ORCID Profile
0000-0003-3066-701X
Current Organisations
Massachusetts Institute of Technology
,
University of Sussex
,
University of Bristol
,
Australian National University
,
London School of Hygiene and Tropical Medicine
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Publications
Projecting Movement, Union, Synergy, Interplay and Cultural-collaboration Across the Silk Road (and Beyond)
Publisher: Elsevier BV
Date: 2017
DOI: 10.2139/SSRN.3398783
Genotyping of whole genome amplified reduced representation libraries reveals a cryptic population of Culicoides brevitarsis in the Northern Territory, Australia
Publisher: Springer Science and Business Media LLC
Date: 30-09-2016
DOI: 10.1186/S12864-016-3124-1
Abstract: The advent of genotyping by Next Generation Sequencing has enabled rapid discovery of thousands of single nucleotide polymorphism (SNP) markers and high throughput genotyping of large populations at an affordable cost. Genotyping by sequencing (GBS), a reduced representation library sequencing method, allows highly multiplexed sequencing of genomic subsets. This method has limitations for small organisms with low amounts of genomic DNA, such as the bluetongue virus (BTV) vectors, Culicoides midges. This study employed the GBS method to isolate SNP markers de novo from whole genome lified Culicoides brevitarsis genomic DNA. The in iduals were collected from regions representing two different Australian patterns of BTV strain distribution: the Northern Territory (NT) and the east coast. We isolated 8145 SNPs using GBS. Phylogenetic analysis conducted using the filtered 3263 SNPs revealed the presence of a distinct C. brevitarsis sub-population in the NT and this was confirmed by analysis of mitochondrial DNA. Two loci showed a very strong signal for selection and were unique to the NT population. Bayesian analysis with STRUCTURE indicated a possible two-population cluster. The results suggest that genotyping vectors with high density markers in combination with biological and environmental data is useful. However, more extensive s ling over a wider spatial and temporal range is needed. The presence of sub-structure in populations and loci under natural selection indicates the need for further investigation of the role of vectors in shaping the two Australian systems of BTV transmission. The described workflow is transferable to genotyping of small, non-model organisms, including arthropod vectors of pathogens of economic and medical importance.
Models for Potentially Biased Evidence in Meta-Analysis using Empirically Based Priors
Publisher: Oxford University Press (OUP)
Date: 08-07-2008
DOI: 10.1111/J.1467-985X.2008.00548.X
Abstract: We present models for the combined analysis of evidence from randomized controlled trials categorized as being at either low or high risk of bias due to a flaw in their conduct. We formulate a bias model that incorporates between-study and between-meta-analysis heterogeneity in bias, and uncertainty in overall mean bias. We obtain algebraic expressions for the posterior distribution of the bias-adjusted treatment effect, which provide limiting values for the information that can be obtained from studies at high risk of bias. The parameters of the bias model can be estimated from collections of previously published meta-analyses. We explore alternative models for such data, and alternative methods for introducing prior information on the bias parameters into a new meta-analysis. Results from an illustrative ex le show that the bias-adjusted treatment effect estimates are sensitive to the way in which the meta-epidemiological data are modelled, but that using point estimates for bias parameters provides an adequate approximation to using a full joint prior distribution. A sensitivity analysis shows that the gain in precision from including studies at high risk of bias is likely to be low, however numerous or large their size, and that little is gained by incorporating such studies, unless the information from studies at low risk of bias is limited. We discuss approaches that might increase the value of including studies at high risk of bias, and the acceptability of the methods in the evaluation of health care interventions.
RareSH2B3coding variants identified in lupus patients impair B cell tolerance and predispose to autoimmunity
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2023
DOI: 10.1101/2023.04.27.538529
Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3 - a negative regulator of cytokine and growth factor receptor signaling – harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, most SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk. Zhang et al . reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.
