School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
Nat Struct Mol Biol. 2024 Mar;31(3):559-567. doi: 10.1038/s41594-024-01235-4. Epub 2024 Mar 6.
Genomes encode for genes and non-coding DNA, both capable of transcriptional activity. However, unlike canonical genes, many transcripts from non-coding DNA have limited evidence of conservation or function. Here, to determine how much biological noise is expected from non-genic sequences, we quantify the regulatory activity of evolutionarily naive DNA using RNA-seq in yeast and computational predictions in humans. In yeast, more than 99% of naive DNA bases were transcribed. Unlike the evolved transcriptome, naive transcripts frequently overlapped with opposite sense transcripts, suggesting selection favored coherent gene structures in the yeast genome. In humans, regulation-associated chromatin activity is predicted to be common in naive dinucleotide-content-matched randomized DNA. Here, naive and evolved DNA have similar co-occurrence and cell-type specificity of chromatin marks, challenging these as indicators of selection. However, in both yeast and humans, extreme high activities were rare in naive DNA, suggesting they result from selection. Overall, basal regulatory activity seems to be the default, which selection can hone to evolve a function or, if detrimental, repress.
基因组编码基因和非编码 DNA，两者都具有转录活性。然而，与典型的基因不同，许多非编码 DNA 的转录物几乎没有保守或功能的证据。在这里，为了确定非基因序列的生物噪声有多少，我们使用酵母中的 RNA-seq 和人类中的计算预测来量化进化上幼稚的 DNA 的调控活性。在酵母中，超过 99%的原始 DNA 碱基被转录。与进化的转录组不同，幼稚的转录物经常与相反的 sense 转录物重叠，这表明选择有利于酵母基因组中连贯的基因结构。在人类中，预测与调节相关的染色质活性在幼稚的二核苷酸含量匹配的随机化 DNA 中很常见。在这里，幼稚和进化的 DNA 具有相似的染色质标记共现和细胞类型特异性，这对这些作为选择指标提出了挑战。然而，在酵母和人类中，幼稚 DNA 中极端高活性的情况很少见，这表明它们是选择的结果。总的来说，基础调控活性似乎是默认的，选择可以利用它来进化出功能，或者如果有害，则可以抑制功能。
