Biobank-scale ancestral recombination graphs: inference and applications to the analysis of complex traits

Across living species, DNA is transmitted from generation to generation via the processes of inheritance, mutation, and recombination. The history of these processes can be recorded using genome-wide gene genealogies. Accurate inference of gene genealogies from genetic data has the potential to facilitate a wide range of analyses, but is computationally challenging. In this thesis, we introduce a scalable method, called ARG-Needle, that uses genotype hashing and a coalescent hidden Markov model to infer genome-wide genealogies from sequencing or genotyping array data in modern biobanks. We develop strategies that utilise the inferred genome-wide genealogies within linear mixed models to perform association and other analyses of biomedical traits. We validate the accuracy and scalability of ARG-Needle through extensive coalescent simulations, and use ARG-Needle to build genome-wide genealogies from genotypes of 337,464 UK Biobank individuals. We perform genealogy-based association analysis of 7 complex traits, detecting more rare and ultra-rare signals (N = 133, frequency range 0.0004% − 0.1%) than genotype imputation from ∼65,000 sequenced haplotypes (N = 65). We validate these signals using exome sequencing data from 138,039 individuals. ARG-Needle associations strongly tag (average r = 0.72) underlying sequencing variants that are enriched for missense (2.3×) and loss-of-function (4.5×) variation. Compared to imputation, inferred genealogies also capture additional signals for higher frequency variants. These results demonstrate that biobank-scale inference of gene genealogies may be leveraged in the analysis of complex traits, complementing approaches that require the availability of large, population-specific sequencing panels

28th Annual Symposium on Combinatorial Pattern Matching : CPM 2017, July 4-6, 2017, Warsaw, Poland

Peer reviewe

"I Feel This Challenge - But I Don't Have The Background" : Teachers' Responses To Their Bilingual Pupils In 6 Scottish Primary Schools : An Ethnographic Study

The central question of this research project may be stated as 'What are the beliefs about best practice whic influence non-specialist mainstream class teachers when teaching bilingual pupils and how have these beliefs been formed?' This thesis reports on an investigation into the influences on mainstream teachers' practice as they respond to the needs of bilingual children in primary classrooms in the area of Scotland which, until 1996, formed Strathclyde Region. The research reported in this thesis derived from Smyth and McKee (1996) which found that newly qualifying teachers in Scotland did not feel equipped to support bilingual learners in the classroom. a multi-site case study was conducted in twelve classrooms in six education authorities using non-participant observation and interviews with class teachers. The transcriptions of the interviews were analysed to find the cultural models which inform teachers' practice. This analysis found that the Master Model which informed teachers' practice in the context being researched was that 'bilingual pupils need to become monolingual to succeed'. This master model helps to shape and organise the teachers' beliefs and leads to a number of related cultural models. This thesis discusses three of these: - Parents who do not speak English hinder the child's academic progress, by definition, their ability to become monolingual; - the role of schools and literacy events is to promote monolingualism; - those bilingual learners who do not fit the 'Master Model' i.e. those who do not operate monolingually in the dominant language are problematic and require learning support. The cultural models which were found to influence the teachers' practices were not exclusive to teachers in one school or of a certain length of experience, but were found to pertain across the sample of seventeen teachers, albeit with overlaps and internal contradictions. The subtractive view of bilingualism which was found to dominate the Cultural Models in the policy vacuum that exists as regards education for bilingual children in Scotland has been shown (Skutnabb-Kangas, 1981; Cummins, 1984; Gibbons, 1991; Thomas and Collier, 1997) to have long-term detrimental effects on bilingual children’s educational achievement