Population and phylogenomic decomposition via genotyping-by-sequencing in Australian Pelargonium
Publisher: Wiley
Date: 05-2016
DOI: 10.1111/MEC.13584
Abstract: Species delimitation has seen a paradigm shift as increasing accessibility of genomic-scale data enables separation of lineages with convergent morphological traits and the merging of recently erged ecotypes that have distinguishing characteristics. We inferred the process of lineage formation among Australian species in the widespread and highly variable genus Pelargonium by combining phylogenomic and population genomic analyses along with breeding system studies and character analysis. Phylogenomic analysis and population genetic clustering supported seven of the eight currently described species but provided little evidence for differences in genetic structure within the most widely distributed group that containing P. australe. In contrast, morphometric analysis detected three deep lineages within Australian Pelargonium with P. australe consisting of five previously unrecognized entities occupying separate geographic ranges. The genomic approach enabled elucidation of parallel evolution in some traits formerly used to delineate species, as well as identification of ecotypic morphological differentiation within recognized species. Highly variable morphology and trait convergence each contribute to the discordance between phylogenomic relationships and morphological taxonomy. Data suggest that genetic ergence among species within the Australian Pelargonium may result from allopatric speciation while morphological differentiation within and among species may be more strongly driven by environmental differences.
Dynamic Interplay of Innate and Adaptive Immunity During Sterile Retinal Inflammation: Insights From the Transcriptome.
Publisher: Frontiers Media SA
Date: 18-07-2018
Correction to: Tissue and cell-specific transcriptomes in cotton reveal the subtleties of gene regulation underlying the diversity of plant secondary cell walls
Publisher: Springer Science and Business Media LLC
Date: 17-04-2018
Projecting Movement, Union, Synergy, Interplay & Cultural-collaboration across the Silk Road (& beyond)
Publisher: Center for Open Science
Date: 04-06-2019
Abstract: Interplay between culture and globalisation, and in particular the musical connection between the two has been forwarded as an illustrative, hopeful, and harmonious ex le of how humanity as a global race may enhance mutual understanding and cross-cultural appreciation of its many erse groups. In particular, this study aims to investigate the global community-building behind the relatively recent Silkroad initiative, and to what degree has its aims been achieved, and how.
Small RNA changes en route to distinct cellular states of induced pluripotency
Publisher: Springer Science and Business Media LLC
Date: 10-12-2014
DOI: 10.1038/NCOMMS6522
Abstract: MicroRNAs (miRNAs) are critical to somatic cell reprogramming into induced pluripotent stem cells (iPSCs), however, exactly how miRNA expression changes support the transition to pluripotency requires further investigation. Here we use a murine secondary reprogramming system to s le cellular trajectories towards iPSCs or a novel pluripotent 'F-class' state and perform small RNA sequencing. We detect sweeping changes in an early and a late wave, revealing that distinct miRNA milieus characterize alternate states of pluripotency. miRNA isoform expression is common but surprisingly varies little between cell states. Referencing other omic data sets generated in parallel, we find that miRNA expression is changed through transcriptional and post-transcriptional mechanisms. miRNA transcription is commonly regulated by dynamic histone modification, while DNA methylation/demethylation consolidates these changes at multiple loci. Importantly, our results suggest that a novel subset of distinctly expressed miRNAs supports pluripotency in the F-class state, substituting for miRNAs that serve such roles in iPSCs.
Whole Exome Sequencing of Extreme Morbid Obesity Patients: Translational Implications for Obesity and Related Disorders
Publisher: MDPI AG
Date: 25-08-2014
DOI: 10.3390/GENES5030709
The PHF21B gene is associated with major depression and modulates the stress response
Publisher: Springer Science and Business Media LLC
Date: 25-10-2017
DOI: 10.1038/MP.2016.174
Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-01-2019
DOI: 10.1212/WNL.0000000000006952
Abstract: To identify novel genetic associations with white matter hyperintensities (WMH). We performed a genome-wide association meta-analysis of WMH volumes in 11,226 in iduals, including 8,429 population-based in iduals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 in iduals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013] p = 1.6 × 10 −8 ), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent s le (overall p value, 2.4 × 10 −9 ). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03–1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00–1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020 β [SE] = 0.106 [0.016] p = 1.2 × 10 −11 and rs7596872 β [SE] = 0.143 [0.021] p = 3.4 × 10 −12 ). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.
StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritise potentially pathogenic genetic variation
Publisher: Cold Spring Harbor Laboratory
Date: 02-12-2021
DOI: 10.1101/2021.11.28.470298
Abstract: Missense mutations that change protein stability are strongly associated with human inherited genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel algorithm to prioritise variants predicted to strongly destabilise essential proteins, available as both a standalone software package and a web-based tool. We demonstrate the utility of this tool by showing that at values of the Stability Sort Z-score above 1.6, pathogenic, protein-destabilising variants from ClinVar are detected at a 58% enrichment, over and above the destabilising (but presumably non-pathogenic) variation already present in the HapMap NA12878 genome. StabilitySort is available as both a web service ( 130.56.244.113/StabilitySort/ ) and can be deployed as a standalone system ( aaron/StabilitySort ). Dan.Andrews@anu.edu.au
Isolation by distance and isolation by environment contribute to population differentiation in Protea repens (Proteaceae L.), a widespread South African species
Publisher: Wiley
Date: 05-2017
DOI: 10.3732/AJB.1600232
Abstract: The Cape Floristic Region (CFR) of South Africa is renowned for its botanical ersity, but the evolutionary origins of this ersity remain controversial. Both neutral and adaptive processes have been implicated in driving ersification, but population‐level studies of plants in the CFR are rare. Here, we investigate the limits to gene flow and potential environmental drivers of selection in Protea repens L. (Proteaceae L.), a widespread CFR species. We s led 19 populations across the range of P. repens and used genotyping by sequencing to identify 2066 polymorphic loci in 663 in iduals. We used a Bayesian F ST outlier analysis to identify single‐nucleotide polymorphisms (SNPs) marking genomic regions that may be under selection we used those SNPs to identify potential drivers of selection and excluded them from analyses of gene flow and genetic structure. A pattern of isolation by distance suggested limited gene flow between nearby populations. The populations of P. repens fell naturally into two or three groupings, which corresponded to an east‐west split. Differences in rainfall seasonality contributed to ersification in highly ergent loci, as do barriers to gene flow that have been identified in other species. The strong pattern of isolation by distance is in contrast to the findings in the only other widespread species in the CFR that has been similarly studied, while the effects of rainfall seasonality are consistent with well‐known patterns. Assessing the generality of these results will require investigations of other CFR species.
Recurrent miscalling of missense variation from short-read genome sequence data
Publisher: Springer Science and Business Media LLC
Date: 07-2019
APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease
Publisher: Springer Science and Business Media LLC
Date: 12-2016
DOI: 10.1038/MP.2015.177
StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritize potentially pathogenic genetic variation
Publisher: Oxford University Press (OUP)
Date: 08-07-2022
DOI: 10.1093/BIOINFORMATICS/BTAC465
Abstract: Missense mutations that change protein stability are strongly associated with human genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel tool to prioritize variants predicted to cause strong instability in essential proteins. We show that by filtering by ΔΔG values and then prioritizing by StabilitySort Z-scores, we are able to more accurately discriminate pathogenic, protein-destabilizing mutations from population variation, compared with other mutation effect predictors. StabilitySort is available as a web service (www.stabilitysort.org), as a data download for integration with other tools (ownload) or can be deployed as a standalone system from source code (aaron/StabilitySort). Supplementary data are available at Bioinformatics online.
