Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome.
Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome.
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DOI：
10.1371/journal.pone.0066729
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kubota T
中科院分区：
文献类型：
--
作者：
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
同卵双胞胎已被广泛用于遗传研究，以确定遗传和环境在人类疾病中的相对作用。受影响的单卵双胞胎之间疾病表现的不一致性归因于环境因素或X染色体失活（XCI）的不同模式。然而，最近的研究已经确定了单卵双胞胎之间的遗传和表观遗传差异，从而挑战了公认的区分先天和后天影响的实验模型。在这里，我们报告的基因组和表观基因组序列在皮肤成纤维细胞的不和谐的单卵双胞胎与Rett综合征，一个X连锁的神经发育障碍的特点是自闭症的功能，癫痫发作，步态共济失调和刻板的手部运动。这对双胞胎在MECP2基因的外显子4（G269AfsX288）上有相同的从头突变，该突变起源于父系，发生在精子发生过程中。双胞胎的XCI模式在淋巴细胞、皮肤成纤维细胞和毛细胞（它们起源于外胚层，就像神经元组织一样）中没有差异。在单核苷酸多态性（SNPs）、插入-缺失多态性（indels）或拷贝数变异方面，双胞胎之间没有检测到可重复的差异。双胞胎之间的DNA甲基化差异在涉及脑功能和骨骼组织的基因上游区域的成纤维细胞中检测到，如Mohawk同源框（MKX），脑型肌酸激酶（CKB）和FYN酪氨酸激酶原癌基因（FYN）。这些上游区域的甲基化水平与基因表达水平呈负相关。因此，DNA甲基化模式的差异可能是双胞胎之间Rett表型不一致的基础。
Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.
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DOI：
10.1111/j.1601-183x.2012.00781.x
发表时间：
2012-07
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Goebel-Goody SM;Wilson-Wallis ED;Royston S;Tagliatela SM;Naegele JR;Lombroso PJ
通讯作者：
Lombroso PJ
影响因子：
5.2
作者：
Knudsen, Gun Peggy S.;Neilson, Tracey C. S.;Orstavik, Karen Helene
通讯作者：
Orstavik, Karen Helene
影响因子：
3.1
作者：
Burbaeva, GS;Savushkina, OK;Boksha, IS
通讯作者：
Boksha, IS
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0500398102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fraga, MF;Ballestar, E;Esteller, M
通讯作者：
Esteller, M