Epigenetics Flashcards
Describe epigenetic process - cite
Epigenetics, as first described by Conrad Waddington, used to explain the dynamic way by which genetic variation interacts with environmental exposures across development to produce a phenotype. This is through dynamic changes in the transcription independent of the genomic DNA sequence, primarily via modifications of the DNA, histones and chromatin structure.
Genetic information flows from DNA to mRNA to protein. Changes in the rate of transcription of mRNA are used to control the rate at which genes produce proteins and can be based on responses to environmental changes.
Epigenetics is a related to this gene expression and focuses on understanding a developmentally stable change in certain mechanisms in gene expression that do not alter DNA sequence and can be passed from one cell to its daughter cells (Bird, 2007).
These epigenetic marks that tell your genes to switch on or off. It may be through epigenetic marks that environmental factors like diet and stress can change gene expression from one cell to its daughter cells, and in some cases from one generation to the next, known as imprinting.
who first decribed epigenetics?
Conrad Waddington,
factors that should be considered in choosing between approaches include ..
amount of DNA available, presence or lack of a priori hypotheses regarding biological pathways of interest, and cost
what is the most widely studied mechanism of epigenetic regulation? and what is this? (CITE)
DNA methlyation (DNAm) = DNAm is an epigenetic process that regulates gene expression and has emerged as a potentional mechanism through which the genome can capture the effects of environmental exposures and propagate their influences (McKay et al 2012).
DNAm refers to the addition of a methyl group to the 5th carbon in cytosine ring, primarily in the context of cytosine guanine (CpG) dinucleotides. CpG sites tend to cluster in CpG islands, which themselves tend to be in embedded in promotor regions of genes. Increased methylation in these regions is associated with inhibition of gene transcription (i.e gene silencing) which provides a mechanism by which DNAm can trigger long term alterations in the phenotype.
increased methlyation of promotor regions is associated with..
inhibition of gene transcription (i.e gene silencing) which provides a mechanism by which DNAm can trigger long term alterations in the phenotype.
Candidate study: intelligence
Haggarty et al., (2010) - used candidate polymorphisms
in four DNA methyltransferases involved in epigenetic marking and related these to childhood and adult general intelligence in a population who had all taken the same test of intelligence at age 11yrs.
= They found a significant association between the minor T allele of DNMT3L SNP 11330C>T and a higher childhood intelligence score
The association between genetic variation in DNMT3L and childhood intelligence reported here must be considered an initial and as yet un-replicated finding, with the priority being to replicate the association in other populations. An association between DNMT3L and intelligence would be consistent with the critical role of DNMT3L in imprinting and the evidence linking imprinting to cognitive function but more work is needed to determine which function of DNMT3L is influenced by the 11330C>T variant and to investigate how this process might influence human intelligence.
The role of epigenetics in human complex traits such as intelligence is difficult to study for a number of reasons. Epigenetic status can be influenced by factors such as diet and alcohol therefore, depending on the epigenetic mark of interest, there is a danger of reverse causality, where lifestyle choices linked to intelligence may influence epigenetic status.
what was the variant found by Haggarty et al., 2010
the minor T allele of DNMT3L SNP 113330C>T allele
what is EWAS?
EWAS methods examine the methylation state at tens of thousands of loci throughout the genome to determine if any of the loci are associated with a phenotype or disease.
EWAS can be performed using microarrays, these assess the degree of expression of all genes in the genome including non-coding RNA (the transcriptome) and profiles of DNA methylation of all coding genes in the genome (epigenome). Because gene expression and methylation are sensitive to the environment, the transcriptome and epigenome could be useful biomarkers of environmental change.
evaluations of EWAS
Conversely to candidate approach, the genome-wide approach offers advantages of novel discovery and detection of genome-wide effects and epigenetic marks in previously unconsidered biological systems.
But, EWAS carries its own challenges of larger volume of input DNA, higher cost, large datasets, and complex statistical methods to account for multiple testing.
However, overall coverage of CpG sites is still low (2% of all sites in human genome, meaning many regions are underrepresented. None of these methods covers all of the CpG sites in the human genome, which can only be accomplished through whole genome bisulfite sequencing (WGBS). The method of WGBS assays over a billion reads per sample across the entire methylome at single-base pair resolution, but is costly.
what method covers all CpG sites?
whole genome bisulfite sequencing (WGBS).
DNA methylation levels change with age and are influenced by lifestyle and environmental factors as well as by genetic variation (CITE)
Bell et al., 2012
EWAS example study - describe initial study then the follow-up EWAS
Marioni et al., 2015 - test whether differences between people’s chronological ages (the number of years a person has lived) and DNA methylation age, predict all-cause mortality in later life.
