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bioRxiv · 10.1101/2023.07.03.547394

A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice

Agata, A.·Ohtsuka, S.·Noji, R.·Gotoh, H.·Ono, K.·Nomura, T.
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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.

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Agata, A., Ohtsuka, S., Noji, R., Gotoh, H., Ono, K., Nomura, T.. 2023-07-03. A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice. https://doi.org/10.1101/2023.07.03.547394

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