DNA Modifications and Alzheimer's Disease

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this recordAlzheimer's disease (AD) is a complex neurodegenerative disease, affecting millions of people worldwide. While a number of studies have focused on identifying genetic variants that contribute to the development and progression of late-onset AD, the majority of these only have a relatively small effect size. There are also a number of other risk factors, for example, age, gender, and other comorbidities; however, how these influence disease risk is not known. Therefore, in recent years, research has begun to investigate epigenetic mechanisms for a potential role in disease etiology. In this chapter, we discuss the current state of play for research into DNA modifications in AD, the most well studied being 5-methylcytosine (5-mC). We describe the earlier studies of candidate genes and global measures of DNA modifications in human AD samples, in addition to studies in mouse models of AD. We focus on recent epigenome-wide association studies (EWAS) in human AD, using microarray technology, examining a number of key study design issues pertinent to such studies. Finally, we discuss how new technological advances could further progress the research field

The Pagoda Sequence: a Ramble through Linear Complexity, Number Walls, D0L Sequences, Finite State Automata, and Aperiodic Tilings

We review the concept of the number wall as an alternative to the traditional linear complexity profile (LCP), and sketch the relationship to other topics such as linear feedback shift-register (LFSR) and context-free Lindenmayer (D0L) sequences. A remarkable ternary analogue of the Thue-Morse sequence is introduced having deficiency 2 modulo 3, and this property verified via the re-interpretation of the number wall as an aperiodic plane tiling

Elucidating novel dysfunctional pathways in Alzheimer's disease by integrating loci identified in genetic and epigenetic studies

PublishedReviewJournalThis is the author accepted manuscript. The final version is freely available from Elsevier via the DOI in this record.© 2016 The Authors.Alzheimer's disease is a complex neurodegenerative disorder. A large number of genome-wide association studies have been performed, which have been supplemented more recently by the first epigenome-wide association studies, leading to the identification of a number of novel loci altered in disease. Twin studies have shown monozygotic twin discordance for Alzheimer's disease (Gatz et al., 2006), leading to the conclusion that a combination of genetic and epigenetic mechanisms is likely to be involved in disease etiology (Lunnon & Mill, 2013). This review focuses on identifying overlapping pathways between published genome-wide association studies and epigenome-wide association studies, highlighting dysfunctional synaptic, lipid metabolism, plasma membrane/cytoskeleton, mitochondrial, and immune cell activation pathways. Identifying common pathways altered in genetic and epigenetic studies will aid our understanding of disease mechanisms and identify potential novel targets for pharmacological intervention.This work was funded by a grant from Bristol Research into Alzheimer's and Care of the Elderly and the Alzheimer's Society (grant AS-PG-14-038) to KL

DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson’s Individuals with GBA1 Mutations

Parkinson’s disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated

Meanders and the Temperley-Lieb algebra

The statistics of meanders is studied in connection with the Temperley-Lieb algebra. Each (multi-component) meander corresponds to a pair of reduced elements of the algebra. The assignment of a weight $q$ per connected component of meander translates into a bilinear form on the algebra, with a Gram matrix encoding the fine structure of meander numbers. Here, we calculate the associated Gram determinant as a function of $q$, and make use of the orthogonalization process to derive alternative expressions for meander numbers as sums over correlated random walks.Comment: 85p, uuencoded, uses harvmac (l mode) and epsf, 88 figure

Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue

Background: DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. Results: We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions (p < 0.05) in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples (N = 3 matched donors). Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. Using unsupervised hierarchical clustering analysis of the mitochondrial DNA methylome, we were able to identify tissue-specific patterns of mitochondrial DNA methylation between blood, cerebellum and cortex. Conclusions: Our study represents a comprehensive analysis of the mitochondrial methylome using pre-existing Methylated DNA Immunoprecipitation Sequencing data to identify brain region-specific patterns of mitochondrial DNA methylation

