Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice.
Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice.
复制标题
DOI：
10.1016/j.immuni.2015.06.011
复制
发表时间：
2015-07-21
期刊：
影响因子：
32.4
通讯作者：
Vandenabeele P
中科院分区：
文献类型：
--
作者：
Vanden Berghe T;Hulpiau P;Martens L;Vandenbroucke RE;Van Wonterghem E;Perry SW;Bruggeman I;Divert T;Choi SM;Vuylsteke M;Shestopalov VI;Libert C;Vandenabeele P
小鼠中的靶向诱变是基因功能分析的有力工具。然而，用于靶向的胚胎干细胞（ESC，以前几乎完全是129品系来源）和受体品系（通常是C57BL/6J）之间的遗传变异通常会产生同类系小鼠，其中靶向基因两侧是可能含有突变的ESC来源的过客DNA。对129和C57BL/6J小鼠品系的比较基因组分析显示，在129品系基因组的1084个基因中存在插入缺失和单核苷酸多态性，导致氨基酸序列发生改变或异常。将这些过客突变标注到使用129品系ESC产生的已报道的转基因同类系小鼠上，结果显示几乎所有这些小鼠都具有多个可能影响表型结果的过客突变。我们通过几个案例研究说明了129品系来源的过客突变的这种表型干扰，并开发了一个Me - PaMuFind - It网络工具来估计感兴趣的转基因小鼠中过客突变的数量和可能的影响。
Targeted mutagenesis in mice is a powerful tool for functional analysis of genes. However, genetic variation between embryonic stem cells (ESCs) used for targeting (previously almost exclusively 129-derived) and recipient strains (often C57BL/6J) typically results in congenic mice in which the targeted gene is flanked by ESC-derived passenger DNA potentially containing mutations. Comparative genomic analysis of 129 and C57BL/6J mouse strains revealed indels and single nucleotide polymorphisms resulting in alternative or aberrant amino acid sequences in 1,084 genes in the 129-strain genome. Annotating these passenger mutations to the reported genetically modified congenic mice that were generated using 129-strain ESCs revealed that nearly all these mice possess multiple passenger mutations potentially influencing the phenotypic outcome. We illustrated this phenotypic interference of 129-derived passenger mutations with several case studies and developed a Me-PaMuFind-It web tool to estimate the number and possible effect of passenger mutations in transgenic mice of interest.