Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution

Area of Science:

• Evolutionary biology
• Human adaptation
• Genetics

Background:

• Humans possess the highest eccrine sweat gland density among primates, considered a significant evolutionary adaptation for thermoregulation.
• The genetic underpinnings of this increased sweat gland density have remained largely unknown.
• Engrailed 1 (EN1) expression is linked to eccrine gland development in humans and influences gland density variation in mice.

Purpose of the Study:

• To investigate the genetic basis for the evolution of high eccrine sweat gland density in humans.
• To identify specific genetic elements regulating EN1 expression during human evolution.
• To understand how changes in EN1 regulation contributed to human adaptation.

Main Methods:

• Comparative genomics to identify human-specific genetic elements.
• Functional validation of a novel human EN1 skin enhancer (hECE18) in mouse models and human keratinocytes.
• Analysis of enhancer activity and EN1 expression changes due to derived substitutions.

Main Results:

• A human-specific EN1 skin enhancer, hECE18, was identified.
• Multiple interacting mutations within hECE18 demonstrably increased its activity compared to non-human ape orthologs.
• hECE18 positively regulates EN1 expression in human keratinocytes and increases eccrine gland formation in a humanized mouse model.

Conclusions:

• Regulation of EN1 evolved on the human lineage, specifically through the hECE18 enhancer, to promote eccrine gland formation.
• This study reveals a genetic mechanism involving multiple mutations within a single enhancer driving a key human evolutionary adaptation.
• The findings provide insight into the genetic basis of human uniqueness and evolutionary change.