Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis - PubMed (original) (raw)
. 2010 Apr 29;464(7293):1351-6.
doi: 10.1038/nature08990.
Joann Mudge, Jennifer C van Velkinburgh, Pouya Khankhanian, Irina Khrebtukova, Neil A Miller, Lu Zhang, Andrew D Farmer, Callum J Bell, Ryan W Kim, Gregory D May, Jimmy E Woodward, Stacy J Caillier, Joseph P McElroy, Refujia Gomez, Marcelo J Pando, Leonda E Clendenen, Elena E Ganusova, Faye D Schilkey, Thiruvarangan Ramaraj, Omar A Khan, Jim J Huntley, Shujun Luo, Pui-Yan Kwok, Thomas D Wu, Gary P Schroth, Jorge R Oksenberg, Stephen L Hauser, Stephen F Kingsmore
Affiliations
- PMID: 20428171
- PMCID: PMC2862593
- DOI: 10.1038/nature08990
Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis
Sergio E Baranzini et al. Nature. 2010.
Abstract
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.
Conflict of interest statement
The authors declare no competing financial interests.
Figures
Figure 1. Comparison of the genomic locations of heterozygous cSNPs exhibiting imbalanced allelic expression in mRNA of twins 041896-001 and -101.
a, b, Allelic imbalance for 041896-001 (a) and 041896-101 (b) was detected in cSNPs called by ≥10 gDNA reads with Q ≥ 20 and where 20–80% of uniquely aligning gDNA reads called the SNP, together with detection in ≥10 mRNA reads with Q ≥ 20. Out of 14,461 heterozygous cSNPs, 268 (1.9%) showed significant allelic imbalance in expression (P < 10-7), of which 153 (57%) were of the same magnitude and direction in both subjects. TCRVB is the T cell receptor beta locus, V (variable) segment, locus symbol TRB@. WDR40B is also known as DCAF12L1. PowerPoint slide
Figure 2. Comparisons of methylation of genomic CpG sites in CD4+ lymphocytes and breast and lung tissue samples.
a, Frequency distribution of CpG site methylation in 041896-001 (blue) and -101 (red) using ELAND-extended. b–j, Pairwise comparisons of CpG site methylation using ELAND-extended in CD4+ lymphocytes from monozygotic twin siblings 041896-001 and -101 (b), 230178-001 and -101 (c) and 041907-001 and -101 (d); inter-individual differences between CD4+ lymphocytes from 041896-001 and 041907-001 (e) and 041896-001 and 230178-101 (f); neoplastic differences between breast tissue and breast cancer (g) and between normal lung tissue and lung cancer (h); and between-tissue differences between CD4+ lymphocytes and breast tissue (i) and lung tissue (j). PowerPoint slide
Comment in
- Contribution of genetic, epigenetic and transcriptomic differences to twin discordance in multiple sclerosis.
Handunnetthi L, Handel AE, Ramagopalan SV. Handunnetthi L, et al. Expert Rev Neurother. 2010 Sep;10(9):1379-81. doi: 10.1586/ern.10.116. Expert Rev Neurother. 2010. PMID: 20819009
Similar articles
- Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome.
Miyake K, Yang C, Minakuchi Y, Ohori K, Soutome M, Hirasawa T, Kazuki Y, Adachi N, Suzuki S, Itoh M, Goto Y, Andoh T, Kurosawa H, Oshimura M, Sasaki M, Toyoda A, Kubota T. Miyake K, et al. PLoS One. 2013 Jun 21;8(6):e66729. doi: 10.1371/journal.pone.0066729. Print 2013. PLoS One. 2013. PMID: 23805272 Free PMC article. - Effects of smoking on genome-wide DNA methylation profiles: A study of discordant and concordant monozygotic twin pairs.
van Dongen J, Willemsen G; BIOS Consortium; de Geus EJC, Boomsma DI, Neale MC. van Dongen J, et al. Elife. 2023 Aug 10;12:e83286. doi: 10.7554/eLife.83286. Elife. 2023. PMID: 37643467 Free PMC article. - Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins.
Elboudwarej E, Cole M, Briggs FB, Fouts A, Fain PR, Quach H, Quach D, Sinclair E, Criswell LA, Lane JA, Steck AK, Barcellos LF, Noble JA. Elboudwarej E, et al. J Autoimmun. 2016 Apr;68:23-9. doi: 10.1016/j.jaut.2015.12.003. Epub 2016 Jan 9. J Autoimmun. 2016. PMID: 26782299 Free PMC article. - Using epigenomic studies in monozygotic twins to improve our understanding of cancer.
Roos L, Spector TD, Bell CG. Roos L, et al. Epigenomics. 2014 Jun;6(3):299-309. doi: 10.2217/epi.14.13. Epigenomics. 2014. PMID: 25111484 Review. - [Epigenetics and its new progress in monozygotic twins].
Li CT, Zhao SM, Li L. Li CT, et al. Fa Yi Xue Za Zhi. 2009 Jun;25(3):212-6. Fa Yi Xue Za Zhi. 2009. PMID: 19697783 Review. Chinese.
Cited by
- Functional landscape of genome-wide postzygotic somatic mutations between monozygotic twins.
Yamamoto K, Lee Y, Masuda T, Ozono K, Iwatani Y, Watanabe M, Okada Y, Sakai N. Yamamoto K, et al. DNA Res. 2024 Oct 1;31(5):dsae028. doi: 10.1093/dnares/dsae028. DNA Res. 2024. PMID: 39306676 Free PMC article. - Comprehensive pan-cancer analysis reveals that C5orf34 regulates the proliferation and mortality of lung cancer.
Yang M, Deng Y, Ma Y, Song C, Wu Z, Yibulayin X, Sun X, Guo Y, He D. Yang M, et al. Funct Integr Genomics. 2024 Jun 29;24(4):119. doi: 10.1007/s10142-024-01397-w. Funct Integr Genomics. 2024. PMID: 38951221 - Functional genomics in inborn errors of immunity.
Hurabielle C, LaFlam TN, Gearing M, Ye CJ. Hurabielle C, et al. Immunol Rev. 2024 Mar;322(1):53-70. doi: 10.1111/imr.13309. Epub 2024 Feb 8. Immunol Rev. 2024. PMID: 38329267 Review. - Stochastic gene expression and environmental stressors trigger variable somite segmentation phenotypes.
Keseroglu K, Zinani OQH, Keskin S, Seawall H, Alpay EE, Özbudak EM. Keseroglu K, et al. Nat Commun. 2023 Oct 14;14(1):6497. doi: 10.1038/s41467-023-42220-7. Nat Commun. 2023. PMID: 37838784 Free PMC article.
References
Publication types
MeSH terms
Substances
Grants and funding
- R01 NS046297-06/NS/NINDS NIH HHS/United States
- R01NS26799/NS/NINDS NIH HHS/United States
- U19 HD077693/HD/NICHD NIH HHS/United States
- U01 AI066569-05/AI/NIAID NIH HHS/United States
- R01 NS026799-20A1/NS/NINDS NIH HHS/United States
- P20 RR016480-09/RR/NCRR NIH HHS/United States
- R01NS46297/NS/NINDS NIH HHS/United States
- R01 NS026799/NS/NINDS NIH HHS/United States
- R01 NS046297/NS/NINDS NIH HHS/United States
- P20 RR016480/RR/NCRR NIH HHS/United States
- U01 AI066569/AI/NIAID NIH HHS/United States
- RR016480/RR/NCRR NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials