PDF(Pubmed)
Abstract：
Changes in genomic structures underlie phenotypic diversification in organisms. Amino acid-changing mutations affect pleiotropic functions of proteins, although little is known about how mutated proteins are adapted in existing developmental programs. Here we investigate the biological effects of a variant of the GLI3 transcription factor (GLI3R1537C) carried in Neanderthals and Denisovans, which are extinct hominins close to modern humans. R1537C does not compromise protein stability or GLI3 activator-dependent transcriptional activities. In contrast, R1537C affects the regulation of downstream target genes associated with developmental processes. Furthermore, genome-edited mice carrying the Neanderthal/Denisovan GLI3 mutation exhibited various alterations in skeletal morphology. Our data suggest that an extinct hominin-type GLI3 contributes to species-specific anatomical variations, which were tolerated by relaxed constraint in developmental programs during human evolution.
摘要：
基因组结构的变化是生物体表型多样化的基础。氨基酸改变突变影响蛋白质的多效性功能，尽管对突变的蛋白质如何在现有的发育程序中适应知之甚少。在这里，我们研究了尼安德特人和丹尼索瓦人携带的GLI3转录因子（GLI3R1537C）变体的生物学效应，这是接近现代人类的灭绝的人类。R1537C不损害蛋白质稳定性或GLI3激活因子依赖性转录活性。相比之下,R1537C影响与发育过程相关的下游靶基因的调节。此外，携带尼安德特人/丹尼索瓦人GLI3突变的基因组编辑小鼠在骨骼形态上表现出各种改变。我们的数据表明，已灭绝的人源蛋白型GLI3有助于物种特异性解剖变异，在人类进化过程中，发展计划的放松约束是可以容忍的。