LIPIcs, Volume 261, ICALP 2023, Complete Volume

LIPIcs, Volume 261, ICALP 2023, Complete Volum

Agency and exchange: an ethnography of a heroin marketplace

This thesis is concerned with the exchange of heroin in localised, street-based marketplaces. Commercial exchange of heroin in such sites has been a characteristic of the Australian heroin scene since the early 1990s. Although some qualitative investigations have been undertaken, the dominant approach to understanding these sites in Australia has been quantitative (primarily epidemiological and criminological). These efforts largely adopt a narrow and under-developed conception of 'markets' and much of this work adopts a narrow and circumscribed conception of the subjects who act within these sites. In contrast, this thesis is positioned within a long tradition of ethnographic accounts of drug users as active agents and of drug markets as embedded in particular social, cultural and economic contexts.In this thesis, I explore two related questions: 1) what are the social relations and processes constituting street-based drug markets, and 2) how do participants in these street-based drug markets express agency, given that, in public and research discourses, they are often understood and depicted either as lacking agency or as expressing agency only through profit-seeking, criminality or both. I explore these questions through an ethnographic examination of the everyday lives of Vietnamese heroin user/dealers who participate in a local heroin marketplace in the Melbourne suburb of Footscray. The key analytical concerns are the social relations through which this particular market is constituted, the social and cultural processes of exchange through which the market is produced and reproduced, and the ways in which participants in the market express agency, including the ways in which their agency might be constrained.My ethnography of the Footscray drug marketplace reveals that the marketplace is constituted by complex and dynamic social processes and relations. With a focus on drug user/dealers, my analysis condenses to two major themes - those of agency and exchange. Throughout the thesis, I show how, and in what ways, drug marketplace participants act on the world, achieve diverse outcomes (intended or otherwise, constrained or not) and, thus, express their agency. I also demonstrate the complexities of heroin exchange in the marketplace, revealing that heroin is exchanged in multiple ways (e.g. through trade, barter and gifts) for multiple purposes and according to multiple and fluid classifications of social relationships. My account shows the embeddedness of the Footscray drug marketplace - that it is shaped by its particular historical, social, cultural, political and economic context. I show also how market processes - such as exchange - are shaped by culturally patterned ideas about what is right, wrong and even conceivable. This thesis also problematises dominant constructions of drug user subjectivity. Such conceptions have ethical and political implications with regard to the ways in which drug users are understood, judged, regulated and governed. My analysis suggests that the subjectivity of Footscray dealers is ambiguous, contradictory and multiple, constituted not simply by instrumental rationality but by a complex of motivations and by the cultural and social formations which shape these motivations.This thesis provides an alternative to the dominant approaches to understanding Australian drug markets and marketplaces. Accounts of drug markets tend to privilege an etic view that is theoretically underpinned by neo-classical economic models of markets. Additionally, the quantitative methodological approaches that predominate in Australian drug market research tend to preclude considerations of process and temporality. In contrast, in this thesis I privilege an emic account of the drug marketplace. Influenced by theoretical frameworks drawn from anthropology, in my examination of the everyday lives of drug user/dealers, I stress the importance of the social, political and cultural dimensions of these people's lives and direct attention to the importance and creativity of personal agency.Drug users and dealers are widely stigmatised and demonised as 'other', juxtaposed against supposedly 'normal' non-drug users. Dominant representations of drug users are unidimensional and do not capture the complexity of drug user agency and subjectivity. This thesis demonstrates that the people who sell heroin in the Footscray marketplace actively engage in a range of exchanges, for a range of purposes - subsistence, the creation of identity, the pursuit of prestige, reciprocity, sociality, the production and reproduction of social relations, and profit-making. My account, therefore, repositions drug users, challenging their stigmatisation by revealing that, in their everyday lives, they struggle with many of the same challenges that confront us all