The importance of replicating genomic analyses to verify phylogenetic signal for recently evolved lineages
Publisher: Wiley
Date: 04-07-2016
DOI: 10.1111/MEC.13708
Abstract: Genomewide SNP data generated by nontargeted methods such as RAD and GBS are increasingly being used in phylogenetic and phylogeographic analyses. When these methods are used in the absence of a reference genome, however, little is known about the locations and evolution of the SNPs. In using such data to address phylogenetic questions, researchers risk drawing false conclusions, particularly if a representative number of SNPs is not obtained. Here, we empirically test the robustness of phylogenetic inference based on SNP data for closely related lineages. We conducted a genomewide analysis of 75 712 SNPs, generated via GBS, of southern bull-kelp (Durvillaea). Durvillaea chathamensis co-occurs with D. antarctica on Chatham Island, but the two species have previously been found to be so genetically similar that the status of the former has been questioned. Our results show that D. chathamensis, which differs from D. antarctica ecologically as well as morphologically, is indeed a reproductively isolated species. Furthermore, our replicated analyses show that D. chathamensis cannot be reliably distinguished phylogenetically from closely related D. antarctica using subsets (ranging in size from 400 to 10 000 sites) of the 40 912 parsimony-informative SNPs in our data set and that bootstrap values alone can give misleading impressions of the strength of phylogenetic inferences. These results highlight the importance of independently replicating SNP analyses to verify that phylogenetic inferences based on nontargeted SNP data are robust. Our study also demonstrates that modern genomic approaches can be used to identify cases of recent or incipient speciation that traditional approaches (e.g. Sanger sequencing of a few loci) may be unable to detect or resolve.
Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren’s syndrome
Publisher: Springer Science and Business Media LLC
Date: 02-06-2015
Dichloroacetate prevents cisplatin-induced nephrotoxicity without compromising cisplatin anticancer properties
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-03-2016
Abstract: Cisplatin is an effective anticancer drug however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin.
Species trees from consensus single nucleotide polymorphism (SNP) data: Testing phylogenetic approaches with simulated and empirical data
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.YMPEV.2017.07.018
Abstract: Datasets of hundreds or thousands of SNPs (Single Nucleotide Polymorphisms) from multiple in iduals per species are increasingly used to study population structure, species delimitation and shallow phylogenetics. The principal software tool to infer species or population trees from SNP data is currently the BEAST template SNAPP which uses a Bayesian coalescent analysis. However, it is computationally extremely demanding and tolerates only small amounts of missing data. We used simulated and empirical SNPs from plants (Australian Craspedia, Asteraceae, and Pelargonium, Geraniaceae) to compare species trees produced (1) by SNAPP, (2) using SVD quartets, and (3) using Bayesian and parsimony analysis with several different approaches to summarising data from multiple s les into one set of traits per species. Our aims were to explore the impact of tree topology and missing data on the results, and to test which data summarising and analyses approaches would best approximate the results obtained from SNAPP for empirical data. SVD quartets retrieved the correct topology from simulated data, as did SNAPP except in the case of a very unbalanced phylogeny. Both methods failed to retrieve the correct topology when large amounts of data were missing. Bayesian analysis of species level summary data scoring the two alleles of each SNP as independent characters and parsimony analysis of data scoring each SNP as one character produced trees with branch length distributions closest to the true trees on which SNPs were simulated. For empirical data, Bayesian inference and Dollo parsimony analysis of data scored allele-wise produced phylogenies most congruent with the results of SNAPP. In the case of study groups ergent enough for missing data to be phylogenetically informative (because of additional mutations preventing lification of genomic fragments or bioinformatic establishment of homology), scoring of SNP data as a presence/absence matrix irrespective of allele content might be an additional option. As this depends on s ling across species being reasonably even and a random distribution of non-informative instances of missing data, however, further exploration of this approach is needed. Properly chosen data summary approaches to inferring species trees from SNP data may represent a potential alternative to currently available in idual-level coalescent analyses especially for quick data exploration and when dealing with computationally demanding or patchy datasets.
FluoMEP: A new genotyping method combining the advantages of randomly amplified polymorphic DNA and amplified fragment length polymorphism
Publisher: Wiley
Date: 04-2007
Increased burden of rare variants in genes of the endosomal Toll-like receptor pathway in patients with systemic lupus erythematosus
Publisher: SAGE Publications
Date: 16-07-2021
DOI: 10.1177/09612033211033979
Abstract: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls. 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF 0.005), uncommon (MAF 0.005–0.02), and common (MAF .02). This was compared to the results for 65 randomly selected genes. Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, in iduals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants. Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.
