Petersen Britt-Sabina, Spehlmann Martina E, Raedler Andreas, Stade Björn, Thomsen Ingo, Rabionet Raquel, Rosenstiel Philip, Schreiber Stefan, Franke Andre
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany.
BMC Genomics. 2014 Jul 5;15(1):564. doi: 10.1186/1471-2164-15-564.
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.
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.
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.
克罗恩病（CD）是一种由遗传和环境因素引起的炎症性肠病。已确定超过160个IBD易感位点，但很大一部分遗传变异仍无法解释。最近的研究表明，长期以来被认为基因完全相同的同卵双胞胎之间存在基因差异。
我们旨在通过对一对双胞胎肠道直接受影响组织和血液样本以及另外两对同卵不一致双胞胎的血液外显子组进行全基因组和外显子组测序，来测试体细胞突变是否在CD病因中起作用。我们的目标是识别仅存在于患病双胞胎中的突变，以找出CD易感位点的新候选基因。我们对测序个体进行了全面的基因特征分析，但在双胞胎对中未检测到一致的差异。然而，基于已知CD位点对CD易感性的估计表明，与1920名健康个体相比，所有三对双胞胎的突变负荷更高。
体细胞镶嵌现象似乎在同卵CD双胞胎的不一致性中不起作用。我们的研究是首次对CD双胞胎进行全基因组测序，因此为未来研究提供了有价值的参考数据集。我们提供了一个用于镶嵌现象检测的示例框架，并指出了这类分析中的挑战。
