Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis
Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis
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DOI：
10.1111/j.1601-183x.2012.00795.x
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发表时间：
2012-07-01
影响因子：
2.5
通讯作者：
Palmer, A. A.
中科院分区：
文献类型：
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作者：
Bryant, C. D.;Kole, L. A.;Palmer, A. A.
我们先前使用C57 BL/6 J（B6）x A/J小鼠染色体置换株（CSS）面板，以确定影响甲基苯丙胺（MA）诱导的运动活动的11号染色体上的主要数量性状位点（QTL）。然后，我们在CSS-11和B6之间进行F2杂交，并缩小基因座（贝叶斯可信区间：79109 Mb），该基因座是显性遗传的，占CSS面板中表型方差的14%。在本研究中，我们创建了具有该QTL杂合部分的同源和亚同源系，以缩小间隔。我们确定了一个线（8496 Mb），概括的QTL，从而缩小了该地区的12 Mb。该时间间隔也使先前盐水处理后的自发活动略有减少。当我们产生跨越整个12 Mb区域的亚同源系时，MA敏感性的表型差异突然消失，表明上位性机制。我们还评估了MA（2 mg/kg，i. p.）在84- 96-Mb同源系中使用条件位置偏好（CPP）测试。我们在MA配对的CPP室中复制了运动差异，但没有观察到基因型对MA-CPP的影响，这支持了该QTL在这些条件下对MA诱导的运动活性的特异性。最后，为了帮助确定负责该QTL的候选基因的优先级，我们使用了AffysseGeneChip（R）Mouse Gene 1.0ST Array来鉴定未用药的同类小鼠纹状体中含有表达QTL（eQTL）的基因。这些发现突出了使用同源系精细定位QTL的困难，并说明上位性如何可能会阻碍这种努力。
We previously used the C57BL/6J (B6) x A/J mouse chromosome substitution strain (CSS) panel to identify a major quantitative trait locus (QTL) on chromosome 11 influencing methamphetamine (MA)-induced locomotor activity. We then made an F2 cross between CSS-11 and B6 and narrowed the locus (Bayes credible interval: 79109 Mb) which was inherited dominantly and accounted for 14% of the phenotypic variance in the CSS panel. In the present study, we created congenic and subcongenic lines possessing heterozygous portions of this QTL to narrow the interval. We identified one line (8496 Mb) that recapitulated the QTL, thus narrowing the region to 12 Mb. This interval also produced a small decrease in locomotor activity following prior saline treatment. When we generated subcongenic lines spanning the entire 12-Mb region, the phenotypic difference in MA sensitivity abruptly disappeared, suggesting an epistatic mechanism. We also evaluated the rewarding properties of MA (2 mg/kg, i.p.) in the 84- to 96-Mb congenic line using the conditioned place preference (CPP) test. We replicated the locomotor difference in the MA-paired CPP chamber yet observed no effect of genotype on MA-CPP, supporting the specificity of this QTL for MA-induced locomotor activity under these conditions. Lastly, to aid in prioritizing candidate genes responsible for this QTL, we used the Affymetrix GeneChip (R) Mouse Gene 1.0ST Array to identify genes containing expression QTLs (eQTL) in the striatum of drug-naIve, congenic mice. These findings highlight the difficulty of using congenic lines to fine map QTLs and illustrate how epistasis may thwart such efforts.