ORCID Profile
0000-0002-3277-6562
Current Organisations
Stanford University
,
Simon Fraser University
,
Peter MacCallum Cancer Centre
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Publisher: Elsevier BV
Date: 05-2004
Publisher: eLife Sciences Publications, Ltd
Date: 29-01-2019
Publisher: Proceedings of the National Academy of Sciences
Date: 26-02-2004
Abstract: Bacterial pathogenicity islands (PAI) often encode both effector molecules responsible for disease and secretion systems that deliver these effectors to host cells. Human enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli , and the mouse pathogen Citrobacter rodentium (CR) possess the locus of enterocyte effacement (LEE) PAI. We systematically mutagenized all 41 CR LEE genes and functionally characterized these mutants in vitro and in a murine infection model. We identified 33 virulence factors, including two virulence regulators and a hierarchical switch for type III secretion. In addition, 7 potential type III effectors encoded outside the LEE were identified by using a proteomics approach. These non-LEE effectors are encoded by three uncharacterized PAIs in EHEC O157, suggesting that these PAIs act cooperatively with the LEE in pathogenesis. Our findings provide significant insights into bacterial virulence mechanisms and disease.
Publisher: American Society for Microbiology
Date: 09-2004
DOI: 10.1128/IAI.72.9.5115-5125.2004
Abstract: Salmonella enterica is a gram-negative, facultative intracellular pathogen that causes disease symptoms ranging from gastroenteritis to typhoid fever. A key virulence strategy is the translocation of bacterial effector proteins into the host cell, mediated by the type III secretion systems (TTSSs) encoded in Salmonella pathogenicity island 1 (SPI-1) and SPI-2. In S. enterica serovar Typhimurium LT2, we identified the protein products of STM4157 and STM2137 as novel candidate secreted proteins by comparison to known secreted proteins from enterohemorrhagic Escherichia coli and Citrobacter rodentium . The STM4157 and STM2137 proteins, which we have designated SseK1 and SseK2, respectively, are 61% identical at the amino acid level and differ mainly in their N termini. Western analysis showed that in vitro accumulation and secretion of these proteins in serovar Typhimurium were affected by mutations in the two-component systems SsrA/B and PhoP/Q, which are key mediators of intracellular growth and survival. SPI-2 TTSS-dependent translocation of recombinant SseK1::Cya was evident at 9 h postinfection of epithelial cells, while translocation of SseK2::Cya was not detected until 21 h. Remarkably, the translocation signal for SseK1 was contained within the N-terminal 32 amino acids. Fractionation of infected epithelial cells revealed that following translocation SseK1 localizes to the host cytosol, which is unusual among the currently known Salmonella effectors. Phenotypic analysis of Δ sseK1 , Δ sseK2 , and Δ sseK1 /Δ sseK2 mutants provided evidence for a role that was not critical during systemic infection. In summary, this work demonstrates that SseK1 and SseK2 are novel translocated proteins of serovar Typhimurium.
Publisher: Cold Spring Harbor Laboratory
Date: 12-01-2010
Abstract: Here, we demonstrate how comparative sequence analysis facilitates genome-wide base-pair-level interpretation of in idual genetic variation and address two questions of importance for human personal genomics: first, whether an in idual's functional variation comes mostly from noncoding or coding polymorphisms and, second, whether population-specific or globally-present polymorphisms contribute more to functional variation in any given in idual. Neither has been definitively answered by analyses of existing variation data because of a focus on coding polymorphisms, ascertainment biases in favor of common variation, and a lack of base-pair-level resolution for identifying functional variants. We resequenced 575 licons within 432 in iduals at genomic sites enriched for evolutionary constraint and also analyzed variation within three published human genomes. We find that single-site measures of evolutionary constraint derived from mammalian multiple sequence alignments are strongly predictive of reductions in modern-day genetic ersity across a range of annotation categories and across the allele frequency spectrum from rare ( %) to high frequency ( % minor allele frequency). Furthermore, we show that putatively functional variation in an in idual genome is dominated by polymorphisms that do not change protein sequence and that originate from our shared ancestral population and commonly segregate in human populations. These observations show that common, noncoding alleles contribute substantially to human phenotypes and that constraint-based analyses will be of value to identify phenotypically relevant variants in in idual genomes.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Public Library of Science (PLoS)
Date: 18-03-2011
Publisher: Springer Science and Business Media LLC
Date: 04-2010
Publisher: Cold Spring Harbor Laboratory
Date: 09-08-2018
DOI: 10.1101/388363
Abstract: Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumours, we show many transcriptional changes in tumours are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-06-2020
Abstract: Bacteria adapt to harsh conditions such as antibiotic exposure by acquiring new mutations, a process called stress-induced mutagenesis. Cipponi et al. investigated whether similar programs of mutagenesis play a role in the response of cancer cells to targeted therapies. Using in vitro models of intense drug selection and genome-wide functional screens, the authors found evidence for an analogous process in cancer and showed that it is regulated by the mammalian target of rapamycin (mTOR) signaling pathway. This pathway appears to mediate a stress-related switch to error-prone DNA repair, resulting in the generation of mutations that facilitate the emergence of drug resistance. Science , this issue p. 1127
