Microarray-assisted fine mapping of quantitative trait loci on chromosome 15 for susceptibility to seizure-induced cell death in mice.
Microarray-assisted fine mapping of quantitative trait loci on chromosome 15 for susceptibility to seizure-induced cell death in mice.
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DOI：
10.1111/ejn.12351
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Schauwecker PE
中科院分区：
文献类型：
--
作者：
Schauwecker PE
先前对FVB/NJ（FVB;对海人酸诱导的细胞死亡敏感）小鼠和对海人酸诱导的细胞死亡具有抗性的小鼠C57 BL/6 J（B6）的杂交研究揭示了在染色体15（Chr. 15）上存在影响对海人酸诱导的细胞死亡（Sicd 2）的敏感性的数量性状基因座（QTL）。在一项早期研究中，我们证实了Sicd 2间隔含有通过创建FVB. B6-Sicd 2同源株而赋予针对细菌诱导的细胞死亡的强保护作用的基因，并创建了三个在染色体15上包含Sicd 2的间隔特异性同源系（ISCL）以精细定位该基因座。为了进一步定位该Sicd 2 QTL，创建了携带B6区段的重叠间隔的另外的同源系（ISCL-4），并将其与先前创建的ISCL-1-3进行比较，并评估了细菌诱导的细胞死亡表型。虽然所有的ISCL都表现出与B6表型相关的细胞死亡减少，但其中最引人注目的是，ISCL-4在所有海马子域中显示出最广泛的海马诱导细胞死亡减少。为了使用该ISCL表征Sicd 2上的易感基因座并鉴定引人注目的候选基因，我们采用了一种综合基因组策略，比较了该新开发的Chr. 15亚同源系（ISCL-4）和FVB样同窝仔海马中外显子转录本丰度。我们确定了10个假定的候选基因，这些基因在菌株之间进行选择性剪接，并可能决定菌株依赖性差异对尿素诱导的兴奋性毒性细胞死亡的易感性。这些结果说明了在表达研究中识别转录组学变体的重要性，并暗示了新的候选基因赋予对细胞凋亡诱导的细胞死亡的易感性。
Prior studies with crosses of the FVB/NJ (FVB; seizure-induced cell death susceptible) mouse and the seizure-induced cell death resistant mouse, C57BL/6J (B6), revealed the presence of a quantitative trait locus (QTL) on chromosome 15 (Chr. 15) that influenced susceptibility to kainic acid-induced cell death (Sicd2). In an earlier study, we confirmed that the Sicd2 interval harbors gene(s) conferring strong protection against seizure-induced cell death through the creation of the FVB.B6-Sicd2 congenic strain and created three interval-specific congenic lines (ISCLs) that encompass Sicd2 on Chr. 15 to fine-map this locus. To further localize this Sicd2 QTL, an additional congenic line carrying overlapping intervals of the B6 segment was created (ISCL-4) and compared to previously created ISCLs-1-3 and assessed for seizure-induced cell death phenotype. While all of the ISCLs exhibited reduced cell death associated with the B6 phenotype, the most dramatic of these, ISCL-4 showed the most extensive reduction in seizure-induced cell death throughout all hippocampal subfields. In order to characterize the susceptibility loci on Sicd2 using this ISCL and identify compelling candidate genes, we have undertaken an integrative genomic strategy of comparing exon transcript abundance in the hippocampus of this newly developed Chr. 15 subcongenic line (ISCL-4) and FVB-like littermates. We identified ten putative candidate genes that are alternatively spliced between the strains and may govern strain-dependent differences in susceptibility to seizure-induced excitotoxic cell death. These results illustrate the importance of identifying transcriptomics variants in expression studies, and implicate novel candidate genes conferring susceptibility to seizure-induced cell death.
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