
Journal of Neurotrauma | Year: 2013

The development and utilization of newer neuroimaging modalities provides the capability to more accurately detect the extent of pathology after TBI. The current study examined the ability of susceptibility-weighted imaging (SWI) to detect lesions after TBI as well as the relationship to subsequent clinical outcome. The performance of SWI was compared to that of fluid-attenuated inversion recovery (FLAIR). This study comprised 79 individuals with mild-To-severe TBI, 38 of whom completed neuropsychological tests of attention, working memory, processing speed, memory, and executive functions. SWI was found to quantify a greater lesion volume over the entire brain, specifically in frontal, central, limbic, subcortical gray, and parietal brain regions, than did FLAIR. Moreover, SWI was able to identify TBI-related lesions in almost one third of patients for whom FLAIR was unable to detect any lesions. Greater overall SWI volume, as well as frontal SWI volume, was found to relate to the severity of TBI. Conversely, no association was found between FLAIR lesion volume and injury severity. In addition, there was some evidence that higher lesion volume, for both SWI and FLAIR, were associated with poorer memory as well as processing speed impairment. This study suggests that SWI may provide additional sensitivity in the detection of lesions after TBI. Consequently, this imaging sequence may provide a more accurate representation of the severity of individuals' injuries and their subsequent neuropsychological outcomes. © Copyright 2013, Mary Ann Liebert, Inc. 2013.


Wong N.C.,Murdoch Childrens Research Institute | Wong N.C.,Ludwig Institute for Cancer Research | Ng J.,Murdoch Childrens Research Institute | Hall N.E.,La Trobe University | And 7 more authors.
Genomics | Year: 2013

Illumina Infinium Human Methylation (HM) BeadChips are widely used for measuring genome-scale DNA methylation, particularly in relation to epigenome-wide association studies (EWAS) studies. The methylation profile of human samples can be assessed accurately and reproducibly using the HM27 BeadChip (27,578 CpG sites) or its successor, the HM450 BeadChip (482,421 CpG sites). To date no mouse equivalent has been developed, greatly hindering the application of this methodology to the wide range of valuable murine models of disease and development currently in existence. We found 1308 and 13,715 probes from HM27 and HM450 BeadChip respectively, uniquely matched the bisulfite converted reference mouse genome (mm9). We demonstrate reproducible measurements of DNA methylation at these probes in a range of mouse tissue samples and in a murine cell line model of acute myeloid leukaemia. In the absence of a mouse counterpart, the Infinium Human Methylation BeadChip arrays have utility for methylation profiling in non-human species. © 2013 Elsevier Inc.


Yeoh L.M.,University of Melbourne | Goodman C.D.,University of Melbourne | Hall N.E.,La Trobe University | Hall N.E.,Life science Computation Center | And 3 more authors.
Nucleic Acids Research | Year: 2015

Single genes are often subject to alternative splicing, which generates alternative mature mRNAs. This phenomenon is widespread in animals, and observed in over 90% of human genes. Recent data suggest it may also be common in Apicomplexa. These parasites have small genomes, and economy of DNA is evolutionarily favoured in this phylum. We investigated the mechanism of alternative splicing in Toxoplasma gondii, and have identified and localized TgSR3, a homologue of ASF/SF2 (alternative-splicing factor/splicing factor 2, a serine-arginine-rich, or SR protein) to a subnuclear compartment. In addition, we conditionally overexpressed this protein, which was deleterious to growth. qRT-PCR was used to confirm perturbation of splicing in a known alternatively-spliced gene. We performed high-throughput RNA-seq to determine the extent of splicing modulated by this protein. Current RNA-seq algorithms are poorly suited to compact parasite genomes, and hence we complemented existing tools by writing a new program, GeneGuillotine, that addresses this deficiency by segregating overlapping reads into distinct genes. In order to identify the extent of alternative splicing, we released another program, JunctionJuror, that detects changes in intron junctions. Using this program, we identified about 2000 genes that were constitutively alternatively spliced in T. gondii. Overexpressing the splice regulator TgSR3 perturbed alternative splicing in over 1000 genes. © 2015 The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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