Tracing the genetic innovation mechanisms in origin and evolution of liver from amphioxus to vertebrates

The emergence of the vertebrate liver is a prime example of the evolution of complex organs, yet the driving factors behind it remain unknown. Here, we utilize in vivo and in vitro experiments, single-cell transcriptomic data, and gene knockout experiments in mice to probe the evolutionary process of liver. We found that the amphioxus hepatic caecum, an evolutionary progenitor of the vertebrate liver, has only basic metabolic and immune functions, whereas the vertebrate liver appears to have diverse new functions. We discovered that the emergence of new genes from two rounds of whole-genome duplications (2R-WGD) significantly contributes to liver functional complexity in vertebrates. In particular, two new genes from 2R-WGD, kdr and flt4, play a significant role in the development of liver sinusoidal endothelial cells. Additionally, we found that liver-related functions such as coagulation and bile production evolved in a step-by-step manner, with new genes from 2R-WGD playing a significant role. Furthermore, the transfer of heme detoxification from the liver to the spleen during vertebrate evolution was also noted. Together, these findings challenge the common hypothesis that organ evolution is primarily driven by changes in gene regulation, underscoring the importance of new genes in the emergence and diversification of complex organ functions.

脊椎动物肝脏的起源是复杂器官演化的典型范例，但其背后的驱动因素至今仍不明晰。本研究通过体内、体外实验，小鼠单细胞转录组数据以及基因敲除实验，探究肝脏的演化历程。研究发现，作为脊椎动物肝脏演化祖先的文昌鱼肝盲囊，仅具备基础的代谢与免疫功能，而脊椎动物肝脏则演化出了多样的新增功能。我们发现，两轮全基因组复制（two rounds of whole-genome duplications, 2R-WGD）所产生的新基因，对脊椎动物肝脏的功能复杂性具有显著贡献。尤为关键的是，2R-WGD产生的两个新基因kdr与flt4，在肝窦内皮细胞的发育过程中发挥了重要作用。此外，我们发现凝血、胆汁生成等肝脏相关功能是以渐进式的方式演化而来，且2R-WGD产生的新基因在此过程中扮演了重要角色。进一步而言，本研究还观察到在脊椎动物演化历程中，血红素解毒功能从肝脏转移至脾脏的现象。综上，这些研究结果挑战了"器官演化主要由基因调控变化驱动"的主流假说，凸显了新基因在复杂器官功能的起源与多样化进程中的重要意义。