Adaptive Evolution of Conserved Noncoding Elements in Mammals

Conserved noncoding elements (CNCs) are an abundant feature of vertebrate genomes. Some CNCs have been shown to act as cis-regulatory modules, but the function of most CNCs remains unclear. To study the evolution of CNCs, we have developed a statistical method called the “shared rates test” to identify CNCs that show significant variation in substitution rates across branches of a phylogenetic tree. We report an application of this method to alignments of 98,910 CNCs from the human, chimpanzee, dog, mouse, and rat genomes. We find that ∼68% of CNCs evolve according to a null model where, for each CNC, a single parameter models the level of constraint acting throughout the phylogeny linking these five species. The remaining ∼32% of CNCs show departures from the basic model including speed-ups and slow-downs on particular branches and occasionally multiple rate changes on different branches. We find that a subset of the significant CNCs have evolved significantly faster than the local neutral rate on a particular branch, providing strong evidence for adaptive evolution in these CNCs. The distribution of these signals on the phylogeny suggests that adaptive evolution of CNCs occurs in occasional short bursts of evolution. Our analyses suggest a large set of promising targets for future functional studies of adaptation.

保守非编码元件（Conserved noncoding elements, CNCs）是脊椎动物基因组中广泛存在的一类特征序列。已有研究证实部分保守非编码元件可作为顺式调控模块发挥功能，但绝大多数此类元件的具体功能仍未明确。为探究保守非编码元件的演化规律，我们开发了一种名为“共享速率检验（shared rates test）”的统计方法，用于识别在系统发育树各分支上替换速率存在显著差异的保守非编码元件。本研究将该方法应用于来自人类、黑猩猩、犬、小鼠和大鼠基因组的98910个保守非编码元件的序列比对集。分析结果显示，约68%的保守非编码元件遵循零假设模型：对于每一个此类元件，仅需单个参数即可模拟其在连接这五个物种的系统发育树全程所承受的选择约束水平。剩余约32%的保守非编码元件则偏离该基础模型，具体表现为在特定分支上出现演化速率加快或减慢，部分元件在不同分支上还存在多次速率改变事件。我们发现，部分经检验显著的保守非编码元件在特定分支上的演化速率显著高于局部中性演化速率，这为这些元件发生适应性演化提供了强有力的证据。此类适应性演化信号在系统发育树上的分布特征表明，保守非编码元件的适应性演化多以偶发的短期快速演化爆发形式进行。本研究的分析结果为未来开展适应性演化功能研究提供了大量极具研究价值的候选靶标。