Advances in Forensic Genetics

The book has 25 articles about the status and new directions in forensic genetics. Approximately half of the articles are invited reviews, and the remaining articles deal with new forensic genetic methods. The articles cover aspects such as sampling DNA evidence at the scene of a crime; DNA transfer when handling evidence material and how to avoid DNA contamination of items, laboratory, etc.; identification of body fluids and tissues with RNA; forensic microbiome analysis with molecular biology methods as a supplement to the examination of human DNA; forensic DNA phenotyping for predicting visible traits such as eye, hair, and skin colour; new ancestry informative DNA markers for estimating ethnic origin; new genetic genealogy methods for identifying distant relatives that cannot be identified with conventional forensic DNA typing; sensitive DNA methods, including single-cell DNA analysis and other highly specialised and sensitive methods to examine ancient DNA from unidentified victims of war; forensic animal genetics; genetics of visible traits in dogs; statistical tools for interpreting forensic DNA analyses, including the most used IT tools for forensic STR-typing and DNA sequencing; haploid markers (Y-chromosome and mitochondria DNA); inference of ethnic origin; a comprehensive logical framework for the interpretation of forensic genetic DNA data; and an overview of the ethical aspects of modern forensic genetics

Absorbing the Worlds of Others: Ruth Prawer Jhabvala’s Adapted Screenplays

Despite being a prolific and well-decorated adapter and screenwriter, the screenplays of Ruth Prawer Jhabvala are largely overlooked in adaptation studies. This is likely, in part, because her life and career are characterised by the paradox of being an outsider on the inside: whether that be as a European writing in and about India, as a novelist in film or as a woman in industry. The aims of this thesis are threefold: to explore the reasons behind her neglect in criticism, to uncover her contributions to the film adaptations she worked on and to draw together the fields of screenwriting and adaptation studies. Surveying both existing academic studies in film history, screenwriting and adaptation in Chapter 1 -- as well as publicity materials in Chapter 2 -- reveals that screenwriting in general is on the periphery of considerations of film authorship. In Chapter 2, I employ Sandra Gilbert’s and Susan Gubar’s notions of ‘the madwoman in the attic’ and ‘the angel in the house’ to portrayals of screenwriters, arguing that Jhabvala purposely cultivates an impression of herself as the latter -- a submissive screenwriter, of no threat to patriarchal or directorial power -- to protect herself from any negative attention as the former. However, the archival materials examined in Chapter 3 which include screenplay drafts, reveal her to have made significant contributions to problem-solving, characterisation and tone. I argue that she develops themes pertinent to her and in Chapter 4 I posit outsider characters in particular as sites of her authorship. In the final chapter I explore the collaborative nature of the working environment which made these contributions possible. I adapt Kamilla Elliott’s incarnational concept of adaptation to reincarnation in order to argue that adaptation and screenwriting are both continual, collaborative processes. Segments of Chapters 2 and 5 have been included in published articles and feature in the appendices: ‘A room with many views: Ruth Prawer Jhabvala’s and Andrew Davies’ adapted screenplays for A Room with a View (1985, 2007)’; and ‘Screenwriting, adaptation and reincarnation: Ruth Prawer Jhabvala’s self-adapted screenplays’.Midlands 3 Cities and the Arts and Humanities Research Counci

A revaluation of E.M. Forster's fiction

This thesis seeks to re-examine the nature of E.M. Forster’s fiction and its place within the canon of modernist writers, examining criticism of Forster’s fiction and claims that it is transitional in its relation to modernism, founded on a liberal humanist outlook antithetical to modernist innovation. The thesis contends that this is a misreading of turn of the century Liberalism, taking Forster’s friend Goldsworthy Lowes Dickinson as an inspiration for Forster’s political and stylistic beliefs, articulated in the latter’s fiction. Following a survey of New Liberalism, the thesis compares Dickinson’s and Forster’s politics and dialogism, charting how Forster transformed Dickinson’s dialogic method into polyphonic prose. After a survey of other self-reflexive narrative practices in Forster’s prose that might also be considered modernist, the thesis turns to Forster’s dialogic construction of inter-negating discourses at play for dominance throughout his fiction. It uses a model of social intervention derived from New Liberalism as the model for articulating the coercive attempts of discourses to gain dominance as truth over individual subjects, focusing particularly on emerging discourses of homosexual identity and their dialogic relation in Forster’s fiction. The thesis claims that Forster’s fiction is dialogic and liberal in its modernism