ORCID Profile
0000-0002-6104-3763
Current Organisation
New South Wales Health Pathology
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Public Library of Science (PLoS)
Date: 16-08-2011
Publisher: Springer Science and Business Media LLC
Date: 04-06-2019
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2018
Abstract: Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting in idual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer.
Publisher: Informa UK Limited
Date: 03-2012
Publisher: Informa UK Limited
Date: 10-2012
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419366.V1
Abstract: Supplementary Tables as a word document including: Supplementary Table S1. Clinical presentation, sequencing statistics and genomic variation. Supplementary Table S2. Mitochondrial DNA genotypes and their frequency across six African patients between McCrow et al. (2016) and this study. Supplementary Table S3. Sequencing library statistics for tumor and blood s les. Supplementary Table S4. Total number and impact of small somatic variations in primary prostate cancer from African men. Supplementary Table S8. Prostate cancer risk alleles observed within the SAPCS cohort. Supplementary Table S12. Transposable elements and other repeats observed within acquired duplication events of UP2133. Supplementary Table S13. Genes impacted by a single chromoplexic event in UP2133 tumor.
Publisher: Impact Journals, LLC
Date: 04-08-2017
Publisher: Oxford University Press (OUP)
Date: 10-09-2008
DOI: 10.1093/BIOINFORMATICS/BTN482
Abstract: Motivation: We present PCIT, an algorithm for the reconstruction of gene co-expression networks (GCN) that combines the concept partial correlation coefficient with information theory to identify significant gene to gene associations defining edges in the reconstruction of GCN. The properties of PCIT are examined in the context of the topology of the reconstructed network including connectivity structure, clustering coefficient and sensitivity. Results: We apply PCIT to a series of simulated datasets with varying levels of complexity in terms of number of genes and experimental conditions, as well as to three real datasets. Results show that, as opposed to the constant cutoff approach commonly used in the literature, the PCIT algorithm can identify and allow for more moderate, yet not less significant, estimates of correlation (r) to still establish a connection in the GCN. We show that PCIT is more sensitive than established methods and capable of detecting functionally validated gene–gene interactions coming from absolute r values as low as 0.3. These bona fide associations, which often relate to genes with low variation in expression patterns, are beyond the detection limits of conventional fixed-threshold methods, and would be overlooked by studies relying on those methods. Availability: FORTRAN 90 source code to perform the PCIT algorithm is available as Supplementary File 1. Contact: tony.reverter-gomez@csiro.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Impact Journals, LLC
Date: 03-2017
Publisher: Public Library of Science (PLoS)
Date: 04-11-2010
Publisher: Wiley
Date: 07-09-2010
DOI: 10.1111/J.1365-2052.2010.02053.X
Abstract: Beef cattle breeds consist of three major genetic sub isions. The taurine group is adapted to temperate environments, and the zebu and Sanga groups are both adapted to tropical environments. With the advent of genotyping and sequencing technologies in agriculture, genome-wide exploration of the genetic basis for the differences in tropical adaptation has only just become possible. In this study, approximately 9000 single nucleotide polymorphism markers were genotyped on 317 animals of a selection of taurine, zebu, and composite breeds to characterize any systematic differences between these groups. We identified 91 intra-breed-class markers 78 were polymorphic only within the zebu animals, while 13 were polymorphic only in the taurine animals. There were no fixed differences (fixed for alternate alleles between the two breed types) between zebu and taurine animals. We found 14 regions with significantly different allele frequencies between zebu and taurine animals indicative of variable selection pressure or genetic drift. We also found 12 independent regions of differential extended haplotype homozygosity (EHH), indicative of recent selection or rapid fixation of the alternate allele within a short period of time in one of the two breed classes. A preliminary functional genomics analysis of these regions pointed towards signatures of tropical attributes including keratins, heat-shock proteins and heat resistance genes. We anticipate this investigation to be a stepping-stone for future studies to identify genomic regions specific to the two cattle groups, and to subsequently assist in the discrimination between temperate and tropically adapted cattle.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6510366.V1
Abstract: Abstract African-American men are more likely than any other racial group to die from prostate cancer. The contribution of acquired genomic variation to this racial disparity is largely unknown, as genomic from Africa is lacking. Here, we performed the first tumor-normal paired deep whole-genome sequencing for Africa. A direct study-matched comparison between African- and European-derived, treatment-naïve, high-risk prostate tumors for 15 cases allowed for further comparative analyses of existing data. Excluding a single hypermutated tumor with 55 mutations per megabase, we observed a 1.8-fold increase in small somatic variants in African- versus European-derived tumors ( i P /i = 1.02e–04), rising to 4-fold when compared with published tumor-matched data. Furthermore, we observed an increase in oncogenic driver mutations in African tumors ( i P /i = 2.92e–03) roughly 30% of impacted genes were novel to prostate cancer, and 79% of recurrent driver mutations appeared early in tumorigenesis. Although complex genomic rearrangements were less frequent in African tumors, we describe a uniquely hyperduplicated tumor affecting 149 transposable elements. Comparable with African Americans, i ERG /i fusions and i PIK3CA /i mutations were absent and i PTEN /i loss less frequent. i CCND1 /i and i MYC /i were frequently gained, with somatic copy-number changes more likely to occur late in tumorigenesis. In addition to traditional prostate cancer gene pathways, genes regulating calcium ion-ATPase signal transduction were disrupted in African tumors. Although preliminary, our results suggest that further validation and investigation into the potential implications for elevated tumor mutational burden and tumor-initiating mutations in clinically unfavorable prostate cancer can improve patient outcomes in Africa. Significance: The first whole-genome sequencing study for high-risk prostate cancer in African men allows a simultaneous comparison of ethnic differences relative to European populations and of the influences of the environment relative to African-American men. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419372.V1