Publisher: Public Library of Science (PLoS)
Date: 31-01-2006
Publisher: Public Library of Science (PLoS)
Date: 22-07-2013
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2013
Abstract: Short insertions and deletions (indels) are the second most abundant form of human genetic variation, but our understanding of their origins and functional effects lags behind that of other types of variants. Using population-scale sequencing, we have identified a high-quality set of 1.6 million indels from 179 in iduals representing three erse human populations. We show that rates of indel mutagenesis are highly heterogeneous, with 43%–48% of indels occurring in 4.03% of the genome, whereas in the remaining 96% their prevalence is 16 times lower than SNPs. Polymerase slippage can explain upwards of three-fourths of all indels, with the remainder being mostly simple deletions in complex sequence. However, insertions do occur and are significantly associated with pseudo-palindromic sequence features compatible with the fork stalling and template switching (FoSTeS) mechanism more commonly associated with large structural variations. We introduce a quantitative model of polymerase slippage, which enables us to identify indel-hypermutagenic protein-coding genes, some of which are associated with recurrent mutations leading to disease. Accounting for mutational rate heterogeneity due to sequence context, we find that indels across functional sequence are generally subject to stronger purifying selection than SNPs. We find that indel length modulates selection strength, and that indels affecting multiple functionally constrained nucleotides undergo stronger purifying selection. We further find that indels are enriched in associations with gene expression and find evidence for a contribution of nonsense-mediated decay. Finally, we show that indels can be integrated in existing genome-wide association studies (GWAS) although we do not find direct evidence that potentially causal protein-coding indels are enriched with associations to known disease-associated SNPs, our findings suggest that the causal variant underlying some of these associations may be indels.
Publisher: Public Library of Science (PLoS)
Date: 02-12-2010
Publisher: Cold Spring Harbor Laboratory
Date: 21-04-2023
DOI: 10.1101/2023.04.20.537744
Abstract: Metazoans inherited genes from unicellular ancestors that perform essential biological processes such as cell ision, metabolism and protein translation. Functioning multicellularity requires careful control and coordination of these unicellular genes to maintain tissue integrity and homeostasis. Gene regulatory networks (GRNs) formed during metazoan evolution to regulate conserved biological processes are frequently altered in cancer, resulting in over-expression of unicellular genes. We propose an imbalance in co-expression of unicellular (UC) and multicellular (MC) genes is a driving force in cancer. To investigate, we combined gene co-expression analysis to infer changes to GRNs in cancer with protein sequence conservation data to distinguish genes with UC and MC origins. Co-expression networks created using RNA sequencing data from 31 tumour types and normal tissue s les were ided into modules enriched for UC genes, MC genes or a mix of both (Mixed UC-MC modules). The greatest differences between tumour and normal tissue co-expression networks occurred within Mixed UC-MC modules. In particular, MC and UC genes not commonly co-expressed in normal tissues formed distinct co-expression modules seen only in tumours. The degree of rewiring of genes within Mixed UC-MC modules increased with both tumour grade and stage. Mixed UC-MC modules were enriched for somatic mutations in cancer genes, particularly copy-number lifications, suggesting an important driver of the rewiring observed in tumours are copy-number changes. Overall, our study shows the greatest changes to gene co-expression patterns during tumour progression occur between genes of MC and UC origins, implicating the breakdown and rewiring of metazoan gene regulatory networks in cancer development and progression. Multicellular organism cells follow certain rules that control and coordinate their growth and behavior. This happens because gene regulatory networks formed during the evolution of multicellularity to control the activity of genes inherited from unicellular ancestors. Cancer cells disobey these rules, growing and iding in a competitive fashion analogous to that of colonial unicellular organisms. Here, we test the hypothesis that breakdown of gene regulatory networks enforcing multicellularity drives cancer progression by investigating 31 tumour types. Based on sequence similarity, genes were categorized as having origins in either unicellular or multicellular species. We found that the balance of expression unicellular and multicellular genes changes dramatically in cancer. Genes expressed together in normal tissues stop being co-expressed in tumors, while unicellular and multicellular genes that would not normally be expressed together in normal tissues become highly co-expressed. This phenomenon is more pronounced in cancers at more advanced stages, and sometimes occurs in association with gain or loss of parts of certain chromosomes. Our work indicates disruption and rewiring of gene regulatory networks that evolved to enforce multicellularity drives cancer progression by upsetting the carefully coordinated balance in the activity of unicellular and multicellular genes.
Publisher: eLife Sciences Publications, Ltd
Date: 26-02-2019
DOI: 10.7554/ELIFE.40947
Abstract: Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumors, we show many transcriptional changes in tumors are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.
Publisher: Wiley
Date: 04-02-2004
Publisher: Elsevier BV
Date: 09-2016
Location: Australia
Start Date: 2013
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded Activity