Ayroles Julien F, Buchanan Sean M, O'Leary Chelsea, Skutt-Kakaria Kyobi, Grenier Jennifer K, Clark Andrew G, Hartl Daniel L, de Bivort Benjamin L
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138; Harvard Society of Fellows, Harvard University, Cambridge, MA 02138; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853;
Rowland Institute at Harvard, Cambridge, MA 02142; and.
Proc Natl Acad Sci U S A. 2015 May 26;112(21):6706-11. doi: 10.1073/pnas.1503830112. Epub 2015 May 7.
Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.
数量遗传学主要专注于描述基因对性状均值的影响，很大程度上忽略了等位基因变异对性状变异性的影响，这可能遗漏了导致个体间表型差异的一个重要遗传变异轴。为了研究基因对个体间表型变异性（或基因型内变异性）的影响，我们使用了果蝇近交系，并测量了果蝇在 Y 形迷宫中单独行走时的自发运动行为，重点关注运动偏好性的变异性，这是一种为测量变异性而优化的检测方法。我们发现，一些品系个体间的基因型内变异性始终很高，而变异性低的品系在每次左右转向决策时的表现就好像在抛硬币。我们证明变异性程度本身是可遗传的。以基因型内变异性程度作为跨品系的表型进行全基因组关联研究（GWAS），我们鉴定出几个在大脑中表达的基因，它们影响偏好性的变异性但不影响均值。其中一个基因 Ten-a，表明果蝇大脑中央复合体中的一个神经纤维网会影响行为变异性的大小，该脑区参与感觉整合和运动协调。我们使用基因缺失、无效等位基因和可诱导的 RNAi 转基因验证了这些结果。我们的研究揭示了单一基因型可能产生的一系列表型，并表明不同的遗传背景在表型变异性倾向上存在显著差异。由于传统的以均值为重点的 GWAS 忽略了变异性对整体表型变异的贡献，当前方法可能会遗漏基因型和表型之间的重要联系。