Abstract: Supplementary Fig. S1 Transition and transversion rates of somatic SNVs observed among six SAPCS patients. Ti and Tv indicate transitional and transversional changes, respectively. Supplementary Fig. S2 Genomic rearrangements between African and European cohorts. A, Those observed for deletions (DEL), inter-chromosomal translocations (CTX), inversions (INV) and tandem duplications (DUP). B, Those observed for the four following types of large deletions: chromosomal deletions (CD), exon losses (EL), splice acceptor variant (SA), and splice donor variant (SD). Supplementary Fig. S3 Complex genomic rearrangements. A, Circos plots depicting coordinated chained events of chromoplexy in SAPCS (n = 1/6) and APCRCEUR (n = 5/9). Somatic copy number gains (red) and losses (blue) are depicted in the inner ring, while chromoplexic events between chromosomes are linked with blue lines and rearrangements not assigned to a chained event are depicted as gray lines within the plot. B, Maximal chromothriptic scores observed among tumor-matched blood pairs of SAPCS and APCRCEUR cohorts. Tumors with a ShatterProof score over 0.39 are defined as having chromothriptic characteristics two from the APCRC are 0.43 and 0.44, which are higher than scores from their matched blood. Supplementary Fig. S4 Recurrent somatic aberrations within SAPCS, compared to AAPC (African American), TCGA, and COSMIC prostate cancer datasets. Genes or chromosome regions affected are shown next to oncoplots, with the total number of mutations within SAPCS tumors in the rightmost column. Note that a multiple hit accounts for more than one count. Abbreviations include: TFBS, transcription factor binding site DHS, DNase I hypersensitive site and CN, copy number. Supplementary Fig. S5 Unsupervised hierarchical clustering of SCNA segmented data observed within this study and the Memorial Sloan Kettering Cancer Center cohort (MSKCC n = 157 primary tumors). Selected genomic regions indicative of copy number subtypes are labeled. Each column represents a genomic region. Ward's clustering with the Manhattan distance metric was applied to cluster the rows (patients) with consensus clustering. PGA, percentage of genome alteration. Supplementary Fig. S6 Model of prostate carcinogenesis among patients of African ancestry. Tajima's D statistic per chromosome of somatic SNVs present in each clone or subclone across six study participants was computed and averaged using VCFtools (Danecek et al, 2011). Abbreviations: AR, androgen receptor PI3K, phosphoinositide 3-kinase WNT, canonical wingless-type MMTV integration site family.
Publisher: Oxford University Press (OUP)
Date: 07-05-2020
DOI: 10.1093/BIB/BBAA056
Abstract: Somatic structural variants (SVs), which are variants that typically impact & nucleotides, play a significant role in cancer development and evolution but are notoriously more difficult to detect than small variants from short-read next-generation sequencing (NGS) data. This is due to a combination of challenges attributed to the purity of tumour s les, tumour heterogeneity, limitations of short-read information from NGS and sequence alignment ambiguities. In spite of active development of SV detection tools (callers) over the past few years, each method has inherent advantages and limitations. In this review, we highlight some of the important factors affecting somatic SV detection and compared the performance of seven commonly used SV callers. In particular, we focus on the extent of change in sensitivity and precision for detecting different SV types and size ranges from s les with differing variant allele frequencies and sequencing depths of coverage. We highlight the reasons for why some SV callers perform well in some settings but not others, allowing our evaluation findings to be extended beyond the seven SV callers examined in this paper. As the importance of large SVs become increasingly recognized in cancer genomics, this paper provides a timely review on some of the most impactful factors influencing somatic SV detection that should be considered when choosing SV callers.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419366
Abstract: Supplementary Tables as a word document including: Supplementary Table S1. Clinical presentation, sequencing statistics and genomic variation. Supplementary Table S2. Mitochondrial DNA genotypes and their frequency across six African patients between McCrow et al. (2016) and this study. Supplementary Table S3. Sequencing library statistics for tumor and blood s les. Supplementary Table S4. Total number and impact of small somatic variations in primary prostate cancer from African men. Supplementary Table S8. Prostate cancer risk alleles observed within the SAPCS cohort. Supplementary Table S12. Transposable elements and other repeats observed within acquired duplication events of UP2133. Supplementary Table S13. Genes impacted by a single chromoplexic event in UP2133 tumor.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419369
Abstract: Supplementary Excel Tables include Supplementary Table S5. Segmented copy number alterations in six African PCa patients identified by WGS. Supplementary Table S6. Clinical characteristics of previously published prostate tumors compared in this study. Supplementary Table S7. Allele distribution for known PCa risk alleles in SAPCS. Supplementary Table S9. Small somatic mutations in six African (SAPCS) and nine European (APCRC) patients with high-risk PCa. Supplementary Table S10. Oncogenic driver mutations in six African PCa patients. Supplementary Table S11. Somatic SVs in six African (SAPCS) and nine European (APCRC) patients with high-risk PCa. Supplementary Table S14. Machine learning prediction results of missense mutations (CanDrA program) showing potential oncogenic drivers in six African PCa patients and the impact of the drivers on cellular pathway alterations using PANTHER classification system. Supplementary Table S15. Recurrent SCNAs in six African PCa patients. Supplementary Table S16. Gene level copy number alterations in six African PCa patients. Columns 4 - 9 are absolute values and Columns 10 - 15 are relative values for percentage genome alteration, including 276 signature genes in Columns 16 - 19. Positive and negative values indicate gains and losses, respectively. Zero means neutral copy number variation.
