Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Biol. 2010 Feb 23;8(2):e1000320. doi: 10.1371/journal.pbio.1000320.
Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype ( approximately two X chromosomes and four sets of autosomes, or 2X;4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system "anticipates" the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal-independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components.
在非整倍体中，广泛偏离平衡的基因剂量是高度有害的。然而，我们对非整倍体细胞中基因拷贝数和表达之间的关系知之甚少。我们通过 DNA-Seq 和 RNA-Seq 确定了果蝇 S2 细胞中基因组的拷贝数和转录丰度（表达）的全基因组水平。我们发现 S2 细胞存在超过 43Mb 的基因组非整倍体，主要在一个到五个拷贝的范围内，并且表现出雄性基因型（大约两个 X 染色体和四组常染色体，或 2X；4A）。X 染色体和常染色体都表现出表达剂量补偿。X 染色体的表达以固定的倍数升高，而不考虑实际的基因剂量。从工程学的角度来看，该系统“预测”了 X 剂量引起的扰动，而不是对扰动引起的错误做出反应。只有当 X 剂量是常染色体剂量的一半时，这种前馈调节才能产生精确的剂量补偿。在较低的 X 染色体剂量下，补偿不足，而在较高的剂量下，表达过度。雄性特异致死复合物的 RNAi 敲低消除了前馈调节。常染色体和 X 染色体基因都表现出不依赖于雄性特异致死的补偿，符合一阶剂量反应曲线。我们的数据表明，表达剂量补偿减轻了全基因组改变 DNA 拷贝数的影响。对于 X 染色体，补偿包括固定和剂量依赖的成分。