A data-driven approach to preprocessing Illumina 450K methylation array data

As the most stable and experimentally accessible epigenetic mark, DNA methylation is of great interest to the research community. The landscape of DNA methylation across tissues, through development and in disease pathogenesis is not yet well characterized. Thus there is a need for rapid and cost effective methods for assessing genome-wide levels of DNA methylation. The Illumina Infinium HumanMethylation450 (450K) BeadChip is a very useful addition to the available methods for DNA methylation analysis but its complex design, incorporating two different assay methods, requires careful consideration. Accordingly, several normalization schemes have been published. We have taken advantage of known DNA methylation patterns associated with genomic imprinting and X-chromosome inactivation (XCI), in addition to the performance of SNP genotyping assays present on the array, to derive three independent metrics which we use to test alternative schemes of correction and normalization. These metrics also have potential utility as quality scores for datasets.|The standard index of DNA methylation at any specific CpG site is β = M/(M + U + 100) where M and U are methylated and unmethylated signal intensities, respectively. Betas (βs) calculated from raw signal intensities (the default GenomeStudio behavior) perform well, but using 11 methylomic datasets we demonstrate that quantile normalization methods produce marked improvement, even in highly consistent data, by all three metrics. The commonly used procedure of normalizing betas is inferior to the separate normalization of M and U, and it is also advantageous to normalize Type I and Type II assays separately. More elaborate manipulation of quantiles proves to be counterproductive.|Careful selection of preprocessing steps can minimize variance and thus improve statistical power, especially for the detection of the small absolute DNA methylation changes likely associated with complex disease phenotypes. For the convenience of the research community we have created a user-friendly R software package called wateRmelon, downloadable from bioConductor, compatible with the existing methylumi, minfi and IMA packages, that allows others to utilize the same normalization methods and data quality tests on 450K data

Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer's disease: looking in the correct place at the right time?

This is the final version. Available from Springer Verlag via the DOI in this record.Even though the etiology of Alzheimer's disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.Funds have been provided by the Joint Programme—Neurodegenerative Disease Research (JPND) for the EPI-AD consortium focusing on epigenetic dysregulation in the brainstem in Alzheimer’s Disease (http://www.neurodegenerationresearch.eu/wp-content/uploads/2015/10/Factsheet_EPI-AD.pdf). The project is supported through the following funding organizations under the aegis of JPND—http://www.jpnd.eu, The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw); United Kingdom, Medical Research Council; Germany, German Federal ministry of Education and Research (BMBF); Luxembourg, National Research Fund (FNR). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 643417. Additional support has been provided by the UK Medical Research Council (MRC) Grant MR/N027973/1 (K.L), Alzheimer’s Association (US) New Investigator Research Grant NIRG-14-320878 (K.L), Alzheimer’s Society (UK) Grant AS-PG-14-038 (K.L), the Internationale Stichting Alzheimer Onderzoek (ISAO) Grants 7551 and 11532 (D.L.A vdH.), the ISAO Grant 12530 (G.K), the ISAO Grant 13515 (B.P.F.R), and the Netherlands Organization for Scientific Research (NWO) Grant 916.11.086 (Veni Award) (B.P.F.R)

Classification of one-dimensional quasilattices into mutual local-derivability classes

One-dimensional quasilattices are classified into mutual local-derivability (MLD) classes on the basis of geometrical and number-theoretical considerations. Most quasilattices are ternary, and there exist an infinite number of MLD classes. Every MLD class has a finite number of quasilattices with inflation symmetries. We can choose one of them as the representative of the MLD class, and other members are given as decorations of the representative. Several MLD classes of particular importance are listed. The symmetry-preserving decorations rules are investigated extensively.Comment: 42 pages, latex, 5 eps figures, Published in JPS

Transcriptional Signatures of Tau and Amyloid Neuropathology

Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.WT_/Wellcome Trust/United Kingdom MR/M008924/1/MRC_/Medical Research Council/United Kingdompublished version, accepted version, submitted versio