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Aims The Irish DNA Atlas is a DNA collection being assembled with the aim of describing the fine-scale population structure in Ireland. Understanding such structure can inform on optimal design of clinical genetic studies as well as the history of the Irish population. We will present an overview of and the preliminary findings from the study. Methods We are recruiting individuals with all eight greatgrandparents born in Ireland, within 30 kilometres of each other. Participants are asked to complete a detailed birth-brief, which records place and date of birth of three generations of ancestors. We also collect some basic health-related details. DNA is extracted from a saliva sample. We have genotyped using an Illumina OmniExpressdense SNP genotyping platform. We present a number of analyses designed to visualise genetic structure, including; Principle Component, ADMIXTURE, and Runs of Homozygosity analysis. Results To date we have recruited 162 participants. The mean great-grandparental area is 32 kilometres, with an average greatgrandparental date of birth of 1850. Therefore the individuals in the Atlas provide insight to the genetic landscape of Ireland before significant movement of people from the 20th century onwards. An analysis of dense genotyping data from 142participants shows that the Atlas participants cluster closely with British individuals in a Europe wide PCA, but present different ancestral population components when compared with British, and other European populations. Irish individuals also present slightly higher levels of homozygosity relative to mainland European levels. PCA targeted at specific areas of interest within Ireland also hint at fine-scale substructure. Conclusion Ireland shows typical features of a homogenous population, well suited to the study of rare variation in disease risk., Background Progress in diagnostic and therapeutic strategies in medicine is dependent upon high-quality biomedical research. Translation of research findings into the clinic relies on patient participation in innovative clinical trials. We investigated attitudes to genetic research in Ireland, in particular with respect to commercial and financial implications. Methods A multi-centre cross-sectional survey study was performed. Consecutive patients attending four out-patient clinics were asked to complete paper-based questionnaires. An electronic version of the same questionnaire was created on Survey Monkey with a link made public on a social media website for a period of 24 hours. Data was analysed using SPSS. Results 351 questionnaires were completed (99 paper, 252 electronic). The majority of respondents were female (n = 288, 82%), and highly educated, with 244 (70%) attending college/university. Most participants supported genetic research (267, 76%), more frequently for common diseases (274, 78%) than rare disorders (204, 58%, p < 0.001, x2). 103 (29%) had participated in scientific research, and 57(16%) had donated material to a bio-bank. The majority (n = 213, 61%) would not support research with potential financial/commercial gain. 106(30%) would decline to participate in research if researchers would benefit financially, compared to 49(14%) if the research was supported by a pharmaceutical company, (p < 0.001, x2). Respondents would provide buccal samples (258, 74%) more readily than tissue (225, 64%) or blood (222, 63%). Conclusion A high level of support for genetic research exists among the Irish population, but active participation is dependent upon a number of factors, notably, type of biological material required, frequency of the disease in question, and commercial interest of the researchers., Introduction Although the etiology of schizophrenia (SZ) is largely unknown, it is increasingly clear that genetic and environmental interactions contribute to cognitive deficits associated with this disorder. Recent Genome wide association studies (GWAS) have indicated a link between SZ and immune dysregulation, especially genetic mutations related to the major histocompatibility complex (MHC). Cognitive deficits are core features of Schizophrenia and related disorders, which relate to genetic risk. This study aims to explore the relationship between MHC risk variants for SZ and cognitive deficits, while also relating findings to brain activity. Methods To test if MHC risk variants impair cognition, ANCOVA analysis is performed on genetics data previously collected in a GWAS. Cognition measures are compared in groups with and without MHC genetic risk, in a population of SZ sufferers and healthy controls. Functional MRI imaging will also be performed to test if genetic risk relates to altered neural activity. Results Preliminary analyses suggest that MHC risk variants contribute to impairments in cognition in domains of social cognition, IQ and attention. Further analysis will be performed to test for environmental mediators of this relationship, looking at cannabis use and urbanicity. BOLD fMRI will also be used to test for a relationship between MHC risk and altered neural activity, using MATLAB SPM. Conclusions The MHC genetic variant may serve as a significant risk marker for schizophrenia, and further elucidate etiology of this neurodevelopmental disorder. Future studies on neurobiology of social cognition, and greater knowledge of genetic risk may establish targets for interventions., Aim To create a bioluminescence mouse model which expresses firefly luciferase in the corneal epithelium to assess gene editing and gene silencing for the cornea. Methods A gene targeting vector was generated where the Krt12 coding sequence in and the splice donor site of exon 1 were replaced with a transgene cassette containing a luc2-Multiple Targeting Cassette (MTC) gene fusion. The vector was transfected by electroporation into the Taconic Artemis C57BL/6N Tac ES cell line. Homologous recombinant clones were isolated and validated, and the mice bred with luc2-positive/ PuroR-negative offspring used for colony establishment. To visualise the expression of luc2 within the corneal epithelium, luciferin substrate diluted in viscotears was applied to the front of the eye and then luciferase expression was imaged and assessed using a Xenogen IVIS Lumina Imager and LivingImage 3.2 software. Intrastromal injection of siGlo siRNA was used to determine the localisation of siRNA within the corneal epithelium and then the established mouse model was treated with either native or Accell “self-delivery” siRNA. Results The Accell “self-delivery” siRNA induced potent sustained allele specific silencing for 7 days, while native versions of siRNA resulted in significant knock-down for 1 day only (p < 0.05). We have created and validated a bioluminescence mouse model and have utilised it to assess siRNA in vivo. This mouse model coupled with the Lumina imager will allow us to assess topical delivery of gene therapies to the ocular surface allowing validation for future translation to clinical use., Background Methylation of DNA sequences at promoters, CpG islands and other elements plays a vital role in regulating gene activity. In human, loss of methylation is known to play a causative role in imprinting disorders and in inappropriate germline gene expression in cancers. While in mouse, loss of function mutants have given great insight into the targets of methylation, functional studies in human have been largely limited to cancer cells and more recently stem cells, not normal adult cells. Methods Stable knockdowns of the maintenance methyltransferase DNMT1 were generated in normosomic hTERT-immortalised adult fibroblasts. Genome-wide methylation levels were assayed using the Illumina 450K bead array. Results were analysed using RnBeads and Galaxy. Locusspecific methylation was verified using pyrosequencing and clonal analysis. Validation was achieved using transient siRNA. Results Loss of function was poorly tolerated and all clonally-expanded cell lines had spontaneously restored DNMT1 levels by silencing of the shRNA. Evidence for a genome-wide methylation erasure event followed by a wave of remethylation could be clearly traced. Gene bodies and the shores of CpG islands showed the clearest loss of methylation overall. While most CpG islands are normally unmethylated and so unaffected, both imprints and germline genes fall into the rarer category of normally methylated islands: of these two, lasting loss of methylation was much more common among imprints than germline genes. Conclusions 1: transient loss of methylation is poorly tolerated; 2: a robust mechanism for remethylation exists even in adult cells; 3: aberrant remethylation is frequent on recovery and 4: Imprints are particularly sensitive., Background Dihydrofolate reductase (DHFR) is essential for the conversion of folic acid to active folate needed for one-carbon metabolism. Common genetic variation within DHFR is restricted to the noncoding regions and previous studies have focused on a 19 bp deletion/insertion polymorphism (rs70991108) within intron 1. Reports of an association between this polymorphism and blood folate biomarker concentrations are conflicting. Objective We aimed to evaluate whether the DHFR 19bp deletion/ insertion polymorphism affects circulating folate biomarkers in the largest cohort to address this question to date. Methods Young healthy Irish individuals (n= 2,507) between 19 to 36 years old were recruited between February 2003 and 2004. Folic acid intake from supplements and fortified foods was assessed using a customized food intake questionnaire. Concentrations of serum folate and vitamin B-12, red blood cell (RBC) folate and plasma total homocysteine (tHcy) concentration were measured. Data were analysed using linear regression models. Results Folic acid intake was positively associated with serum (P 326μg folic acid/day; P = 0.96). A non-significant trend towards lower RBC folate by genotype (P = 0.09) was observed in the lowest folic acid intake quintile (0 – 51 μg/day). Conclusion In this cohort of young healthy individuals the DHFR 19bp deletion allele does not significantly affect circulating folate status, irrespective of folic acid intake. Our data rule out a strong functional effect of this polymorphism on blood folate concentrations.

