1,720,981 research outputs found
The role of inherited DNA repair deficiencies in cancer susceptibility and evolution
No full textMultiple DNA surveillance and repair mechanisms act on the human genome, maintaining
high replication fidelity and genome stability. Deficiencies in these processes result in an
accumulation of post-zygotic mutations with characteristic signatures. This genomic instability is associated with the heritability of multiple cancer syndromes. I explored the role of inherited DNA repair deficiencies in cancer predisposition, progression and evolution.
Using whole genome sequencing from family trios and a carefully curated variant calling
pipeline, my results support the hypothesis that inherited DNA repair deficiencies impact
germline mutational processes. Offspring from parents with germline DNA repair deficiencies have significantly increased burdens of pre-zygotic de novo mutations (DNMs) with characteristic spectra. However, phenotypic consequences of these DNMs are rare, making them unlikely to cause non-cancer diseases or developmental disorders.
Next, I investigated the recessive inheritance of variants within the base excision repair (BER) genes MUTYH and MBD4, which are associated with colorectal cancer, among other cancer types. The impact of heterozygous variants in BER pathway components is widely debated due to mixed evidence. My analyses utilising germline and somatic data from large publicly available datasets suggest that germline heterozygous variants in MUTYH do not confer significantly increased risk. Heterozygous MBD4 variants are extremely rare but may be linked to cancer susceptibility.
Finally, I identified inherited DNA repair deficiencies in ∼20% of a high grade serous ovarian carcinoma cohort. The mutational profiles of tumours indicate that inherited DNA repair deficiencies are associated with a specific signature and evolutionary trajectory of chromosomal instability. However, there may be alternative routes to chromosomal instability in tumours with proficient DNA repair.
In summary, my work demonstrates how integration of the germline and somatic mutational landscapes increases our understanding of how inherited DNA repair deficiencies impact cancer risk and evolution
High-resolution copy-number mutational signatures for ovarian cancer patient stratification
No full textDuring tumour evolution, diverse mutational processes can affect copy number state across the genome, by deleting or duplicating sections of genomic material. The activity of mutational processes can be identified through the patterns - mutational signatures - they leave in genomic
data.
Mutational signatures of copy number have previously been extracted from micro-array data. These signatures have been used to predict overall survival and drug response at the point of diagnosis. However, these signatures are of limited use in ovarian cancer, which is dominated by smaller scale changes that are not accurately captured by low-resolution micro-array data. These changes can be resolved with higher resolution approaches, such as deep whole genome sequencing (WGS).
Here, existing low-resolution signatures are quantified in downsampled high-resolution WGS data, and are related to these more complex genomic features of ovarian cancer. This has not previously been attempted in an ovarian-specific dataset of this size. A negative correlation between two of the existing signatures was evident in the cohort. Hierarchical clustering separated the cohort into two patient subgroups, those with homologous recombination deficiency (HRD) and chromoplexy (whereby chains of translocations and deletions occur across multiple chromosomes), and those with variation caused by chromosome segregation errors. However, a survival analysis suggested no significant difference in survival time or time to relapse
between the two groups.
Three copy-number signatures were then extracted de novo from the complete high-resolution data, which, when quantified in the same cohort, also produced two patient subgroups. Again, these were separated by the presence or absence of HRD and chromoplexy. These groups showed clear separation in the survival analysis, suggesting the high-resolution signatures are more effective prognostic indicators than low-resolution signatures quantified in downsampled data.
The results suggest that these high-resolution mutational signatures may have the potential to provide actionable clinical information, at the point of diagnosis, for the prediction of prognosis and to inform treatment plans
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Fairly quantifying insertion and deletion landscapes in mammalian genomes
Get PDFInsertion and deletion mutations (indels) are a major component of genome evolution, and their disruptive properties play an important role in genetic diseases, including cancer. Incidence and sequence context of indels are clinically important in characterising tumours and detecting underlying molecular defects. Despite the functional and clinical importance of indels, they have often been overlooked, discarded as difficult to confidently identify in panels and problematic to meaningfully categorise. A key component of difficulty with indels lies in their association with repetitive sequences. Tandemly repeated sequences (e.g. AAAAA or ACACAC) are often enriched for indels and may be shortened or expanded by indel generating processes. Indels often cannot be unambiguously positioned onto repetitive sequences, adding to their complexity. These features make indels challenging to use in approaches such as mutation signature analysis, which have been illuminating when applied to single nucleotide substitutions. However, indels have considerable potential for mutation signature analysis if their underpinning challenges can be overcome.
This thesis describes the development of a novel framework that quantifies the ambiguity inherent in indel alignment to systematically score the repetitiveness of the local sequence context. This framework provides means for sequence composition correction and to generate null expectations from any sequence. It allows composition corrected indel rates to be compared between genomic regions and species. This has previously been the limiting factor in current indel analyses, as this thesis outlines whilst characterising indel landscapes in four mouse species. Exploring indel rate variation in human colon cancer genomes revealed an indel mutational signature associated with DNA mismatch repair independently of replication timing. Further evaluation of 2-5-bp deletion rate variation at nucleosomes in other cancers did not indicate a local mutation enrichment.
Strand-specific DNA analyses in this thesis identify indel-substitution clusters in mouse liver cancer, showing that 1bp deletions are caused by base-skipping and downstream substitutions by collateral mutagenesis through translesion synthesis (TLS) polymerases bypassing DNA lesions. Conversely, 1bp insertions downstream of substitutions are caused by collateral mutagenesis rather than DNA damage. In human melanoma, similar deletion-substitution clusters with 1bp deletions in dipyrimidine context were detected. The mutational signature of substitutions downstream of deletions are reminiscent of the collateral mutations found in mouse tumours, suggesting that these clusters are the result of TLS polymerases bypassing UV-induced DNA lesions. Surprisingly, these clusters show that UV-induced damaged Ts in dipyrimidine context may mutate through translesion synthesis. This is typically undetected when considering single base substitutions but these results revealed T mutations as deletions.
Together, this work demonstrates that sequence alignment ambiguity scoring can account for variability in sequence composition in order to make accurate comparison of indel mutation rates across the genome and better resolve aetiology of the events and processes leading to cancer
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
- …
