Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
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同卵双胞胎（或更准确地说是“同卵双胞胎”）被广泛用于研究遗传和环境对人类疾病的影响。一项针对三对同卵双胞胎的研究，其中一对双胞胎患有多发性硬化症，另一对没有，将基因组测序和分析的最新技术带到了这一领域，并偶然发表了第一个女性人类基因组序列。确定了一对双胞胎的全序列，并确定了这些和其他两对CD 4+淋巴细胞的mRNA转录组和表观基因组序列。令人惊讶的结果是，没有发现任何遗传，表观遗传或转录组差异可以解释为什么双胞胎中的一个患有这种疾病而另一个没有。深入挖掘数据，eQTL（表达数量性状位点）定位揭示了双胞胎之间值得仔细研究的诱人差异。一些可能的原因可以排除。未来的工作可能有益地集中在其他细胞类型和表观遗传修饰的研究上。本文的在线版本（doi：10.1038/nature 08990）包含补充材料，可供授权用户使用。对同卵双胞胎的研究被广泛用于剖析基因和环境对人类疾病的贡献。在多发性硬化症（一种自身免疫性脱髓鞘疾病）中，同卵双胞胎经常表现出差异。这可能表明，在这种情况下，环境的影响是最重要的，但同卵双胞胎之间的遗传和表观遗传差异已经被描述。然而，在这里，对同卵双胞胎的研究显示，没有证据表明遗传，表观遗传或转录组差异可以解释疾病的不一致性。本文的在线版本（doi：10.1038/nature 08990）包含补充材料，可供授权用户使用。单卵或“同卵”双胞胎已被广泛研究，以剖析遗传和环境在人类疾病中的相对作用。多发性硬化症（MS）是一种自身免疫性脱髓鞘疾病，也是年轻人神经变性和残疾的常见原因，单卵双胞胎的疾病不一致性已被解释为表明其发病机制中的环境重要性。然而，单卵双胞胎之间的遗传和表观遗传差异已经被描述，这对消除先天和后天影响的公认实验模型提出了挑战。在这里，我们报告的基因组序列的MS不一致的单卵双胞胎对，信使RNA转录组和表观基因组序列的CD 4+淋巴细胞从三个MS不一致，单卵双胞胎对。在10360万个单核苷酸多态性（SNP）或1020万个插入-缺失多态性中，没有检测到共同双胞胎之间的可重复差异。在三对双胞胎的兄弟姐妹之间也没有观察到HLA单倍型、确认的MS易感性SNP、拷贝数变异、mRNA和基因组SNP和插入-缺失基因型或CD 4 + T细胞中19，000个基因的表达的任何可重复的差异。在这三对双胞胎的同胞之间，仅检测到2 - 176个1200万个CpG二核苷酸的甲基化差异，而在无关个体的T细胞之间，有1800个甲基化差异，在组织之间或正常组织与癌组织之间，有数千个差异。在第一次系统性的努力，以估计单卵双胞胎之间的序列变异，我们没有发现证据的遗传，表观遗传或转录组差异，解释疾病的不一致性。据我们所知，这是首次报道的女性、双胞胎和自身免疫性疾病个体基因组序列。本文的在线版本（doi：10.1038/nature 08990）包含补充材料，可供授权用户使用。
Identical (or more correctly 'monozygotic') twins are widely used to study the contributions of genetics and environment to human disease. A study that focused on three pairs of monozygotic twins, in which one twin had multiple sclerosis and the other did not, has brought the latest techniques of genome sequencing and analysis to this field, and incidentally published the first female human genome sequences. Full sequences were determined for one pair of twins, and for these and the other two pairs the mRNA transcriptome and epigenome sequences of CD4+ lymphocytes were determined. The striking result is that no genetic, epigenetic or transcriptome differences were found that explained why one twin had the disease and the other did not. Digging deeper into the data, eQTL (expression quantitative trait locus) mapping revealed tantalizing differences within twin pairs that merit closer examination. And some possible causes can be ruled out. Future work might usefully concentrate on studies of other cell types and epigenetic modifications. The online version of this article (doi:10.1038/nature08990) contains supplementary material, which is available to authorized users. Studies of identical twins are widely used to dissect the contributions of genes and the environment to human diseases. In multiple sclerosis, an autoimmune demyelinating disease, identical twins often show differences. This might suggest that environmental effects are most significant in this case, but genetic and epigenetic differences between identical twins have been described. Here, however, studies of identical twins show no evidence for genetic, epigenetic or transcriptome differences that could explain disease discordance. The online version of this article (doi:10.1038/nature08990) contains supplementary material, which is available to authorized users. 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 ∼3.6 million single nucleotide polymorphisms (SNPs) or ∼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 ∼19,000 genes in CD4+ T cells. Only 2 to 176 differences in the methylation of ∼2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to ∼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. The online version of this article (doi:10.1038/nature08990) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
McDonald, WI;Compston, A;Wolinsky, JS
通讯作者：
Wolinsky, JS
影响因子：
3.7
作者：
Mudge, Joann;Miller, Neil A.;Khrebtukova, Irina;Lindquist, Ingrid E.;May, Gregory D.;Huntley, Jim J.;Luo, Shujun;Zhang, Lu;van Velkinburgh, Jennifer C.;Farmer, Andrew D.;Lewis, Sharon;Beavis, William D.;Schilkey, Faye D.;Virk, Selene M.;Black, C. Forrest;Myers, M. Kathy;Mader, Lar C.;Langley, Ray J.;Utsey, John P.;Kim, Ryan W.;Roberts, Rosalinda C.;Khalsa, Sat Kirpal;Garcia, Meredith;Ambriz-Griffith, Victoria;Harlan, Richard;Czika, Wendy;Martin, Stanton;Wolfinger, Russell D.;Perrone-Bizzozero, Nora I.;Schroth, Gary P.;Kingsmore, Stephen F.
通讯作者：
Kingsmore, Stephen F.
影响因子：
9.9
作者：
MUMFORD, CJ;WOOD, NW;COMPSTON, DAS
通讯作者：
COMPSTON, DAS
DOI：
10.1073/pnas.0712345105
发表时间：
2008-03-18
影响因子：
11.1
作者：
Jones, Sian;Chen, Wei-dong;Markowitz, Sanford D.
通讯作者：
Markowitz, Sanford D.
影响因子：
3.5
作者：
Heap GA;Yang JH;Downes K;Healy BC;Hunt KA;Bockett N;Franke L;Dubois PC;Mein CA;Dobson RJ;Albert TJ;Rodesch MJ;Clayton DG;Todd JA;van Heel DA;Plagnol V
通讯作者：
Plagnol V