Human-specific insertions play important roles in human phenotypes and diseases.Here we reported a 446-bp insertion(Insert-446)in intron 11 of the TBC1D8B gene,located on chromosome X,and traced its origin to a portio...Human-specific insertions play important roles in human phenotypes and diseases.Here we reported a 446-bp insertion(Insert-446)in intron 11 of the TBC1D8B gene,located on chromosome X,and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5.Interestingly,Insert-446 was present in the human Neanderthal and Denisovans genomes,and was fixed in humans after human-chimpanzee divergence.We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques.In addition,over-expression TBC1D8B promoted cell proliferation and migration through“a dual finger”catalytic mechanism(Arg538 and Gln573)in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo.Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells.Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene.These findings provide a significant insight into the effects of human-specific insertions on evolution.展开更多
Human’s robust cognitive abilities,including creativity and language,are made possible,at least in large part,by evolutionary changes made to the cerebral cortex.This paper reviews the biology and evolution of mammal...Human’s robust cognitive abilities,including creativity and language,are made possible,at least in large part,by evolutionary changes made to the cerebral cortex.This paper reviews the biology and evolution of mammalian cortical radial glial cells(primary neural stem cells)and introduces the concept that a genetically step wise process,based on a core molecular pathway already in use,is the evolutionary process that has molded cortical neurogenesis.The core mechanism,which has been identified in our recent studies,is the extracellular signal-regulated kinase(ERK)-bone morphogenic protein 7(BMP7)-GLI3 repressor form(GLI3R)-sonic hedgehog(SHH)positive feedback loop.Additionally,I propose that the molecular basis for cortical evolutionary dwarfism,exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor,is an increase in SHH signaling in radial glia,that antagonizes ERK-BMP7 signaling.Finally,I propose that:(1)SHH signaling is not a key regulator of primate cortical expansion and folding;(2)human cortical radial glial cells do not generate neocortical interneurons;(3)human-specific genes may not be essential for most cortical expansion.I hope this review assists colleagues in the field,guiding research to address gaps in our understanding of cortical development and evolution.展开更多
基金supported by Key Research and Development Program of Yunnan(202203AC100010)the National Natural Science Foundation of China(31760311,32160236,81830087,U2102203)+4 种基金the National Key Research and Development Program of China(2022YFC2601604,2018YFC2000400,2020YFA0112300)Spring City Plan:the Highlevel Talent Promotion and Training Project of Kunming(2022SCP001)the Yunnan Fundamental Research Projects(CY22624104,202101AS070050)the open project of State Key Laboratory of Genetic Resources and Evolution,Kunming Institute of Zoology,Chinese Academy of Sciences(GREKF17-01)Yunnan University's new round of"Double First-Class"Construction Project—For People’s Life and Health(CY22624104)。
文摘Human-specific insertions play important roles in human phenotypes and diseases.Here we reported a 446-bp insertion(Insert-446)in intron 11 of the TBC1D8B gene,located on chromosome X,and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5.Interestingly,Insert-446 was present in the human Neanderthal and Denisovans genomes,and was fixed in humans after human-chimpanzee divergence.We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques.In addition,over-expression TBC1D8B promoted cell proliferation and migration through“a dual finger”catalytic mechanism(Arg538 and Gln573)in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo.Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells.Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene.These findings provide a significant insight into the effects of human-specific insertions on evolution.
基金supported by the Ministry of Science and Technology of China(STI2030-2021ZD0202300)the National Natural Science Foundation of China(32070971,32100768,32200776,and 32200792)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)。
文摘Human’s robust cognitive abilities,including creativity and language,are made possible,at least in large part,by evolutionary changes made to the cerebral cortex.This paper reviews the biology and evolution of mammalian cortical radial glial cells(primary neural stem cells)and introduces the concept that a genetically step wise process,based on a core molecular pathway already in use,is the evolutionary process that has molded cortical neurogenesis.The core mechanism,which has been identified in our recent studies,is the extracellular signal-regulated kinase(ERK)-bone morphogenic protein 7(BMP7)-GLI3 repressor form(GLI3R)-sonic hedgehog(SHH)positive feedback loop.Additionally,I propose that the molecular basis for cortical evolutionary dwarfism,exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor,is an increase in SHH signaling in radial glia,that antagonizes ERK-BMP7 signaling.Finally,I propose that:(1)SHH signaling is not a key regulator of primate cortical expansion and folding;(2)human cortical radial glial cells do not generate neocortical interneurons;(3)human-specific genes may not be essential for most cortical expansion.I hope this review assists colleagues in the field,guiding research to address gaps in our understanding of cortical development and evolution.
