Intra- and inter-individual genetic differences in gene expression (BXD Kidney)

Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52-79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intra-individual differences. This will create substantial challenges in humans, where multiple tissues are not readily available. Common reference design where each hybridisation compares a single BxD strain to a common reference of C57BL/6J in the green channel. Two-colour, spotted glass arrays were used. No dye swaps were employed.已知遗传变异可影响基因所产生的信使RNA（mRNA）的表达量。由于分子机器调控多个基因的mRNA水平，我们推测这类机器组分中的遗传变异会以相似的方式对多个基因产生调控影响。本研究通过分析小鼠品系队列中多组织的mRNA水平相关性以检测共享的遗传调控效应，证实了上述推测的正确性。此类基因共相关群（CGGs）具有集体调控特性，平均可解释其组成基因52%~79%的表达变异，且其成员可包含编码功能相关蛋白的基因。研究发现，此类遗传调控效应本质上具有组织特异性：因此，同一动物体内的同一种遗传变异，可能在某一组织中上调某一CGG，却在另一组织中下调该CGG。此外，本研究还观察到不同个体的同一组织内，CGGs也呈现出类似的悖论性调控行为。由此可见，此类遗传变异可导致复杂的个体间及个体内表达差异。而在人类研究中，由于难以便捷获取多组织样本，这一现象将带来极大的研究挑战。实验采用通用参考设计：每一次芯片杂交均通过绿色通道将单个BXD品系与通用参考样本C57BL/6J进行比对。本研究使用双色点样玻璃芯片，且未进行染料互换实验。