Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations.
Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations.
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DOI：
10.1186/s13059-016-1024-y
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发表时间：
2016-08-01
期刊：
影响因子：
12.3
通讯作者：
Keane TM
中科院分区：
文献类型：
--
作者：
Doran AG;Wong K;Flint J;Adams DJ;Hunter KW;Keane TM
小鼠基因组计划是一个正在进行的合作努力，以测序常见的实验室小鼠品系的基因组。2011年，对17个菌株的序列变异的初步分析发现了56.7 M独特的单核苷酸多态性（SNP）和8.8 M indel。我们对另外13个近交系（BUB/BnJ、C57 BL/10 J、C57 BR/cdJ、C58/J、DBA/1 J、I/LnJ、KK/HiJ、MOLF/EiJ、NZB/B1 NJ、NZW/LacJ、RF/J、SEA/GnJ和ST/bJ）进行了深度测序，对品系内和品系间的分子变异进行了编目。这些菌株包括免疫反应、白血病、与年龄相关的听力损失和类风湿性关节炎的重要模型。我们现在有几个例子，完全测序密切相关的菌株是不同的几种疾病表型。与C57 BL/6 J参考基因组（GRCm 38）相比，在这些菌株中鉴定了约27.4 M独特SNP和5 M indel。在近交系实验室小鼠基因组中发现的变异量已增加到71 M SNP和12 M indel。我们研究了RF/J中高度渗透性癌症易感性的遗传基础，发现了DNA损伤修复和高度癌症相关基因中的私人新错义突变。我们使用两个高度相关的菌株（DBA/1 J和DBA/2 J）来研究胶原诱导的关节炎易感性的遗传基础。本文显着扩大目录完全测序实验室小鼠品系，现在包含几个例子的高度遗传相似的菌株不同的表型。我们展示了如何研究私人错义突变可以导致深入了解一个高度渗透表型的遗传机制。本文的在线版本（doi：10.1186/s13059-016-1024-y）包含补充材料，可供授权用户使用。
The Mouse Genomes Project is an ongoing collaborative effort to sequence the genomes of the common laboratory mouse strains. In 2011, the initial analysis of sequence variation across 17 strains found 56.7 M unique single nucleotide polymorphisms (SNPs) and 8.8 M indels. We carry out deep sequencing of 13 additional inbred strains (BUB/BnJ, C57BL/10J, C57BR/cdJ, C58/J, DBA/1J, I/LnJ, KK/HiJ, MOLF/EiJ, NZB/B1NJ, NZW/LacJ, RF/J, SEA/GnJ and ST/bJ), cataloguing molecular variation within and across the strains. These strains include important models for immune response, leukaemia, age-related hearing loss and rheumatoid arthritis. We now have several examples of fully sequenced closely related strains that are divergent for several disease phenotypes. Approximately 27.4 M unique SNPs and 5 M indels are identified across these strains compared to the C57BL/6 J reference genome (GRCm38). The amount of variation found in the inbred laboratory mouse genome has increased to 71 M SNPs and 12 M indels. We investigate the genetic basis of highly penetrant cancer susceptibility in RF/J finding private novel missense mutations in DNA damage repair and highly cancer associated genes. We use two highly related strains (DBA/1J and DBA/2J) to investigate the genetic basis of collagen-induced arthritis susceptibility. This paper significantly expands the catalogue of fully sequenced laboratory mouse strains and now contains several examples of highly genetically similar strains with divergent phenotypes. We show how studying private missense mutations can lead to insights into the genetic mechanism for a highly penetrant phenotype. The online version of this article (doi:10.1186/s13059-016-1024-y) contains supplementary material, which is available to authorized users.