Demography and the age of rare variants

Large whole-genome sequencing projects have provided access to much of the rare variation in human populations, which is highly informative about population structure and recent demography. Here, we show how the age of rare variants can be estimated from patterns of haplotype sharing and how these ages can be related to historical relationships between populations. We investigate the distribution of the age of variants occurring exactly twice (f2 variants) in a worldwide sample sequenced by the 1000 Genomes Project, revealing enormous variation across populations. The median age of haplotypes carrying f2 variants is 50 to 160 generations across populations within Europe or Asia, and 170 to 320 generations within Africa. Haplotypes shared between continents are much older with median ages for haplotypes shared between Europe and Asia ranging from 320 to 670 generations. The distribution of the ages of f2 haplotypes is informative about their demography, revealing recent bottlenecks, ancient splits, and more modern connections between populations. We see the signature of selection in the observation that functional variants are significantly younger than nonfunctional variants of the same frequency. This approach is relatively insensitive to mutation rate and complements other nonparametric methods for demographic inference.Comment: Revised versio

Digital health technologies in a deprived community: a qualitative co-design study.

An ever-growing body of literature is recognising the multitude of ways in which digital health technologies are impacting health. In Scotland, healthcare is becoming increasingly digitised. However, access to and usage of digital health technologies is unequal between socioeconomic positions. Despite this, research remains silent on digital health and health inequalities. The present study investigates the health and well-being needs of a deprived community, and how digital health technologies could be implemented to meet those needs. An interpretative, qualitative approach was adopted. Eighteen residents from the deprived community of Raploch, Stirling were recruited. Participants were split into two age cohorts 26-49 (N=4) and 50+ years of age (N=14). Three focus group discussions and a semi-structured interview were used to explore the digital health needs of the residents, using open-ended questions and co-design activities. Grounded theory was used to analyse the transcribed data. The findings revealed that there are a multitude of accessibility and affordability relations that influenced the everyday experience of the residents. The complex assemblage of relations must be understood and addressed if digital health interventions are to be successfully implemented into a deprived community. The study indicated that the co-designed ideas of community hub digital health interventions and digital video consultations could alleviate, rather than exacerbate, health and well-being issues in the community with appropriate support

The Practice of graphic design and architectural theory: A Study of two disciplines

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Spatiotemporal dynamics of the DNA double strand break marker 53BP1 after exposure to ionising radiation

This thesis was submitted for the degree of Doctor of Philosophy and was awarded by Brunel University53BP1 is known to be involved in the DNA damage response and has been shown to localise into discrete foci at the site of DNA double strand breaks (DSBs) after exposure to ionising radiation (IR). Quantification of radiation induced foci (RIF) at varying times after exposure has been used to assess the induction of DSB and kinetics of their decline, suggestive of repair. In addition, the size and relative nuclear distribution of foci, observed at different times after IR, could provide insights into the dynamics of these foci that may be relevant for understanding mechanisms of chromosome exchange. To assess this human bronchial epithelial (HBEp) cells, which are the primary target for 50% of our average annual radiation exposure, have been irradiated with low linear energy transfer (LET) 60Co γ-rays (0- 2.0 Gy) or 238Pu high LET α-particles (~1α-particle/nucleus LET 121-235 keV/μm). DSB were quantified at various time points (0-24hrs) after IR, stained for 53BP1 and categorised into three sizes (1.0μm in diameter).The data generated was used to ask questions on the radiobiological DSB response of HBEp cells (chapter 4), the recruitment of 53BP1 to DSB and the possible dynamics of DSB for repair. In addition, immortalised HBEp cells transfected with 53BP1-GFP fusion protein were irradiated with 60Co γ-rays and analysed to further assess the spatio-temporal aspects of DSB in live cells. After exposure to 2Gy γ-rays peak induction of 53BP1 was observed within 30 min (22foci) with a subsequent decline to sham levels (2 foci) after 24hrs. For the quantification of spatiotemporal dynamics (chapter 5), a bespoke foci analysis tool was developed (chapter 3) to provide detailed measurements of RIF number, size and relative location with greater speed and reliability than manual counting and categorising method. This novel approach to foci analysis provides evidence for limited (<1μm) movement of foci is presented that may support the ICN model for chromosomal exchange aberrations

Development and validation of 'AutoRIF': Software for the automated analysis of radiation-induced foci