The difference between DNA methylation age and chronological age (T) was calculated in four longitudinal cohorts of older people using two epigenetic markers (Hannum et al., 2013).
= A 5-year higher (T) is associated with a 21% higher mortality risk, adjusting for age and sex.
=After further adjustments for childhood IQ, education, social class, hypertension, diabetes and cardiovascular disease, there is a 16% increased mortality risk for those with a 5-year (T).
=heritability of T was 0.43.
= DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.
Individual genetic or environmental exposures that drive the associations are not yet known… lead onto other Marioni 2015…
Marioni et al., 2015 - later examined cross-sectional and longitudinal associations between the epigenetic clock and four mortality-linked markers of physical and mental fitness: lung function, walking speed, grip strength and cognitive ability.
= there was evidence to link DNA methylation-based age acceleration with measures of physical and mental fitness. They found significant cross-sectional correlations at 70 years between age acceleration and fluid cognitive ability, grip strength and lung function; higher methylation age acceleration was linked to poorer fitness
= BUT – although all of the fitness variables declined over time, age acceleration did not correlate with subsequent change over 6 years.
= There were no significant associations between individual CpG methylation sites and any of the four fitness traits. No EWAS hits.
There are several explanations for these null results: (i) there are genuinely no longitudinal associations;(ii) the rate of change in the fitness variables is small, which means larger samples or longer follow-up periods may be required to identify effects; or (iii) related to the previous point, the cohort under investigation may be too young and fit to observe sufficiently large and reliable declines.
A strength of the study is the availability of longitudinal measures of fitness and DNA methylation on a moderately large sample with a narrow age range.
DNA methylation provides a mechanism by which environmental factors, including exercise, could modify genetic predisposition to disease
Implications of epigenetics
Discordance of monozygotic twins is usually explained by the differential effect of environmental factors, however identification of disease-specific environmental factors has been a significant challenge… such differential expression, congruent with disease discordance, might indicate causal genes that are differentially activated by epigenetic factors Petronis, 2001
Although carrying identical DNA sequences, MZ might exhibit numerous epigenetic differences. An epigenetic defect might progress after separation of the twins and reach the ‘threshold’ of clinical symptoms in one twin, whereas the other twin might remain below and show no symptoms at all. Such epigenetic differences in the critical DNA region could result in differences in the age of onset, disease severity and the symptom profile; that is, variable expressivity.
Because epigenetic mechanisms are known to respond to both genes and environment, they represent a mechanism by which we can explain the gene-environment interplay (Meaney, 2010). Epigenetic modifications may therefore be a useful marker of prior environmental exposures that cannot otherwise be assessed.
Delineating the mechanistic role of DNAm is crucial to clarify its potential utility in the prevention, detection and treatment of psychopathology. If a DNAm casual link is identified in the aetiology of a disease, then reversing the epigenetic markers might help alleviate the burdens of disease. However, it is equally possible that DNAm functions as a non-causal biomarker of environmental risk exposure – DNAm may be the consequence of disease aetiology rather than a causal mechanism within the disease process.
Limitations and overcoming these
• A key issue is reverse causation, whereby the observed DNAm changes may be a consequence – as opposed to a risk factor for – psychopathology. This can be partially addressed by using a prospective design that accurately captures temporal order, especially in the case where the availability of repeated measures data make it possible to trace longitudinal interrelationships between risk exposures, DNAm and psychopathology.
• First, we need to reach a more complete understanding of environmental effects on DNAm. Exposures are often correlated – for example, stress levels in pregnancy have been associated with quality of diet (Barker, et al, 2013). Yet, epigenetic studies to date have typically examined single exposures in isolation, potentially resulting in the overestimation of effects observed. In future, modelling multiple exposures and/or outcomes simultaneously (e.g. via path analysis) may help to isolate specific risk pathways with greater accuracy,
variability. Unlike the genome – which remains mostly stable across the life span – DNAm is dynamic over time and varies across multiple factors, including sex, age, tissue and cell type. A study found that methylation was associated with age in 28% of CpG sites (Xu and Taylor, 2014). Consequently, it has been difficult to establish what a ‘normative’ profile of DNAm is and how far such profile must deviate in order to confer risk for psychopathology.
o The second aspect is scale. At present, we are only able to access a small part of a much wider system that needs to be fully mapped out. Indeed, commonly used platforms such as the Illumina 450k only capture around 2% of methylomic variation across the genome. In turn, the methylome as a whole is only one of multiple epigenetic mechanisms that work in concert, including noncoding RNAs, histone modifications and other types of chromatin remodelling. As a result, many epigenetic patterns of potential relevance to psychopathology remain largely inaccessible (Non & Thayer, 2015).