Publisher: Oxford University Press (OUP)
Date: 07-2010
DOI: 10.1534/GENETICS.109.108522
Abstract: With the improvement and decline in cost of high-throughput genotyping and phenotyping technologies, genome-wide association (GWA) studies are fast becoming a preferred approach for dissecting complex quantitative traits. Glucosinolate (GSL) secondary metabolites within Arabidopsis spp. can serve as a model system to understand the genomic architecture of quantitative traits. GSLs are key defenses against insects in the wild and the relatively large number of cloned quantitative trait locus (QTL) controlling GSL traits allows comparison of GWA to previous QTL analyses. To better understand the specieswide genomic architecture controlling plant-insect interactions and the relative strengths of GWA and QTL studies, we conducted a GWA mapping study using 96 A. thaliana accessions, 43 GSL phenotypes, and ∼230,000 SNPs. Our GWA analysis identified the two major polymorphic loci controlling GSL variation (AOP and MAM) in natural populations within large blocks of positive associations encompassing dozens of genes. These blocks of positive associations showed extended linkage disequilibrium (LD) that we hypothesize to have arisen from balancing or fluctuating selective sweeps at both the AOP and MAM loci. These potential sweep blocks are likely linked with the formation of new defensive chemistries that alter plant fitness in natural environments. Interestingly, this GWA analysis did not identify the majority of previously identified QTL even though these polymorphisms were present in the GWA population. This may be partly explained by a nonrandom distribution of phenotypic variation across population subgroups that links population structure and GSL variation, suggesting that natural selection can hinder the detection of phenotype–genotype associations in natural populations.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2022
DOI: 10.1038/S41586-022-05154-6
Abstract: Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages 1 . The contributing genetic and non-genetic factors, and associated mutational processes, are unknown 2,3 . Here, through whole-genome sequencing of treatment-naive prostate cancer s les from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2 , STK19 , DDX11L1 , PCAT1 and SETBP1 . Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including in iduals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.
Publisher: Wiley
Date: 02-2001
Publisher: Oxford University Press (OUP)
Date: 20-11-2019
DOI: 10.1634/THEONCOLOGIST.2019-0590
Abstract: Current literature is inconsistent in the associations between computed tomography (CT)-based body composition measures and adverse outcomes in older patients with colorectal cancer (CRC). Moreover, the associations with consecutive treatment modalities have not been studied. This study compared the associations of CT-based body composition measures with surgery- and chemotherapy-related complications and survival in older patients with CRC. A retrospective single-center cohort study was conducted in patients with CRC aged ≥65 years who underwent elective surgery between 2010 and 2014. Gender-specific standardized scores of preoperative CT-based skeletal muscle (SM), muscle density, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue, IMAT percentage, SM/VAT, and body mass index (BMI) were tested for their associations with severe postoperative complications, prolonged length of stay (LOS), readmission, and dose-limiting toxicity using logistic regression and 1-year and long-term survival (range 3.7–6.6 years) using Cox regression. Bonferroni correction was applied to account for multiple testing. The study population consisted of 378 patients with CRC with a median age of 73.4 (interquartile range 69.5–78.4) years. Severe postoperative complications occurred in 13.0%, and 39.4% of patients died during follow-up. Dose-limiting toxicity occurred in 77.4% of patients receiving chemotherapy (n = 53). SM, muscle density, VAT, SM/VAT, and BMI were associated with surgery-related complications, and muscle density, IMAT, IMAT percentage, and SM/VAT were associated with long-term survival. After Bonferroni correction, no CT-based body composition measure was significantly associated with adverse outcomes. Higher BMI was associated with prolonged LOS. The associations between CT-based body composition measures and adverse outcomes of consecutive treatment modalities in older patients with CRC were not consistent or statistically significant.
