Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature. 2011 Oct 12;478(7370):476-82. doi: 10.1038/nature10530.
The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
比较相关基因组已经成为解释基因组的有力工具。在这里，我们报告了 29 个真兽类基因组的测序和比较分析。我们证实人类基因组中至少有 5.5%经历了纯化选择，并定位了覆盖基因组约 4.2%的约束元素。我们使用进化特征和与实验数据集的比较，为约 60%的约束碱基提出候选功能。这些元素揭示了少数新的编码外显子、候选终止密码子通读事件以及在蛋白质编码外显子内重叠的同义约束区域超过 10000 个。我们发现了 220 个候选 RNA 结构家族，以及近百万个潜在启动子、增强子和绝缘子区域重叠的元素。我们报告了经历正选择的特定氨基酸残基、28 万个源自移动元件的非编码元件以及 1000 多个灵长类动物和人类加速元件。与疾病相关变异的重叠表明，我们的发现将与人类生物学、健康和疾病的研究相关。
