Serious limitations of the QTL/microarray approach for QTL gene discovery.
Serious limitations of the QTL/microarray approach for QTL gene discovery.
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DOI：
10.1186/1741-7007-8-96
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发表时间：
2010-07-12
期刊：
影响因子：
5.4
通讯作者：
Medrano JF
中科院分区：
文献类型：
--
作者：
Verdugo RA;Farber CR;Warden CH;Medrano JF
已经提出，在非重组亲本或同类菌株中使用基因表达微阵列可以加速分离个体基因的过程，这些个体基因是数量性状位点（QTL）的基础。然而，这一方法的有效性尚未得到评估。回顾了37项在啮齿动物中实施QTL/微阵列方法的研究。约30%的研究显示富集QTL候选者，主要是在同源和背景菌株之间的比较。三项研究鉴定了潜在的QTL基因。为了补充文献结果，使用分离至少25个生物计量QTL的影响的三个小鼠同源品系进行微阵列实验。结果表明，同源供体区域的基因被优先选择。然而，在供体区域内，一旦考虑到基因密度，差异表达基因的分布是均匀的。同源（IBD）区域内的基因不太可能在2号染色体中差异表达，但在11号和17号染色体中则不然。此外，顺式调控的QTL（顺式eQTL）的表达在背景基因型中表现出更高的表达，这部分地解释了单核苷酸多态性（SNP）的存在。文献显示从QTL/微阵列方法鉴定QTL基因的成功有限。我们自己的结果从芯片分析的三个同源株揭示了一个强烈的倾向，选择顺式eQTL的反式eQTL。IBD区域对差异表达率的影响很小，我们提供了IBD不应用于丢弃eQTL候选者的几个原因。此外，错配探针产生的假cis-eQTL不能用当前菌株基因型和低探针密度微阵列完全去除。审查的研究没有考虑到所用平台的覆盖率不足，因此删除了未检测的基因。总之，我们的研究结果解释了报告QTL候选者差异表达的趋势，并表明目前实施的QTL/微阵列的实用性是有限的。提出了利用来自多个实验的微阵列数据来克服所概述的限制的替代方案。
It has been proposed that the use of gene expression microarrays in nonrecombinant parental or congenic strains can accelerate the process of isolating individual genes underlying quantitative trait loci (QTL). However, the effectiveness of this approach has not been assessed. Thirty-seven studies that have implemented the QTL/microarray approach in rodents were reviewed. About 30% of studies showed enrichment for QTL candidates, mostly in comparisons between congenic and background strains. Three studies led to the identification of an underlying QTL gene. To complement the literature results, a microarray experiment was performed using three mouse congenic strains isolating the effects of at least 25 biometric QTL. Results show that genes in the congenic donor regions were preferentially selected. However, within donor regions, the distribution of differentially expressed genes was homogeneous once gene density was accounted for. Genes within identical-by-descent (IBD) regions were less likely to be differentially expressed in chromosome 2, but not in chromosomes 11 and 17. Furthermore, expression of QTL regulated in cis (cis eQTL) showed higher expression in the background genotype, which was partially explained by the presence of single nucleotide polymorphisms (SNP). The literature shows limited successes from the QTL/microarray approach to identify QTL genes. Our own results from microarray profiling of three congenic strains revealed a strong tendency to select cis-eQTL over trans-eQTL. IBD regions had little effect on rate of differential expression, and we provide several reasons why IBD should not be used to discard eQTL candidates. In addition, mismatch probes produced false cis-eQTL that could not be completely removed with the current strains genotypes and low probe density microarrays. The reviewed studies did not account for lack of coverage from the platforms used and therefore removed genes that were not tested. Together, our results explain the tendency to report QTL candidates as differentially expressed and indicate that the utility of the QTL/microarray as currently implemented is limited. Alternatives are proposed that make use of microarray data from multiple experiments to overcome the outlined limitations.
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影响因子：
3.7
作者：
Alberts, Rudi;Terpstra, Peter;Li, Yang;Breitling, Rainer;Nap, Jan-Peter;Jansen, Ritsert C.
通讯作者：
Jansen, Ritsert C.
DOI：
10.1111/j.1530-0277.2007.00397.x
发表时间：
2007-07-01
影响因子：
3.2
作者：
Carr, Lucinda G.;Kimpel, Mark W.;Edenberg, Howard J.
通讯作者：
Edenberg, Howard J.
影响因子：
7
作者：
Curwen, V;Eyras, E;Clamp, M
通讯作者：
Clamp, M
影响因子：
11.4
作者：
de Koning, DJ;Haley, CS
通讯作者：
Haley, CS
影响因子：
1.5
作者：
BRADFORD, GE;FAMULA, TR
通讯作者：
FAMULA, TR