Systems-guided forward genetic screen reveals a critical role of the replication stress response protein ETAA1 in T cell clonal expansion
Publisher: Proceedings of the National Academy of Sciences
Date: 12-06-2017
Abstract: T cells are required for control of many intracellular infections, and a critical component of T cell immunity is the proliferative expansion of effector T cells upon stimulation. Using a forward-based genetic screen, we identify the mouse Etaa1 gene as critically important for T cell proliferative expansion after vaccination and during infection. Consistent with recent findings that ETAA1 prevents DNA damage during proliferation, our data demonstrate elevated DNA damage within Etaa1 -deficient effector T cells, which likely leads to cell death. This phenotype is restricted to effector T cell proliferation, with T cell development and other immune parameters remaining normal. Thus, ETAA1 may represent a novel drug target to selectively suppress pathological T cell responses in transplantation or autoimmunity.
Cross validation of pooling/resampling GWAS using the WTCCC data
Publisher: Herbert Publications PVT LTD
Date: 2015
T-dependent B cell responses toPlasmodiuminduce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein
Publisher: Cold Spring Harbor Laboratory
Date: 15-02-2017
DOI: 10.1101/108746
Abstract: The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to analyze the binding of a murine neutralizing antibody to Plasmodium falciparum CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies. This repeating pattern allows multiple weak interactions of single F AB domains to accumulate and yield a complex with a dissociation constant in the low nM range. Because the CSP protein can potentially cross-link multiple B cell receptors (BCRs) we hypothesized that the B cell response might be T cell independent. However, while there was a modest response in mice deficient in T cell help, the bulk of the response was T cell dependent. By sequencing the BCRs of CSP-repeat specific B cells in inbred mice we found that these cells underwent somatic hypermutation and affinity maturation indicative of a T-dependent response. Last, we found that the BCR repertoire of responding B cells was limited suggesting that the structural simplicity of the repeat may limit the breadth of the immune response. Vaccines aim to protect by inducing the immune system to make molecules called antibodies that can recognize molecules on the surface of invading pathogens. In the case of malaria, our most advanced vaccine candidates aim to promote the production of antibodies that recognize the circumsporozoite protein (CSP) molecule on the surface of the invasive parasite stage called the sporozoite. In this report we use X-ray crystallography to determine the structure of CSP-binding antibodies at the atomic level. We use other techniques such as isothermal titration calorimetry and structural modeling to examine how this antibody interacts with the CSP molecule. Strikingly, we found that each CSP molecule could bind 6 antibodies. This finding has implications for the immune response and may explain why high titers of antibody are needed for protection. Moreover, because the structure of the CSP repeat is quite simple we determined that the number of different kinds of antibodies that could bind this molecule are quite small. However a high avidity interaction between those antibodies and CSP can result from a process called affinity maturation that allows the body to learn how to make improved antibodies specific for pathogen molecules. These data show that while it is challenging for the immune system to recognize and neutralize CSP, it should be possible to generate viable vaccines targeting this molecule.
Genome-wide SNPs reveal fine-scale differentiation among wingless alpine stonefly populations and introgression between winged and wingless forms
Publisher: Wiley
Date: 10-12-2016
DOI: 10.1111/EVO.12826
Abstract: Insect flight loss is a repeated phenomenon in alpine habitats, where wing reduction is thought to enhance local recruitment and increase fecundity. One predicted consequence of flight loss is reduced dispersal ability, which should lead to population genetic differentiation and perhaps ultimately to speciation. Using a dataset of 15,123 SNP loci, we present comparative analyses of fine-scale population structure in codistributed Zelandoperla stonefly species, across three parallel altitudinal transects in New Zealand's Rock and Pillar mountain range. We find that winged populations (altitude 200-500 m Zelandoperla decorata) show no genetic structuring within or among streams, suggesting substantial dispersal mediated by flight. By contrast, wingless populations (Zelandoperla fenestrata altitude 200-1100 m) exhibit distinct genetic clusters associated with each stream, and additional evidence of isolation by distance within streams. Our data support the hypothesis that wing-loss can initiate ersification in alpine insect populations over small spatial scales. The often deep phylogenetic placement of lowland Z. fenestrata within their stream-specific clades suggests the possibility of independent alpine colonization events for each stream. Additionally, the detection of winged, interspecific hybrid in iduals raises the intriguing possibility that a previously flightless lineage could reacquire flight via introgression.