Publisher: Cold Spring Harbor Laboratory
Date: 12-06-2019
DOI: 10.1101/668723
Abstract: Somatic structural variants are an important contributor to cancer development and evolution. Accurate detection of these complex variants from whole genome sequencing data is influenced by a multitude of parameters. However, there are currently no tools for guiding study design nor are there applications that could predict the performance of somatic structural variant detection. To address this gap, we developed Shiny-SoSV, a user-friendly web-based calculator for determining the impact of common variables on the sensitivity and precision of somatic structural variant detection, including choice of variant detection tool, sequencing depth of coverage, variant allele fraction, and variant breakpoint resolution. Using simulation studies, we determined singular and combinatoric effects of these variables, modelled the results using a generalised additive model, allowing structural variant detection performance to be predicted for any combination of predictors. Shiny-SoSV provides an interactive and visual platform for users to easily compare in idual and combined impact of different parameters. It predicts the performance of a proposed study design, on somatic structural variant detection, prior to the commencement of benchwork. Shiny-SoSV is freely available at hcpcg.shinyapps.io/Shiny-SoSV with accompanying user’s guide and ex le use-cases.
Publisher: CSIRO Publishing
Date: 2008
DOI: 10.1071/EA08052
Abstract: In order to uncover genes with transcriptional activity linked to various beef quality phenotypes of interest, we designed a systems biology approach. We focussed on traits representing the three major categories of growth and development, fat depots and meat quality phenotypes. We proceeded by linking bovine gene expression data derived from 147 microarray hybridisation experiments and high density marker data from 9260 single nucleotide polymorphisms (SNP) on 189 steers. The in iduals in the genotyping study were unrelated to the s les used for expression profiling. The linkage was performed by anchoring these data to a gene network for myogenin (MYOG), a muscle-specific transcription factor essential for the development of skeletal muscle. This approach was able to identify and estimate the strength of the relationship between the statistical association of a SNP to a phenotype of interest with the transcriptional activity of genes in the network. The genes from the MYOG-centred network that were significantly associated with the largest number of meat quality traits were PDLIM3, CALM1 and CRYAB. Among our findings, a novel association between desmin and meat colour points to an alternative biochemical basis for meat colour differences involving costameric structures and their previously reported relationship with tenderness. These newly generated hypotheses can help formulate sound research to further illuminate the genetic architecture of beef quality phenotypes.
Publisher: Oxford University Press (OUP)
Date: 04-2020
DOI: 10.1093/GIGASCIENCE/GIAA027
Abstract: The German Shepherd Dog (GSD) is one of the most common breeds on earth and has been bred for its utility and intelligence. It is often first choice for police and military work, as well as protection, disability assistance, and search-and-rescue. Yet, GSDs are well known to be susceptible to a range of genetic diseases that can interfere with their training. Such diseases are of particular concern when they occur later in life, and fully trained animals are not able to continue their duties. Here, we provide the draft genome sequence of a healthy German Shepherd female as a reference for future disease and evolutionary studies. We generated this improved canid reference genome (CanFam_GSD) utilizing a combination of Pacific Bioscience, Oxford Nanopore, 10X Genomics, Bionano, and Hi-C technologies. The GSD assembly is ∼80 times as contiguous as the current canid reference genome (20.9 vs 0.267 Mb contig N50), containing far fewer gaps (306 vs 23,876) and fewer scaffolds (429 vs 3,310) than the current canid reference genome CanFamv3.1. Two chromosomes (4 and 35) are assembled into single scaffolds with no gaps. BUSCO analyses of the genome assembly results show that 93.0% of the conserved single-copy genes are complete in the GSD assembly compared with 92.2% for CanFam v3.1. Homology-based gene annotation increases this value to ∼99%. Detailed examination of the evolutionarily important pancreatic amylase region reveals that there are most likely 7 copies of the gene, indicative of a duplication of 4 ancestral copies and the disruption of 1 copy. GSD genome assembly and annotation were produced with major improvement in completeness, continuity, and quality over the existing canid reference. This resource will enable further research related to canine diseases, the evolutionary relationships of canids, and other aspects of canid biology.
