Makhanova Natalia, Morgan Andrew P, Kayashima Yukako, Makhanov Andrei, Hiller Sylvia, Zhilicheva Svetlana, Xu Longquan, Pardo-Manuel de Villena Fernando, Maeda Nobuyo
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States of America.
Department of Genetics and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America.
PLoS One. 2017 Aug 24;12(8):e0182882. doi: 10.1371/journal.pone.0182882. eCollection 2017.
Quantitative trait locus (QTL) analyses of intercross populations between widely used mouse inbred strains provide a powerful approach for uncovering genetic factors that influence susceptibility to atherosclerosis. Epistatic interactions are common in complex phenotypes and depend on genetic backgrounds. To dissect genetic architecture of atherosclerosis, we analyzed F2 progeny from a cross between apolipoprotein E-null mice on DBA/2J (DBA-apoE) and C57BL/6J (B6-apoE) genetic backgrounds and compared the results with those from two previous F2 crosses of apolipoprotein E-null mice on 129S6/SvEvTac (129-apoE) and DBA-apoE backgrounds, and B6-apoE and 129-apoE backgrounds. In these round-robin crosses, in which each parental strain was crossed with two others, large-effect QTLs are expected to be detectable at least in two crosses. On the other hand, observation of QTLs in one cross only may indicate epistasis and/or absence of statistical power. For atherosclerosis at the aortic arch, Aath4 on chromosome (Chr)2:66 cM follows the first pattern, with significant QTL peaks in (DBAx129)F2 and (B6xDBA)F2 mice but not in (B6x129)F2 mice. We conclude that genetic variants unique to DBA/2J at Aath4 confer susceptibility to atherosclerosis at the aortic arch. A similar pattern was observed for Aath5 on chr10:35 cM, verifying that the variants unique to DBA/2J at this locus protect against arch plaque development. However, multiple loci, including Aath1 (Chr1:49 cM), and Aath2 (Chr1:70 cM) follow the second type of pattern, showing significant peaks in only one of the three crosses (B6-apoE x 129-apoE). As for atherosclerosis at aortic root, the majority of QTLs, including Ath29 (Chr9:33 cM), Ath44 (Chr1:68 cM) and Ath45 (Chr2:83 cM), was also inconsistent, being significant in only one of the three crosses. Only the QTL on Chr7:37 cM was consistently suggestive in two of the three crosses. Thus QTL analysis of round-robin crosses revealed the genetic architecture of atherosclerosis.
对广泛使用的小鼠近交系之间的杂交群体进行数量性状基因座（QTL）分析，为揭示影响动脉粥样硬化易感性的遗传因素提供了一种强大的方法。上位性相互作用在复杂表型中很常见，并且取决于遗传背景。为了剖析动脉粥样硬化的遗传结构，我们分析了DBA/2J（DBA-apoE）和C57BL/6J（B6-apoE）遗传背景下载脂蛋白E基因敲除小鼠杂交产生的F2后代，并将结果与之前在129S6/SvEvTac（129-apoE）和DBA-apoE背景下以及B6-apoE和129-apoE背景下的两个载脂蛋白E基因敲除小鼠F2杂交结果进行了比较。在这些循环杂交中，每个亲本菌株都与另外两个菌株杂交，预计至少在两个杂交中可以检测到具有大效应的QTL。另一方面，仅在一个杂交中观察到QTL可能表明存在上位性和/或缺乏统计效力。对于主动脉弓处的动脉粥样硬化，位于染色体（Chr）2:66 cM处的Aath4遵循第一种模式，在（DBAx129）F2和（B6xDBA）F2小鼠中出现显著的QTL峰值，但在（B6x129）F2小鼠中未出现。我们得出结论，DBA/2J在Aath4处特有的遗传变异赋予了主动脉弓处动脉粥样硬化的易感性。在位于chr10:35 cM处的Aath5上也观察到了类似的模式，证实了DBA/2J在该位点特有的变异可防止主动脉弓斑块的形成。然而，包括Aath1（Chr1:49 cM）和Aath2（Chr1:70 cM）在内的多个基因座遵循第二种模式，仅在三个杂交之一（B6-apoE×129-apoE）中出现显著峰值。至于主动脉根部的动脉粥样硬化，包括Ath29（Chr9:33 cM）、Ath44（Chr1:68 cM）和Ath45（Chr2:83 cM）在内的大多数QTL也不一致，仅在三个杂交之一中显著。只有位于Chr7:37 cM处的QTL在三个杂交中的两个中始终具有提示性。因此，循环杂交的QTL分析揭示了动脉粥样硬化的遗传结构。
