Download: PPT. Genetic parent-of-origin effects: Sex chromosomes and mitochondria Genes on the sex chromosomes are inherited in a parent-of-origin dependent manner and the influence of the Y chromosome has been well documented in mouse EAE  , . Table 1. Parent-of-origin effects at autosomes: Imprinted loci In the next stage, we investigated the impact of epigenetic mechanisms such as imprinting on inheritance of EAE.
Identification and validation of parent-of-origin dependent QTLs in EAE We then used the reciprocal backcross strategy to carry out identification of QTLs that control EAE susceptibility reflected by incidence and onset , EAE severity reflected by maximum score and duration and subclinical disease reflected by weight loss. Table 2. Table 3. Table 5. Table 6. Summary of the parent-of-origin effects detected in QTLs. Figure 2.
Accounting for parent-of-origin effects improves disease inheritance models. Figure 3. Maternal transmission of the disease-predisposing allele. Figure 4. Paternal transmission of the disease-predisposing allele. Dlk1 is a candidate gene underlying paternally transmitted EAE QTL on rat chromosome 6 QTL confidence intervals in backcross populations usually comprise large genomic intervals. Figure 5. Figure 6. Transgenic overexpression of Dlk1 modulates EAE severity and adaptive immune responses. Genotyping Genomic DNA was extracted from tail tips. Ex vivo and in vitro cell culture Single cell suspension was prepared from spleen and lymph node tissue dissected 25 days p.
Supporting Information. Figure S1. Figure S2. Table S1. Table S2. Summary of experimental sets. Table S3. Table S4. Table S5. Table S6. Text S1. Mitochondrial effects. Text S2. Supplementary references. References 1. Trends Mol Med 7— View Article Google Scholar 2. Waterland RA, Jirtle RL Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol — View Article Google Scholar 3. Arthritis and rheumatism — View Article Google Scholar 4. View Article Google Scholar 5.
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The Autoimmune Diseases
Genetics — Ultimately, longitudinal studies will be necessary to establish the timing of the epigenetic change with respect to disease onset, and to investigate its role in disease susceptibility or progression. The major challenges of epigenetics are inherent to its nature and not specific to twin studies. Epigenetic states are often tissue- and cell-specific and a sample of cells may involve a mixture of cells with different profiles. Currently, the solution to this problem is to use blood and adjust for cell sub-type counts. If blood is not available, the epigenetic states can be inferred using DNA methylation signatures from previously purified samples [[ 95 ]].
In the near future, this problem will be addressed with the use of single cell sequencing technologies based on nanopores, which can discriminate between cytosine and methylcytosine [[ 98 ]]. Cell composition is less of a problem for twin studies as many cell populations are genetically controlled. Related to the tissue and cell specificity of epigenetic profiles is the appropriate choice of tissue for the disease of interest. In most cases it will not be possible to study the affected tissue, such as brain in neurodegenerative diseases.
Most studies use peripheral blood cells, which limits the study of epigenetic marks to those that are shared across tissues. This approach is helpful when looking for markers of the disease. Inferring causal relationships also presents a major challenge. Associations in this field are subject to reverse causation and confounding factors. The conventional observational study at one point in time cannot determine if an epigenetic modification is a cause of the disease or if it is secondary or the result of medication use. The twin design allows us to overcome many confounding effects, but longitudinal studies are needed to determine whether an epigenetic modification precedes disease, as exemplified by Heyn et al.
The difficulty in these approaches is sample and phenotype collection at different time points. The large number of different epigenetic marks is another challenge. DNA methylation is by far the most studied epigenetic mark, but histone modifications can occur in the same locus and the interaction and relative importance of different layers of epigenetic modification remain unknown.
The integrative analysis of genetics, epigenetics, and transcriptomics may give a hint of the underlying regulatory mechanisms. Epigenetics may explain many discordances between twins, but there are limitations when dissimilarities come from other sources. Even though MZ twins were formed from the same zygote, post-zygotic mutations may occur and give rise to somatic mosaicism [[ 51 ]].
In some cases the mutation would be unobserved, but in others it may be the cause of a developmental disorder or may increase susceptibility to a disease in later life. Furthermore, somatic mutations continuously occur and twins may show different somatic mutation rates depending on environmental influences. The twin model assumes that MZ twins are genetically identical, but it is unknown whether these tiny differences have phenotypic consequences and to what extent. Another potential complication is twin chorionicity, which in most cases is unknown for adult twins.
Most studies treat MZ twins as a uniform group, but in fact they can be sub-classified depending on whether they shared the same placenta or not monochorionic or dichorionic, respectively. Chorionicity is considered to be influential in epigenetic status, as reported by Kaminsky et al. Both studies were small but the results are important and require further replication. Twin chorionicity is also in part related to the potential of chimerism in MZ twins, especially when blood samples are used.
In utero , twins can exchange fetal blood through vascular connections, and this can have implications for the detection of genetic or epigenetic events that are related to discordance originating in utero. Lastly, power to detect epigenetic changes using the disease-discordant MZ twin model has not yet been fully investigated and will depend on many factors, including sample size, effect size, assay coverage and sensitivity, epigenetic heritability at the locus of interest, and longitudinal stability of the epigenetic change. Several studies have made locus-specific power estimates for the disease-discordant twin design.
However, most currently used methylation assays target methylation at single CpG sites and formal power calculations for genome-wide coverage at single CpG site resolution have not yet been reported in twins. Autism spectrum disorder. Bipolar disorder. Clustered regularly interspaced short palindromic repeats. Differentially methylated region.
DNA methyltransferase. Intra-pair correlation coefficient. Major depressive disorder. Methylated DNA immunoprecipitation. Major histocompatibility complex. Peripheral blood mononuclear cells. Type 1 diabetes. White blood cell. This article is published under license to BioMed Central Ltd. Table of Contents Abstract Introduction Monozygotic twins and epigenetics Twin discordance for disease and environmental factors Epigenetic studies of twins and disease Implications for disease and medicine Box 1.
Challenges Box 2. Limitations of epigenetic studies on MZ twins Declarations References. Review Open Access.
Epigenetics of discordant monozygotic twins: implications for disease. Genome Medicine 6 Abstract Monozygotic MZ twins share nearly all of their genetic variants and many similar environments before and after birth. Epigenetic disease studies can particularly benefit from the unique study design of disease-discordant MZ twins. Both population-based and twin-based epigenetic studies are susceptible to bias from potential unobserved confounders, and require replication to minimize false positive findings.
Here, we discuss the benefits, challenges Box 1 and limitations Box 2 of epigenetic studies using disease-discordant monozygotic MZ twins also called identical twins , and we review recent findings and their implications for medical research. Figure 1 Shared and non-shared potential epigenetic confounding factors throughout the lifetime of MZ twins and unrelated individuals. The rest of the variation that is not attributed to genetic effects is attributed to environmental influences, which can be divided into shared and unique environmental influences and random error. The twin model also assumes that MZ and DZ twins equally share the environment and that a fraction of the correlation is due to the shared environmental influences.
The fraction corresponding to shared environmental effects is estimated as the difference between the total correlation and the heritability estimate. Finally, the missing variation is attributed to unique environmental effects plus error. Figure 2 Heritable and environmental factors contributing to disease. Here, we focus predominantly on recent genome-wide efforts across four major types of disease. References Waddington CH: The epigenotype. Google Scholar Holliday R: Epigenetics: an overview. Dev Genet. Cytogenet Cell Genet.
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