Publisher: Oxford University Press (OUP)
Date: 2023
DOI: 10.1093/GIGASCIENCE/GIAD018
Abstract: One difficulty in testing the hypothesis that the Australasian dingo is a functional intermediate between wild wolves and domesticated breed dogs is that there is no reference specimen. Here we link a high-quality de novo long-read chromosomal assembly with epigenetic footprints and morphology to describe the Alpine dingo female named Cooinda. It was critical to establish an Alpine dingo reference because this ecotype occurs throughout coastal eastern Australia where the first drawings and descriptions were completed. We generated a high-quality chromosome-level reference genome assembly (Canfam_ADS) using a combination of Pacific Bioscience, Oxford Nanopore, 10X Genomics, Bionano, and Hi-C technologies. Compared to the previously published Desert dingo assembly, there are large structural rearrangements on chromosomes 11, 16, 25, and 26. Phylogenetic analyses of chromosomal data from Cooinda the Alpine dingo and 9 previously published de novo canine assemblies show dingoes are monophyletic and basal to domestic dogs. Network analyses show that the mitochondrial DNA genome clusters within the southeastern lineage, as expected for an Alpine dingo. Comparison of regulatory regions identified 2 differentially methylated regions within glucagon receptor GCGR and histone deacetylase HDAC4 genes that are unmethylated in the Alpine dingo genome but hypermethylated in the Desert dingo. Morphologic data, comprising geometric morphometric assessment of cranial morphology, place dingo Cooinda within population-level variation for Alpine dingoes. Magnetic resonance imaging of brain tissue shows she had a larger cranial capacity than a similar-sized domestic dog. These combined data support the hypothesis that the dingo Cooinda fits the spectrum of genetic and morphologic characteristics typical of the Alpine ecotype. We propose that she be considered the archetype specimen for future research investigating the evolutionary history, morphology, physiology, and ecology of dingoes. The female has been taxidermically prepared and is now at the Australian Museum, Sydney.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2019
DOI: 10.1038/S41586-019-1714-1
Abstract: Anatomically modern humans originated in Africa around 200 thousand years ago (ka)
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419372
Abstract: Supplementary Fig. S1 Transition and transversion rates of somatic SNVs observed among six SAPCS patients. Ti and Tv indicate transitional and transversional changes, respectively. Supplementary Fig. S2 Genomic rearrangements between African and European cohorts. A, Those observed for deletions (DEL), inter-chromosomal translocations (CTX), inversions (INV) and tandem duplications (DUP). B, Those observed for the four following types of large deletions: chromosomal deletions (CD), exon losses (EL), splice acceptor variant (SA), and splice donor variant (SD). Supplementary Fig. S3 Complex genomic rearrangements. A, Circos plots depicting coordinated chained events of chromoplexy in SAPCS (n = 1/6) and APCRCEUR (n = 5/9). Somatic copy number gains (red) and losses (blue) are depicted in the inner ring, while chromoplexic events between chromosomes are linked with blue lines and rearrangements not assigned to a chained event are depicted as gray lines within the plot. B, Maximal chromothriptic scores observed among tumor-matched blood pairs of SAPCS and APCRCEUR cohorts. Tumors with a ShatterProof score over 0.39 are defined as having chromothriptic characteristics two from the APCRC are 0.43 and 0.44, which are higher than scores from their matched blood. Supplementary Fig. S4 Recurrent somatic aberrations within SAPCS, compared to AAPC (African American), TCGA, and COSMIC prostate cancer datasets. Genes or chromosome regions affected are shown next to oncoplots, with the total number of mutations within SAPCS tumors in the rightmost column. Note that a multiple hit accounts for more than one count. Abbreviations include: TFBS, transcription factor binding site DHS, DNase I hypersensitive site and CN, copy number. Supplementary Fig. S5 Unsupervised hierarchical clustering of SCNA segmented data observed within this study and the Memorial Sloan Kettering Cancer Center cohort (MSKCC n = 157 primary tumors). Selected genomic regions indicative of copy number subtypes are labeled. Each column represents a genomic region. Ward's clustering with the Manhattan distance metric was applied to cluster the rows (patients) with consensus clustering. PGA, percentage of genome alteration. Supplementary Fig. S6 Model of prostate carcinogenesis among patients of African ancestry. Tajima's D statistic per chromosome of somatic SNVs present in each clone or subclone across six study participants was computed and averaged using VCFtools (Danecek et al, 2011). Abbreviations: AR, androgen receptor PI3K, phosphoinositide 3-kinase WNT, canonical wingless-type MMTV integration site family.
Publisher: Wiley
Date: 10-12-2015
DOI: 10.1002/PROS.23126
Publisher: Cold Spring Harbor Laboratory
Date: 13-11-2019
DOI: 10.1101/840751
Abstract: Somatic structural variants (SVs) play a significant role in cancer development and evolution, but are notoriously more difficult to detect than small variants from short-read next-generation sequencing (NGS) data. This is due to a combination of challenges attributed to the purity of tumour s les, tumour heterogeneity, limitations of short-read information from NGS, and sequence alignment ambiguities. In spite of active development of SV detection tools (callers) over the past few years, each method has inherent advantages and limitations. In this review, we highlight some of the important factors affecting somatic SV detection and compared the performance of eight commonly used SV callers. In particular, we focus on the extent of change in sensitivity and precision for detecting different SV types and size ranges from s les with differing variant allele frequencies and sequencing depths of coverage. We highlight the reasons for why some SV callers perform well in some settings but not others, allowing our evaluation findings to be extended beyond the eight SV callers examined in this paper. As the importance of large structural variants become increasingly recognised in cancer genomics, this paper provides a timely review on some of the most impactful factors influencing somatic SV detection and guidance on selecting an appropriate SV caller.
