The conserved organization of the human and mouse transcriptomes. The conserved organization of the human and mouse transcriptomes

We characterized by RNA-seq the transcriptional profiles of a large and heterogeneous collection of mouse tissues, augmenting the mouse transcriptome with thousands of novel transcript candidates. Comparison with transcriptome profiles obtained in human cell lines reveals substantial conservation of transcriptional programs, and uncovers a distinct class of genes with levels of expression across cell types and species, that have been constrained early in vertebrate evolution. This core set of genes capture a substantial and constant fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types. Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer. Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but it is associated with strong and conserved epigenetic marking, as well as to a characteristic post-transcriptional regulatory program in which sub-cellular localization and alternative splicing play comparatively large roles. Overall design: Comparison of human and mouse transcriptome profiles has uncovered a distinct class of genes (6600- one third of all expressed genes in both human and mouse) whose variation in expression levels have been constrained irrespective of cell types and species that they are express in. Such constraint appears to have been developed early in vertebrate evolution since it seen in multiple other species. This constraint is not associated with the conservation of the genomic sequences found in each species. Finally, this core set of genes helps in interpreting how non-human organisms like the mouse can better be used as models for human disease and why perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer.

本研究通过RNA测序（RNA-seq）对大量异质性小鼠组织集合的转录组谱进行了表征，并为小鼠转录组补充了数千个全新的转录本候选序列。将其与人类细胞系中获得的转录组谱进行比较后，本研究发现转录程序存在显著保守性，并揭示了一类独特的基因：这类基因在不同细胞类型与物种间的表达水平在脊椎动物演化早期就已受到约束。这类核心基因占据哺乳动物细胞转录输出总量中可观且稳定的比例，并参与所有细胞类型共有的基础功能与结构管家过程。对这些受约束基因的扰动会引发包括胚胎致死与癌症在内的显著表型。基因表达水平的演化约束并未体现在基因组序列的保守性上，而是与强烈且保守的表观遗传标记，以及一类特征鲜明的转录后调控程序密切相关：在该程序中，亚细胞定位与可变剪接发挥了相对重要的作用。
研究设计概述：通过比较人类与小鼠的转录组谱，本研究发现了一类独特的基因（共6600个，约占人类与小鼠中所有表达基因的三分之一），无论其表达所在的细胞类型与物种如何，其表达水平的变异均受到约束。由于在多个其他物种中均观测到该约束现象，提示这类约束在脊椎动物演化早期便已形成。该约束与各物种自身基因组序列的保守性并无关联。综上，这类核心基因有助于阐释为何小鼠等非人类模式生物可更好地作为人类疾病的研究模型，以及为何对这些受约束基因的扰动会引发胚胎致死与癌症等显著表型。