Accounting for continual evolution of deleterious L1 retrotransposon families, which can contain hundreds to thousands of members remains a major issue in mammalian biology. L1 activity generated upwards of 40% of some mammalian genomes, including humans where they remain active, causing genetic defects and rearrangements. L1 encodes a coiled coil-containing protein that is essential for retrotransposition, and the emergence of novel primate L1 families has been correlated with episodes of extensive amino acid substitutions in the coiled coil. These results were interpreted as an adaptive response to maintain L1 activity, however its mechanism remained unknown. Although an adventitious mutation can inactivate coiled coil function, its effect could be buffered by epistatic interactions within the coiled coil, made more likely if the family contains a diverse set of coiled coil sequences—collectively referred to as the coiled coil sequence space. Amino acid substitutions that do not affect coiled coil function (i.e., its phenotype) could be “hidden” from (not subject to) purifying selection. The accumulation of such substitutions, often referred to as cryptic genetic variation, has been documented in various proteins. Here we report that this phenomenon was in effect during the latest episode of primate coiled coil evolution, which occurred 30–10 MYA during the emergence of primate L1Pa7–L1Pa3 families. First, we experimentally demonstrated that while coiled coil function (measured by retrotransposition) can be eliminated by single epistatic mutations, it nonetheless can also withstand extensive amino acid substitutions. Second, principal component and cluster analysis showed that the coiled coil sequence space of each of the L1Pa7-3 families was notably increased by the presence of distinct, coexisting coiled coil sequences. Thus, sampling related networks of functional sequences rather than traversing discrete adaptive states characterized the persistence L1 activity during this evolutionary event.

考虑到有害的L1反转录转座子家族的持续进化，其可能包含数百至数千个成员，仍然是哺乳动物生物学中的主要问题。L1活性产生了一些哺乳动物基因组的40％以上，其中包括人类仍然活跃的基因组，从而导致了遗传缺陷和重排。L1编码含有盘绕的蛋白质，该蛋白质对于逆转座至关重要，并且新的灵长类L1家族的出现与盘绕的线圈中广泛的氨基酸取代有关。这些结果被解释为维持L1活性的适应性反应，但是其机制仍然未知。尽管不定突变可以使盘绕的线圈功能失活，但其作用可以被盘绕的线圈间的上位相互作用所缓冲，如果该族包含一组不同的线圈线圈序列（统称为线圈线圈序列空间），则可能性更大。不影响线圈卷曲功能的氨基酸替代（我。Ë，其表型）可以从（而不是）纯化选择中“隐藏”。这类替代物的积累（通常称为隐秘遗传变异）已在各种蛋白质中得到记录。在这里，我们报道这种现象在灵长类动物盘绕进化的最新一轮中起作用，在灵长类动物L1Pa7–L1Pa3家族出现期间发生了30–10 MYA。首先，我们通过实验证明，虽然可以通过单个上位突变来消除盘绕的线圈功能（通过逆转座测量），但它也可以承受广泛的氨基酸取代。其次，主成分和聚类分析表明，由于存在独特的，共存的卷曲螺旋序列，每个L1Pa7-3家族的卷曲螺旋序列空间显着增加。从而，