Publisher: Springer Science and Business Media LLC
Date: 08-2006
DOI: 10.1038/NG0806-855
Publisher: MDPI AG
Date: 07-05-2020
Abstract: Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to in idualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour s les were derived from prostate, lymph nodes, bone and brain. Results: Most s les had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in in idual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an in idual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an in idual at any stage of the disease.
Publisher: Impact Journals, LLC
Date: 05-10-2016
Publisher: Research Square Platform LLC
Date: 12-2021
DOI: 10.21203/RS.3.RS-1122619/V1
Abstract: Prostate cancer is characterised by significant global disparity mortality rates in Sub-Saharan Africa are double to quadruple those in Eurasia 1 . Hypothesising unknown interplay between genetic and non-genetic factors, tumour genome profiling envisages contributing mutational processes 2,3 . Through whole-genome sequencing of treatment-naïve prostate cancer from 183 ethnically/globally distinct patients (African versus European), we generate the largest cancer genomics resource for Sub-Saharan Africa. Identifying ~2 million somatic variants, Africans carried the greatest burden. We describe a new molecular taxonomy using all mutational types and ethno-geographic identifiers, including Asian. Defined as Global Mutational Subtypes (GMS) A–D, although Africans presented within all subtypes, we found GMS-B to be ‘African-specific’ and GMS-D ‘African-predominant’, including Admixed and European Africans. Conversely, Europeans from Australia, Africa and Brazil predominated within ‘mutationally-quiet’ and ethnically/globally ‘universal’ GMS-A, while European Australians shared a higher mutational burden with Africans in GMS-C. GMS predicts clinical outcomes reconstructing cancer timelines suggests four evolutionary trajectories with different mutation rates (GMS-A, low 0.968/year versus D, highest 1.315/year). Our data suggest both common genetic factors across extant populations and regional environmental factors contributing to carcinogenesis, analogous to gene-environment interaction defined here as a different effect of an environmental surrounding in persons with different ancestries or vice versa. We anticipate GMS acting as a proxy to intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.
Publisher: Informa UK Limited
Date: 20-11-2008
Publisher: Wiley
Date: 14-11-2018
DOI: 10.1002/PROS.23440
Abstract: Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis.
Publisher: Cold Spring Harbor Laboratory
Date: 2003
Publisher: Springer Science and Business Media LLC
Date: 05-2009
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-04-2022
Abstract: Dogs are uniquely associated with human dispersal and bring transformational insight into the domestication process. Dingoes represent an intriguing case within canine evolution being geographically isolated for thousands of years. Here, we present a high-quality de novo assembly of a pure dingo (CanFam_DDS). We identified large chromosomal differences relative to the current dog reference (CanFam3.1) and confirmed no expanded pancreatic amylase gene as found in breed dogs. Phylogenetic analyses using variant pairwise matrices show that the dingo is distinct from five breed dogs with 100% bootstrap support when using Greenland wolf as the outgroup. Functionally, we observe differences in methylation patterns between the dingo and German shepherd dog genomes and differences in serum biochemistry and microbiome makeup. Our results suggest that distinct demographic and environmental conditions have shaped the dingo genome. In contrast, artificial human selection has likely shaped the genomes of domestic breed dogs after ergence from the dingo.
Publisher: American Association for Cancer Research (AACR)
Date: 13-12-2018
DOI: 10.1158/0008-5472.CAN-18-0254
Abstract: The first whole-genome sequencing study for high-risk prostate cancer in African men allows a simultaneous comparison of ethnic differences relative to European populations and of the influences of the environment relative to African-American men.
Publisher: Informa UK Limited
Date: 17-03-2010
Publisher: Public Library of Science (PLoS)
Date: 24-11-2014
Publisher: Wiley
Date: 12-03-2010
Publisher: Cold Spring Harbor Laboratory
Date: 12-2007
DOI: 10.1101/GR.6981507
Abstract: The view that changes to the control of gene expression rather than alterations to protein sequence are central to the evolution of organisms has become something of a truism in molecular biology. In reality, the direct evidence for this is limited, and only recently have we had the ability to look more globally at how genetic variation influences gene expression, focusing upon inter-in idual variation in gene expression and using microarrays to test for differences in mRNA levels. Here, we review the scope of these experimental analyses, what they are designed to tell us about genetic variation, and what are their limitations from both a technical and a conceptual viewpoint. We conclude that while we are starting to understand the impact of this class of genetic variation upon steady-state mRNA levels, we are still far from identifying the potential phenotypic and evolutionary outcomes.
Publisher: Wiley
Date: 09-2011
Publisher: Springer Science and Business Media LLC
Date: 06-2006
DOI: 10.1007/S00335-005-0186-9
Abstract: The analysis of the influence of genetic variation on regulation of gene expression at a near-genome-wide level has become the focus of much recent interest. It is widely appreciated that many genes are expressed in a tissue-specific manner and that others are more ubiquitously expressed but relatively little is known about how genetic variation might influence these tissue patterns of gene expression. In this review we discuss what is known about the tissue specificity of the influence of genetic variation and review the challenges that we face in combining hugely parallel, microarray-based gene analysis with equally expensive genetic analysis. We conclude that the available data suggest that genetic variation is essentially tissue specific in its effects upon gene expression and this has important implications for experimental analysis.
