Castellani C A, Melka M G, Gui J L, Gallo A J, O'Reilly R L, Singh S M
Department of Biology, The University of Western Ontario, London, ON, N6A 5B7, Canada.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Clin Transl Med. 2017 Nov 28;6(1):43. doi: 10.1186/s40169-017-0174-1.
Monozygotic twins are valuable in assessing the genetic vs environmental contribution to diseases. In the era of complete genome sequences, they allow identification of mutational mechanisms and specific genes and pathways that offer predisposition to the development of complex diseases including schizophrenia.
We sequenced the complete genomes of two pairs of monozygotic twins discordant for schizophrenia (MZD), including one representing a family tetrad. The family specific complete sequences have allowed identification of post zygotic mutations between MZD genomes. It allows identification of affected genes including relevant network and pathways that may account for the diseased state in pair specific patient.
We found multiple twin specific sequence differences between co-twins that included small nucleotides [single nucleotide variants (SNV), small indels and block substitutions], copy number variations (CNVs) and structural variations. The genes affected by these changes belonged to a number of canonical pathways, the most prominent ones are implicated in schizophrenia and related disorders. Although these changes were found in both twins, they were more frequent in the affected twin in both pairs. Two specific pathway defects, glutamate receptor signaling and dopamine feedback in cAMP signaling pathways, were uniquely affected in the two patients representing two unrelated families.
We have identified genome-wide post zygotic mutations in two MZD pairs affected with schizophrenia. It has allowed us to use the threshold model and propose the most likely cause of this disease in the two patients studied. The results support the proposition that each schizophrenia patient may be unique and heterogeneous somatic de novo events may contribute to schizophrenia threshold and discordance of the disease in monozygotic twins.
同卵双胞胎对于评估疾病的遗传因素与环境因素贡献具有重要价值。在全基因组序列时代，它们有助于识别导致包括精神分裂症在内的复杂疾病发生的突变机制、特定基因及通路。
我们对两对患精神分裂症的同卵双胞胎（MZD）进行了全基因组测序，其中一对为家系四联体。家系特异性全序列使我们能够识别同卵双胞胎基因组之间的合子后突变。这有助于识别受影响的基因，包括可能导致特定患者患病状态的相关网络和通路。
我们发现双胞胎之间存在多个特异性序列差异，包括小核苷酸变异（单核苷酸变异、小插入缺失和块状替换）、拷贝数变异（CNV）和结构变异。受这些变化影响的基因属于多个经典通路，其中最显著的与精神分裂症及相关疾病有关。尽管这些变化在双胞胎双方均有发现，但在两对双胞胎中，受影响的一方更为常见。在代表两个不相关家系的两名患者中，谷氨酸受体信号通路和cAMP信号通路中的多巴胺反馈这两个特定通路缺陷受到独特影响。
我们在两对患精神分裂症的同卵双胞胎中识别出全基因组范围的合子后突变。这使我们能够运用阈值模型并提出所研究的两名患者中该疾病最可能的病因。结果支持了这样一种观点，即每位精神分裂症患者可能都是独特的，体细胞的新生事件可能导致精神分裂症阈值以及同卵双胞胎中该疾病的不一致性。