Meningococcal disease has had devastating consequences in Northern Ireland since its first description locally in 1859. The incidence of this disease has significantly declined in recent years, however it is important to understand reasons for this changing epidemiology and to acknowledge the diagnostic and clinical management developments that have been made locally. This review aims to examine the changing face of this disease in Northern Ireland over the years, with particular reference to local disease prevention, epidemiology, diagnosis, clinical treatment and management, post-disease sequelae and the role of meningitis charities locally, in terms of patient support and research.

The cornea represents an ideal tissue to elucidate the potential of molecular medicine to treat genetic disorders. It is a small,readily accessible tissue that is easy to monitor treat topically, while a number of corneal disorders are well characterizedwith regard to a known genetic cause. In addition, due to their genetic basis most of these conditions are bilateral, affecting both corneas, allowing for a clear comparison between treated and untreated tissue using the fellow eye as a control.Currently, molecular techniques utilising siRNAs, CRISPR/Cas9, TALENS and ZFNs are being evaluated by many for theirtherapeutic potential for corneal disorders. Methodologies are discussed within this review with particular emphasis on themore recent and emerging field of CRISPR/Cas9-based therapeutics. Since the advent of gene therapies, effective deliveryhas been a challenge. Potential ocular delivery techniques include viral vectors, nanoparticles or physical injection.Studies employing in vitro and in vivo models of corneal disorders have demonstrated promising results for treatment by moleculartechniques. However, many of these studies have not translated into the clinic, perhaps due to a lack of good animal models for preclinical testing or failure to develop suitable delivery methods. Until this occurs it is difficult to fully gauge theusefulness of these techniques to treat corneal disorders in human patients over a sustained time period. Here we present a review of current research into molecular-based therapies for genetic corneal disorders and discuss theapplicability of these studies to advancing translational research for other genetic disorders.

Randomly diluted quantum boson and spin models in two dimensions combine the physics of classical percolation with the well-known dimensionality dependence of ordering in quantum lattice models. This combination is rather subtle for models that order in two dimensions but have no true order in one dimension, as the percolation cluster near threshold is a fractal of dimension between 1 and 2: two experimentally relevant examples are the O(2) quantum rotor and the Heisenberg antiferromagnet. We study two analytic descriptions of the O(2) quantum rotor near the percolation threshold. First a spin-wave expansion is shown to predict long-ranged order, but there are statistically rare points on the cluster that violate the standard assumptions of spin-wave theory. A real-space renormalization group (RSRG) approach is then used to understand how these rare points modify ordering of the O(2) rotor. A new class of fixed points of the RSRG equations for disordered one-dimensional bosons is identified and shown to support the existence of long-range order on the percolation backbone in two dimensions. These results are relevant to experiments on bosons in optical lattices and superconducting arrays, and also (qualitatively) for the diluted Heisenberg antiferromagnet La-2(Zn,Mg)(x)Cu1-xO4.

Diagnostic medical bacteriology consists of two main components: identification and typing. Molecular biology has the potential to revolutionize the way in which diagnostic tests are delivered in order to optimize the care of infected patients, whether they are in hospital or in the community. Since the discovery of the polymerase chain reaction (PCR) in the late 1980s, an enormous amount of research has enabled the introduction of molecular tests into several areas of routine clinical microbiology. Molecular biology techniques continue to evolve rapidly, and many laboratories have been reluctant to introduce these new methods due to concerns that the technology would become outdated. In consequence, the vast majority of clinical bacteriology laboratories do not currently use any molecular diagnostics, although such technology is becoming more widespread in specialized regional laboratories, as well as in national reference laboratories. Presently, molecular biology offers a wide repertoire of techniques and permutations. This chapter is intended to explore the application of these in the diagnostic laboratory setting.

We investigate the bulk band structures and the surface states of Bi2Se3 and Bi2Te3 topological insulators using first principles many body perturbation theory based on the GW approximation. The quasiparticle self energy corrections introduce significant changes to the bulk band structures surprisingly leading to a decrease in the direct band gaps in the band inversion regime as opposed to the usual situation without band inversion. Parametrized “scissors operators” derived from the bulk studies are then used to investigate the electronic structure of slab models which exhibit topologically protected surface states. The introduction of self energy corrections results in significant shifts of the surface state Dirac point energies relative to the bulk bands and in enlarged gap openings from the interactions between the surface states across the thin slab both in agreement with experimental data.