Publisher: Oxford University Press (OUP)
Date: 10-09-2014
DOI: 10.1093/GBE/EVU202
Publisher: Cold Spring Harbor Laboratory
Date: 16-11-2020
DOI: 10.1101/2020.11.15.384057
Abstract: The dingo is Australia’s iconic top-order predator and arrived on the continent between 5,000-8,000 years ago. To provide an unbiased insight into its evolutionary affiliations and biological interactions, we coupled long-read DNA sequencing with a multiplatform scaffolding approach to produce an ab initio genome assembly of the desert dingo (85X coverage) we call CanLup_DDS. We compared this genome to the Boxer (CanFam3.1) and German Shepherd dog (CanFam_GSD) assemblies and characterized lineage-specific and shared genetic variation ranging from single– to megabase pair–sized variants. We identified 21,483 dingo-specific and 16,595 domestic dog-specific homozygous structural variants mediating genic and putative regulatory changes. Comparisons between the dingo and domestic dog builds detected unique inversions on Chromosome 16, structural variations in genes linked with starch metabolism, and seven differentially methylated genes. To experimentally assess genomic differences 17 dingoes and 15 German Shepherd dogs were fed parallel diets for 14 days. In dingoes, low AMY2B copy number and serum amylase levels are linked with high cholesterol and LDL levels. Gut microbiome analyses revealed enrichment of the family Clostridiaceae , which can utilize complex resistant starch, while scat metabolome studies identified high phenylethyl alcohol concentrations that we posit are linked with territory marking. Our study provides compelling genomic, microbiome, and metabolomic links showing the dingo has distinct physiology from domestic breed dogs with a unique role in the ecosystem.
Publisher: Wiley
Date: 06-2008
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419369.V1
Abstract: Supplementary Excel Tables include Supplementary Table S5. Segmented copy number alterations in six African PCa patients identified by WGS. Supplementary Table S6. Clinical characteristics of previously published prostate tumors compared in this study. Supplementary Table S7. Allele distribution for known PCa risk alleles in SAPCS. Supplementary Table S9. Small somatic mutations in six African (SAPCS) and nine European (APCRC) patients with high-risk PCa. Supplementary Table S10. Oncogenic driver mutations in six African PCa patients. Supplementary Table S11. Somatic SVs in six African (SAPCS) and nine European (APCRC) patients with high-risk PCa. Supplementary Table S14. Machine learning prediction results of missense mutations (CanDrA program) showing potential oncogenic drivers in six African PCa patients and the impact of the drivers on cellular pathway alterations using PANTHER classification system. Supplementary Table S15. Recurrent SCNAs in six African PCa patients. Supplementary Table S16. Gene level copy number alterations in six African PCa patients. Columns 4 - 9 are absolute values and Columns 10 - 15 are relative values for percentage genome alteration, including 276 signature genes in Columns 16 - 19. Positive and negative values indicate gains and losses, respectively. Zero means neutral copy number variation.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2012
DOI: 10.1007/S00122-012-1938-Z
Abstract: The first single-nucleotide polymorphism (SNP) maps for watermelon [Citrullus lanatus (Thunb.) Matsum. et Nakai] were constructed and compared. Three populations were developed from crosses between two elite cultivars, Klondike Black Seeded × New H shire Midget (KBS × NHM), an elite cultivar and wild egusi accession, Strain II × PI 560023 (SII × Egusi) and an elite cultivar and a wild citron accession, ZWRM50 × PI 244019 (ZWRM × Citroides). The SII × Egusi and ZWRM × Citroides F(2) populations consisted of 187 and 182 in iduals respectively while the KBS × NHM recombinant inbred line (RIL) population consisted of 164 lines. The length of the genetic maps were 1,438, 1,514 and 1,144 cM with average marker distances of 3.8, 4.2, and 3.4 cM for the KBS × NHM, SII × Egusi and ZWRM × Citroides populations, respectively. Shared markers were used to align the three maps so that the linkage groups (LGs) represented the 11 chromosomes of the species. Marker segregation distortion were observed in all three populations, but was highest (12.7 %) in the ZWRM × Citroides population, where Citroides alleles were favored. The three maps were used to construct a consensus map containing 378 SNP markers with an average distance of 5.1 cM between markers. Phenotypic data was collected for fruit weight (FWT), fruit length (FL), fruit width (FWD), fruit shape index (FSI), rind thickness (RTH) and Brix (BRX) and analyzed for quantitative trait loci (QTL) associated with these traits. A total of 40 QTL were identified in the three populations, including major QTL for fruit size and shape that were stable across genetic backgrounds and environments. The present study reports the first SNP maps for Citrullus and the first map constructed using two elite parents. We also report the first stable QTL associated with fruit size and shape in Citrullus lanatus. These maps, QTL and SNPs should be useful for the watermelon community and represent a significant step towards the potential use of molecular tools in watermelon breeding.
