Allen Institute for Brain Science, Seattle, WA 98103, USA.
Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19049-54. doi: 10.1073/pnas.1003732107. Epub 2010 Oct 18.
Considerable progress has been made in understanding variations in gene sequence and expression level associated with phenotype, yet how genetic diversity translates into complex phenotypic differences remains poorly understood. Here, we examine the relationship between genetic background and spatial patterns of gene expression across seven strains of mice, providing the most extensive cellular-resolution comparative analysis of gene expression in the mammalian brain to date. Using comprehensive brainwide anatomic coverage (more than 200 brain regions), we applied in situ hybridization to analyze the spatial expression patterns of 49 genes encoding well-known pharmaceutical drug targets. Remarkably, over 50% of the genes examined showed interstrain expression variation. In addition, the variability was nonuniformly distributed across strain and neuroanatomic region, suggesting certain organizing principles. First, the degree of expression variance among strains mirrors genealogic relationships. Second, expression pattern differences were concentrated in higher-order brain regions such as the cortex and hippocampus. Divergence in gene expression patterns across the brain could contribute significantly to variations in behavior and responses to neuroactive drugs in laboratory mouse strains and may help to explain individual differences in human responsiveness to neuroactive drugs.
在理解与表型相关的基因序列和表达水平变化方面已经取得了相当大的进展，但遗传多样性如何转化为复杂的表型差异仍知之甚少。在这里，我们研究了七个品系小鼠的遗传背景与基因表达空间模式之间的关系，这是迄今为止对哺乳动物大脑中基因表达进行的最广泛的细胞分辨率比较分析。我们使用全面的大脑解剖覆盖范围（超过 200 个大脑区域），通过原位杂交分析了 49 个编码知名药物靶点的基因的空间表达模式。值得注意的是，超过 50%的检查基因表现出品系间的表达变化。此外，这种可变性在品系和神经解剖区域之间的分布不均匀，表明存在某些组织原则。首先，各品系间的表达方差程度反映了系统发育关系。其次，表达模式的差异集中在更高阶的大脑区域，如皮层和海马体。大脑中基因表达模式的差异可能会极大地导致实验室小鼠品系行为和对神经活性药物反应的变化，并有助于解释人类对神经活性药物反应的个体差异。