Transcriptome Profiling of Melaleuca quinquenervia Challenged by Myrtle Rust Reveals Differences in Defense Responses Among Resistant Individuals
Publisher: Scientific Societies
Date: 04-2018
DOI: 10.1094/PHYTO-09-17-0307-R
Abstract: Plants have developed complex defense mechanisms to protect themselves against pathogens. A wide-host-range fungus, Austropuccinia psidii, which has caused severe damage to ecosystems and plantations worldwide, is a major threat to Australian ecosystems dominated by members of the family Myrtaceae. In particular, the east coast wetland foundation tree species Melaleuca quinquenervia, appears to be variably susceptible to this pathogen. Understanding the molecular basis of host resistance would enable better management of this rust disease. We identified resistant and susceptible in iduals of M. quinquenervia and explored their differential gene expression in order to discover the molecular basis of resistance against A. psidii. Rust screening of germplasm showed a varying degree of response, with fully resistant to highly susceptible in iduals. We used transcriptome profiling in s les collected before and at 5 days postinoculation (dpi). Differential gene expression analysis showed that numerous defense-related genes were induced in susceptible plants at 5 dpi. Mapping reads against the A. psidii genome showed that only susceptible plants contained fungal-derived transcripts. Resistant plants exhibited an overexpression of candidate A. psidii resistance-related genes such as receptor-like kinases, nucleotide-binding site leucine-rich repeat proteins, glutathione S-transferases, WRKY transcriptional regulators, and pathogenesis-related proteins. We identified large differences in the expression of defense-related genes among resistant in iduals.
Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus
Publisher: Springer Science and Business Media LLC
Date: 17-05-2019
DOI: 10.1038/S41467-019-10242-9
Abstract: Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
FluoMEP: A new genotyping method combining the advantages of randomly amplified polymorphic DNA and amplified fragment length polymorphism
Publisher: Wiley
Date: 02-2007
Abstract: PCR-based identification of differences between two unknown genomes often requires complex manipulation of the templates prior to lification and/or gel electrophoretic separation of a large number of s les with manual methods. Here, we describe a new genotyping method, called fluorescent motif enhanced polymorphism (fluoMEP). The fluoMEP method is based on random lified polymorphic DNA (RAPD) assay, but combines the advantages of the large collection of unlabelled 10mer primers (ca. 5000) from commercial sources and the power of the automated CE devices used for the detection of lified fragment length polymorphism (AFLP) patterns. The link between these two components is provided by a fluorescently labeled "common primer" that is used in a two-primer PCR together with an unlabeled RAPD primer. By using the same "common primer" and a series of RAPD primers, DNA templates can be screened quickly and effectively for polymorphisms. Our manuscript describes the optimization of the method and its characterization on different templates. We demonstrate by using several different approaches that the addition of the "common primer" to the PCR changes the profile of lified fragments, allowing for screening various parts of the genome with the same set of unlabeled primers. We also present an in silico analysis of the genomic localization of fragments lified by a RAPD primer with two different "common primers" and alone.
