Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice
Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice
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DOI：
10.1101/gr.171601
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发表时间：
2001-06-01
期刊：
影响因子：
7
通讯作者：
Takahashi, JS
中科院分区：
文献类型：
--
作者：
Shimomura, K;Low-Zeddies, SS;Takahashi, JS
遗传异质性是在昼夜节律中观察到的许多表型变异的基础。在多个近交系小鼠中观察到的昼夜节律行为的连续分布表明，对变异性的固有贡献在本质上是多基因的。为了确定这种复杂行为背后的遗传位点，我们对196只（C57 BL/6 J X BALB/cJ）F-2杂交小鼠进行了全基因组复杂性状分析。我们的特点是在这组F-2小鼠的变化之间的五个昼夜节律表型：自由运行的昼夜节律周期，相位角的夹带，昼夜节律的幅度，昼夜活动水平，和解离的节奏。我们对这些表型的遗传分析已经鉴定出对这种行为具有显著影响的14个基因座，包括对这些表型测量中的三个有贡献的显著主效应基因座：周期、相位和振幅。我们描述了一个额外的基因座检测方法，全基因组通用的相互作用分析，开发，以确定基因座对，可能相互作用上位显着影响表型，使用这种分析，我们确定了两个额外的对位点，有显着的影响解离和活动水平，我们还检测到的相互作用的影响，在基因座的差异，阶段，和幅度。虽然单基因突变可以影响昼夜节律，但对菌株间变异的分析表明，这种行为的基础是显着的遗传复杂性。重要的是，我们通过这些方法检测到的大多数基因座映射到与9个已知时钟基因不同的位置，表明在哺乳动物昼夜节律系统中存在额外的时钟相关基因。这些数据证明了全基因组复杂性状和上位性相互作用分析在进一步了解复杂表型中的分析价值，并指出了在其他哺乳动物（包括人类）中对此类表型进行遗传分析的有前途的方法。
Genetic heterogeneity underlies many phenotypic variations observed in circadian rhythmicity. Continuous distributions in measures of circadian behavior observed among multiple inbred strains of mice suggest that the inherent contributions to variability are polygenic in nature. To identify genetic loci that underlie this complex behavior, we have carried out a genome-wide complex trait analysis in 196 (C57BL/6J X BALB/cJ)F-2 hybrid mice. We have characterized variation in this panel of F-2 mice among five circadian phenotypes: free-running circadian period, phase angle of entrainment, amplitude of the circadian rhythm, circadian activity level, and dissociation of rhythmicity. Our genetic analyses of these phenotypes have led to the identification of 14 loci having significant effects on this behavior, including significant main effect loci that contribute to three of these phenotypic measures: period, phase, and amplitude. We describe an additional locus detection method, genome-wide generic interaction analysis, developed to identify locus pairs that may interact epistatically to significantly affect phenotype, Using this analysis, we identified two additional pairs of loci that have significant effects on dissociation and activity level; we also detected interaction effects in loci contributing to differences of period, phase, and amplitude. Although single gene mutations can affect circadian rhythms, the analysis of interstrain variants demonstrates that significant genetic complexity underlies this behavior. importantly, most of the loci that we have detected by these methods map to locations that differ from the nine known clock genes, indicating the presence of additional clock-relevant genes in the mammalian circadian system. These data demonstrate the analytical value of both genome-wide complex trait and epistatic interaction analyses in further understanding complex phenotypes, and point to promising approaches for genetic analysis of such phenotypes in other mammals, including humans.