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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13 个近交小鼠品系的深度基因组测序和变异分析定义了候选表型等位基因、私人变异和纯合截短突变
DOI：
10.1101/039131
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发表时间：
2016
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影响因子：
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通讯作者：
Doran A
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文献类型：
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作者：
Doran A
背景小鼠基因组计划是一项正在进行的合作工作，目的是对常见的实验室小鼠品系的基因组进行测序。2011年，对17个菌株的序列变异进行了初步分析，发现了56.7百万个独特的单核苷酸多态(SNPs)和8.8亿个插入片段(Indels)。我们对另外13个近交系菌株(BUB/BNJ、C57BL/10J、C57BR/CDJ、C58/J、DBA/1J、I/LnJ、KK/HiJ、Molf/EIJ、NZB/B1NJ、NZW/LacJ、RF/J、SEA/GNJ和ST/BJ)进行了深度测序，编目了菌株内和菌株间的分子变异。这些菌株包括免疫反应、白血病、年龄相关性听力损失和类风湿性关节炎的重要模型。我们现在有几个完全测序的密切相关菌株的例子，这些菌株在几种疾病表型上是不同的。结果与C57BL/6和J参考基因组(GRCm38)相比，在这些菌株中鉴定出大约27.4百万个独特的SNPs和500万个插入片段。在近亲交配的实验室小鼠基因组中发现的变异量已经增加到71个M SNP和12个M Indels。我们调查了RF/J中高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的错义突变。我们使用两个高度相关的菌株(DBA/1J和DBA/2J)来研究胶原性关节炎易感性的遗传基础。结论本论文显著扩大了全序列测定的实验室小鼠品系的目录，现在包含了几个遗传上高度相似但表型不同的菌株的例子。我们展示了研究私人错义突变如何导致对高渗透性表型的遗传机制的洞察。
BackgroundThe 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.ResultsApproximately 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.ConclusionsThis 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.