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

Area of Science:

• Evolutionary biology
• Genetics
• Developmental biology

Background:

• Genomic changes drive phenotypic diversity.
• Understanding how mutations in developmental genes like GLI3 are adapted is crucial.

Purpose of the Study:

• Investigate the biological effects of the GLI3^R1537C variant found in Neanderthals and Denisovans.
• Determine its impact on gene regulation and organismal morphology.

Main Methods:

• Studied the GLI3^R1537C variant's effect on protein stability and transcriptional activity.
• Analyzed regulation of downstream target genes.
• Generated genome-edited mice with the Neanderthal/Denisovan GLI3 mutation.

Main Results:

• The GLI3^R1537C variant did not affect protein stability or GLI3 activator activity.
• This variant altered the regulation of developmental genes.
• Mice with the mutation showed skeletal morphology alterations.

Conclusions:

• Extinct hominin-type GLI3 contributes to species-specific anatomical variations.
• Relaxed developmental constraints may have accommodated such changes during human evolution.