Evolution of Vertebrate Phototransduction: Cascade Activation
Publisher: Oxford University Press (OUP)
Date: 11-05-2016
Transcriptome Sequencing of Two Phenotypic Mosaic Eucalyptus Trees Reveals Large Scale Transcriptome Re-Modelling
Publisher: Public Library of Science (PLoS)
Date: 15-05-2015
Evolution of the shut-off steps of vertebrate phototransduction
Publisher: The Royal Society
Date: 2018
DOI: 10.1098/RSOB.170232
Abstract: Different isoforms of the genes involved in phototransduction are expressed in vertebrate rod and cone photoreceptors, providing a unique ex le of parallel evolution via gene duplication. In this study, we determine the molecular phylogeny of the proteins underlying the shut-off steps of phototransduction in the agnathan and jawed vertebrate lineages. For the G-protein receptor kinases (GRKs), the GRK1 and GRK7 isions arose prior to the ergence of tunicates, with further expansion during the two rounds of whole-genome duplication (2R) subsequently, jawed and agnathan vertebrates retained different subsets of three isoforms of GRK. For the arrestins, gene expansion occurred during 2R. Importantly, both for GRKs and arrestins, the respective rod isoforms did not emerge until the second round of 2R, just prior to the separation of jawed and agnathan vertebrates. For the triplet of proteins mediating shut-off of the G-protein transducin, RGS9 erged from RGS11, probably at the second round of 2R, whereas Gβ5 and R9AP appear not to have undergone 2R expansion. Overall, our analysis provides a description of the duplications and losses of phototransduction shut-off genes that occurred during the transition from a chordate with only cone-like photoreceptors to an ancestral vertebrate with both cone- and rod-like photoreceptors.
Machine Learning Improves Upon Clinicians' Prediction of End Stage Kidney Disease
Publisher: Frontiers Media SA
Date: 16-03-2022
Abstract: Chronic kidney disease progression to ESKD is associated with a marked increase in mortality and morbidity. Its progression is highly variable and difficult to predict. This is an observational, retrospective, single-centre study. The cohort was patients attending hospital and nephrology clinic at The Canberra Hospital from September 1996 to March 2018. Demographic data, vital signs, kidney function test, proteinuria, and serum glucose were extracted. The model was trained on the featurised time series data with XGBoost. Its performance was compared against six nephrologists and the Kidney Failure Risk Equation (KFRE). A total of 12,371 patients were included, with 2,388 were found to have an adequate density (three eGFR data points in the first 2 years) for subsequent analysis. Patients were ided into 80%/20% ratio for training and testing datasets. ML model had superior performance than nephrologist in predicting ESKD within 2 years with 93.9% accuracy, 60% sensitivity, 97.7% specificity, 75% positive predictive value. The ML model was superior in all performance metrics to the KFRE 4- and 8-variable models. eGFR and glucose were found to be highly contributing to the ESKD prediction performance. The computational predictions had higher accuracy, specificity and positive predictive value, which indicates the potential integration into clinical workflows for decision support.
Dynamic interplay of innate and adaptive immunity during sterile retinal inflammation: Insights from the transcriptome
Publisher: Cold Spring Harbor Laboratory
Date: 24-02-2018
DOI: 10.1101/267757
Abstract: The pathogenesis of many retinal degenerations, such as age-related macular degeneration (AMD), is punctuated by an ill-defined network of sterile inflammatory responses. The delineation of innate and adaptive immune milieu amongst the broad leukocyte infiltrate, and the gene networks which construct these responses, are poorly described in the eye. Using photo-oxidative damage in a rodent model of subretinal inflammation, we employed a novel RNA-sequencing framework to map the global gene network signature of retinal leukocytes. This revealed a previously uncharted interplay of adaptive immunity during subretinal inflammation, including prolonged enrichment of myeloid and lymphocyte migration, antigen presentation, and the alternative arm of the complement cascade involving Factor B . We demonstrate Factor B -deficient mice are protected against macrophage infiltration and subretinal inflammation. Suppressing the drivers of retinal leukocyte proliferation, or their capacity to elicit complement responses, may help preserve retinal structure and function during sterile inflammation in diseases such as AMD.
T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein
Publisher: Public Library of Science (PLoS)
Date: 31-07-2017
Tissue and cell-specific transcriptomes in cotton reveal the subtleties of gene regulation underlying the diversity of plant secondary cell walls
Publisher: Springer Science and Business Media LLC
Date: 18-07-2017
Related Organisations
Massachusetts Institute Of Technology
Location: United States of America
University Of Sussex
Location: United Kingdom of Great Britain and Northern Ireland
University Of Bristol
Location: United Kingdom of Great Britain and Northern Ireland
London School Of Hygiene And Tropical Medicine
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Aaron Chuah.