Baranzini, S. E. et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464, 1351-1356

Department of Neurology, University of California at San Francisco, San Francisco, California 94143, USA.
Nature (Impact Factor: 41.46). 04/2010; 464(7293):1351-6. DOI: 10.1038/nature08990
Source: PubMed


Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.

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    • "In multiple sclerosis (MS), the high discordance (approximately 70%) in monozygotic twins has been associated with environment factors, and genetic and epigenetic differences in twin couples have previously been investigated to provide evidence to support this hypothesis (Bell and Spector, 2011). Although a recent genome-wide study of CD4 T cells from MS-discordant twins reported no clear differences that might explain the discordance (Baranzini et al., 2010), several reports suggest Accepted Article 5 epigenetic alterations as underlying factors in MS pathology, both in patients and in preclinical models (Liggett et al., 2010; Guan et al., 2011; Kumagai et al., 2012; Calabrese et al., 2012). "
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    ABSTRACT: Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2′-deoxycytidine (DAC) in two murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease was associated with a reduction in the number of spinal cord infiltrating lymphocytes and amelioration of the histopathological signs associated with EAE. In addition, increased transcript levels of anti-inflammatory cytokines and decreased mRNA expression of pro-inflammatory mediators were also observed. Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 12/2014; 229(12). DOI:10.1002/jcp.24641 · 3.84 Impact Factor
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    • "However, a combined analysis identified genes where differences in DNA methylation between unaffected and affected twins correlated with differences in gene expression [36] and hereby identified several known and novel susceptibility genes. In contrast, sequencing of the genomes of one twin pair and transcriptome sequencing, SNP chip and methylation chip data of three discordant twin pairs revealed no differences between co-twins discordant for multiple sclerosis [17]. "
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    ABSTRACT: BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical. RESULTS: We aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals. CONCLUSION: Somatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses.
    BMC Genomics 07/2014; 15(1):564. DOI:10.1186/1471-2164-15-564 · 3.99 Impact Factor
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    • "Interestingly, they found that no discordant SNVs inferred by one approach were replicated by a second approach, while 98% of concordant SNVs could be replicated by at least two methods. The validation of 15 discordant SNVs via Sanger sequencing showed identical genotypes in the twin pairs [16]. Recent studies of monozygotic twins discordant for VACTERL association, using both WES and high-density microarray approaches, also failed to identify discordant variants that could explain the discordant phenotype [17]. "
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    ABSTRACT: Congenital heart defects (CHD) occur in 40% of patients with trisomy 21, while the other 60% have a structurally normal heart. This suggests that the increased dosage of genes on chromosome 21 is a risk factor for abnormal heart development. Interaction of genes on chromosome 21 or their gene products with certain alleles of genes on other chromosomes could contribute to CHD. Here, we identified a pair of monozygotic twins with trisomy 21 but discordant for a ventricular septal defect and epilepsy. Twin-zygosity was confirmed by microsatellite genotyping. We hypothesized that some genetic differences from post-twinning mutations caused the discordant phenotypes. Thus, next generation sequencing (NGS) technologies were applied to sequence both whole genome and exome of their leukocytes. The post-analyses of the sequencing data revealed 21 putative discordant exonic variants between the twins from either genome or exome data. However, of the 15 variants chosen for validation with conventional Sanger sequencing, these candidate variants showed no differences in both twins. The fact that no discordant DNA variants were found suggests that sequence differences of DNA from leukocytes of monozygotic twins might be extremely rare. It also emphasizes the limitation of the current NGS technology in identifying causative genes for discordant phenotypes in monozygotic twins.
    PLoS ONE 06/2014; 9(6):e100191. DOI:10.1371/journal.pone.0100191 · 3.23 Impact Factor
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