Publisher: Elsevier
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 30-09-2008
Abstract: The success of genome-wide scans depends on the strength and magnitude of linkage disequilibrium (LD) present within the populations under investigation. High density SNP arrays are currently in development for the sheep genome, however little is known about the behaviour of LD in this livestock species. This study examined the behaviour of LD within five sheep populations using two LD metrics, D' and x 2' . Four economically important Australian sheep flocks, three pure breeds (White Faced Suffolk, Poll Dorset, Merino) and a crossbred population (Merino × Border Leicester), along with an inbred Australian Merino museum flock were analysed. Short range LD (0 – 5 cM) was observed in all five populations, however the persistence with increasing distance and magnitude of LD varied considerably between populations. Average LD (x 2' ) for markers spaced up to 20 cM exceeded the non-syntenic average within the White Faced Suffolk, Poll Dorset and Macarthur Merino. LD decayed faster within the Merino and Merino × Border Leicester, with LD below or consistent with observed background levels. Using marker-marker LD as a guide to the behaviour of marker-QTL LD, estimates of minimum marker spacing were made. For a 95% probability of detecting QTL, a microsatellite marker would be required every 0.1 – 2.5 centimorgans, depending on the population used. Sheep populations were selected which were inbred (Macarthur Merino), highly heterogeneous (Merino) or intermediate between these two extremes. This facilitated analysis and comparison of LD (x 2' ) between populations. The strength and magnitude of LD was found to differ markedly between breeds and aligned closely with both observed levels of genetic ersity and expectations based on breed history. This confirmed that breed specific information is likely to be important for genome wide selection and during the design of successful genome scans where tens of thousands of markers will be required.
Publisher: Wiley
Date: 20-03-2009
Publisher: Public Library of Science (PLoS)
Date: 25-03-2015
Publisher: Elsevier BV
Date: 04-2007
Publisher: SAGE Publications
Date: 18-04-2012
Abstract: This article examines the homeownership aspirations and plans of two groups of young Australian adults defined by their class position as ‘disadvantaged’ and ‘middle class’. We draw on Bauman’s idea of liquid modernity and ‘liquid life’ to frame our analysis. Despite being under less pressure to adopt socially prescribed adult transitions that applied to previous generations – a steady job, marriage, family and a house in the suburbs – young adults from both middle-class and disadvantaged backgrounds aspire to homeownership. In spite of an apparent multitude of choices and an increased emphasis on in idual agency, the articulations of their aspirations and plans to achieve it, in the context of the uncertainties of ‘liquid life’, are strongly influenced by their class position, defined primarily through family background and education. The article uses qualitative data drawn from two projects conducted in Melbourne, Australia, 2007–2010.
Publisher: Cold Spring Harbor Laboratory
Date: 27-01-2023
DOI: 10.1101/2023.01.26.525801
Abstract: One difficulty in testing the hypothesis that the Australasian dingo is a functional intermediate between wild wolves and domesticated breed dogs is that there is no reference specimen. Here we link a high-quality de novo long read chromosomal assembly with epigenetic footprints and morphology to describe the Alpine dingo female named Cooinda. It was critical to establish an Alpine dingo reference because this ecotype occurs throughout coastal eastern Australia where the first drawings and descriptions were completed. We generated a high-quality chromosome-level reference genome assembly (Canfam_ADS) using a combination of Pacific Bioscience, Oxford Nanopore, 10X Genomics, Bionano, and Hi-C technologies. Compared to the previously published Desert dingo assembly, there are large structural rearrangements on Chromosomes 11, 16, 25 and 26. Phylogenetic analyses of chromosomal data from Cooinda the Alpine dingo and nine previously published de novo canine assemblies show dingoes are monophyletic and basal to domestic dogs. Network analyses show that the mtDNA genome clusters within the southeastern lineage, as expected for an Alpine dingo. Comparison of regulatory regions identified two differentially methylated regions within glucagon receptor GCGR and histone deacetylase HDAC4 genes that are unmethylated in the Alpine dingo genome but hypermethylated in the Desert dingo. Morphological data, comprising geometric morphometric assessment of cranial morphology place dingo Cooinda within population-level variation for Alpine dingoes. Magnetic resonance imaging of brain tissue show she had a larger cranial capacity than a similar-sized domestic dog. These combined data support the hypothesis that the dingo Cooinda fits the spectrum of genetic and morphological characteristics typical of the Alpine ecotype. We propose that she be considered the archetype specimen for future research investigating the evolutionary history, morphology, physiology, and ecology of dingoes. The female has been taxidermically prepared and is now at the Australian Museum, Sydney.
Publisher: Public Library of Science (PLoS)
Date: 27-08-2020
No related grants have been discovered for Eva Chan.