%0 Journal Article
%T A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice.
%A Agata A
%A Ohtsuka S
%A Noji R
%A Gotoh H
%A Ono K
%A Nomura T
%J Front Cell Dev Biol
%V 11
%N 0
%D 2023
%M 38020913
%F 6.081
%R 10.3389/fcell.2023.1247361
%X 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.