Copyright @ 2012 McVean et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Background: The quantification of radiation-induced foci (RIF) to investigate the induction and subsequent repair of DNA double strands breaks is now commonplace. Over the last decade systems specific for the automatic quantification of RIF have been developed for this purpose, however to ask more mechanistic questions on the spatio-temporal aspects of RIF, an automated RIF analysis platform that also quantifies RIF size/volume and relative three-dimensional (3D) distribution of RIF within individual nuclei, is required. Results: A java-based image analysis system has been developed (AutoRIF) that quantifies the number, size/volume and relative nuclear locations of RIF within 3D nuclear volumes. Our approach identifies nuclei using the dynamic Otsu threshold and RIF by enhanced Laplacian filtering and maximum entropy thresholding steps and, has an application ‘batch optimisation’ process to ensure reproducible quantification of RIF. AutoRIF was validated by comparing output against manual quantification of the same 2D and 3D image stacks with results showing excellent concordance over a whole range of sample time points (and therefore range of total RIF/nucleus) after low-LET radiation exposure. Conclusions: This high-throughput automated RIF analysis system generates data with greater depth of information and reproducibility than that which can be achieved manually and may contribute toward the standardisation of RIF analysis. In particular, AutoRIF is a powerful tool for studying spatio-temporal relationships of RIF using a range of DNA damage response markers and can be run independently of other software, enabling most personal computers to perform image analysis. Future considerations for AutoRIF will likely include more complex algorithms that enable multiplex analysis for increasing combinations of cellular markers.This article is made available through the Brunel Open Access Publishing Fund

Integrating genealogical and dynamical modelling to infer escape and reversion rates in HIV epitopes

The rates of escape and reversion in response to selection pressure arising from the host immune system, notably the cytotoxic T-lymphocyte (CTL) response, are key factors determining the evolution of HIV. Existing methods for estimating these parameters from cross-sectional population data using ordinary differential equations (ODE) ignore information about the genealogy of sampled HIV sequences, which has the potential to cause systematic bias and over-estimate certainty. Here, we describe an integrated approach, validated through extensive simulations, which combines genealogical inference and epidemiological modelling, to estimate rates of CTL escape and reversion in HIV epitopes. We show that there is substantial uncertainty about rates of viral escape and reversion from cross-sectional data, which arises from the inherent stochasticity in the evolutionary process. By application to empirical data, we find that point estimates of rates from a previously published ODE model and the integrated approach presented here are often similar, but can also differ several-fold depending on the structure of the genealogy. The model-based approach we apply provides a framework for the statistical analysis of escape and reversion in population data and highlights the need for longitudinal and denser cross-sectional sampling to enable accurate estimate of these key parameters

The digital health and wellbeing needs, or otherwise, of a deprived Scottish community.

Healthcare is becoming increasingly digitised. Access and usage of digital health technologies however is unequal in deprived communities. Despite this disparity, research remains silent on digital health and health inequalities. The present study investigates the health and well-being needs of a deprived community and how digital health technologies could be implemented to meet those needs. An interpretative, qualitative approach was adopted. 18 residents from the deprived community of Raploch, Stirling were recruited. Participants were split into two age cohorts 26-49 (N=4) and 50+ years of age (N=14). Three focus group discussions and a semi-structured interview were used to explore the digital health needs of the residents using open-ended questions. The findings revealed that there are multitude of accessibility relations that influenced the everyday experience of the residents. The complex assemblage of relations must be understood and addressed if digital health interventions are to be successfully implemented into a deprived community

Molecular evolution of the sheep prion protein gene

Transmissible spongiform encephalopathies (TSEs) are infectious, fatal neurodegenerative diseases characterized by aggregates of modified forms of the prion protein (PrP) in the central nervous system. Well known examples include variant Creutzfeldt-Jakob Disease (vCJD) in humans, BSE in cattle, chronic wasting disease in deer and scrapie in sheep and goats. In humans, sheep and deer, disease susceptibility is determined by host genotype at the prion protein gene (PRNP). Here I examine the molecular evolution of PRNP in ruminants and show that variation in sheep appears to have been maintained by balancing selection, a profoundly different process from that seen in other ruminants. Scrapie eradication programs such as those recently implemented in the UK, USA and elsewhere are based on the assumption that PRNP is under positive selection in response to scrapie. If, as these data suggest, that assumption is wrong, eradication programs will disrupt this balancing selection, and may have a negative impact on the fitness or scrapie resistance of national flocks