Award Abstract # 1847598
The Genetic Basis for the Evolution of Adaptive Skin Appendage Traits in Humans

NSF Org: BCS
Division of Behavioral and Cognitive Sciences
Recipient: TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE
Initial Amendment Date: February 28, 2019
Latest Amendment Date: February 28, 2019
Award Number: 1847598
Award Instrument: Standard Grant
Program Manager: Rebecca Ferrell
rferrell@nsf.gov
 (703)292-7850
BCS
 Division of Behavioral and Cognitive Sciences
SBE
 Directorate for Social, Behavioral and Economic Sciences
Start Date: February 15, 2019
End Date: January 31, 2024 (Estimated)
Total Intended Award Amount: $577,704.00
Total Awarded Amount to Date: $577,704.00
Funds Obligated to Date: FY 2019 = $577,704.00
History of Investigator:
  • Yana Kamberov (Principal Investigator)
    yana2@pennmedicine.upenn.edu
Recipient Sponsored Research Office: University of Pennsylvania
3451 WALNUT ST STE 440A
PHILADELPHIA
PA  US  19104-6205
(215)898-7293
Sponsor Congressional District: 03
Primary Place of Performance: University of Pennsylvania
540 CRB, 415 Curie Blvd
Philadelphia
PA  US  19104-6145
Primary Place of Performance
Congressional District:
03
Unique Entity Identifier (UEI): GM1XX56LEP58
Parent UEI: GM1XX56LEP58
NSF Program(s): Evolution of Develp Mechanism,
Biological Anthropology
Primary Program Source: 01001920DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 1080, 1392
Program Element Code(s): 108000, 139200
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.075

ABSTRACT

The "bare" appearance of human skin is a trait that distinguishes humans from all other primates. This striking appearance results from miniaturized body hair and increased sweat gland density (approximately 10 times higher than that of a chimpanzee). These adaptations allow humans to cool their body temperature through increased air flow over the skin and evaporation of water from the skin surface. This project will find and explain the genomic changes underlying the human-specific evolutionary modifications to hair and sweat gland composition. The biological insights, as well as the data, methods and tools developed as part of this research program, will provide novel assets to transform the investigation of the genetic bases of other adaptive skin traits and skin physiology more generally. The data generated by this project also will advance ongoing efforts to build and properly pattern hair and eccrine glands in vitro, a major obstacle in comprehensive human skin regeneration. In addition, this project will support the training of under-represented minority students and researchers, and fund the development of a public, educational website on human skin evolution, which will highlight outstanding questions in skin evolution and curate ongoing and new discoveries on this topic.

This research program builds on the recent discovery by the research team that a subset of biological signals that increase eccrine gland density also alter hair development, leading to diminished hair size. The working hypothesis of this project is that humans have acquired evolutionary mutations in regulatory sequences leading to concomitantly increased eccrine gland density and diminished hair size relative to other primates. The researchers will (i) map out the regulatory sequences, or enhancers, that control the expression of a key developmental factor, En1, that reciprocally regulates eccrine sweat gland density and hair size; (ii) define the genomic changes within these enhancers that contributed to unique hair and sweat gland traits in humans, by investigating the functional significance of human-specific changes using genome edited mouse models of diverged human and chimpanzee regulatory sequences.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Aldea, Daniel and Atsuta, Yuji and Kokalari, Blerina and Schaffner, Stephen F. and Prasasya, Rexxi D. and Aharoni, Adam and Dingwall, Heather L. and Warder, Bailey and Kamberov, Yana G. "Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution" Proceedings of the National Academy of Sciences , v.118 , 2021 https://doi.org/10.1073/pnas.2021722118 Citation Details
Aldea, Daniel and Kokalari, Blerina and Atsuta, Yuji and Dingwall, Heather L. and Zheng, Ying and Nace, Arben and Cotsarelis, George and Kamberov, Yana G. "Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development" PLOS Genetics , v.19 , 2023 https://doi.org/10.1371/journal.pgen.1010614 Citation Details
Aldea, Daniel and Kokalari, Blerina and Luckhart, Christine and Aharoni, Adam and Albert, Paul R. and Kamberov, Yana G. "The Transcription Factor Deaf1 Modulates Engrailed-1 Expression to Regulate Skin Appendage Fate" Journal of Investigative Dermatology , v.139 , 2019 10.1016/j.jid.2019.05.007 Citation Details
Dingwall, Heather L. and Tomizawa, Reiko R. and Aharoni, Adam and Hu, Peng and Qiu, Qi and Kokalari, Blerina and Martinez, Serenity M. and Donahue, Joan C. and Aldea, Daniel and Mendoza, Meryl and Glass, Ian A. and Birth Defects Research Laboratory (BDRL) "Sweat gland development requires an eccrine dermal niche and couples two epidermal programs" Developmental Cell , v.59 , 2024 https://doi.org/10.1016/j.devcel.2023.11.015 Citation Details
Wark, Abigail R. and Aldea, Daniel and Tomizawa, Reiko R. and Kokalari, Blerina and Warder, Bailey and Kamberov, Yana G. "Ectodysplasin Signaling through XEDAR Is Required for Mammary Gland Morphogenesis" Journal of Investigative Dermatology , v.143 , 2023 https://doi.org/10.1016/j.jid.2023.02.007 Citation Details

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

Sweating is the main mechanism humans use for dumping excess heat and keeping human body temperature within the necessary range required for the proper function of organs and physiological processes. Accordingly, the water-producing eccrine sweat gland is a skin organ that is essential to human survival. Central to humans’ exceptional sweating capabilities, which far exceed those of all other primates, is the evolution of a much higher density of eccrine glands in human skin compared to that of our closest evolutionary relatives such as the chimpanzee. The mechanistic basis for this unique human trait has long been of interest not only for its evolutionary importance, but also for what it can reveal about the biological program that directs and regulates the formation of eccrine glands in the skin. The studies supported by this award identified not only genetic elements and molecular factors that specifically promote the eccrine gland developmental program but also uncovered how and why a subset of these were modified during human evolution to induce the formation of more eccrine glands in human skin.

In line with the primary hypothesis of the funded award, we discovered that a single, primate-specific regulatory element, or enhancer, of the Engrailed 1 (EN1/En1) gene we named EN1 candidate enhancer 18 (ECE18) had accumulated multiple activity-enhancing mutations on the human evolutionary lineage since the split from chimpanzees. We demonstrated that because of the combined activity of these human-specific enhancer mutations, the human ECE18 enhancer induces the expression of higher EN1 levels in the skin at the time when eccrine gland density is being specified, thereby promoting the formation of more eccrine glands. This discovery was the first to provide a genetic basis underlying humans’ high eccrine gland density relative to other primates. We went on to identify a second EN1 enhancer, ECE20, whose activity we showed was utilized more broadly among mammals to upregulate EN1 expression. We showed that in contrast to ECE18, ECE20 was required to activate En1 expression not only in the skin but also in the developing brain. This suggests that differences in the specificity of these two enhancers would have helped to constrain and favor the evolution of human eccrine traits via the ECE18 enhancer, thus avoiding the potential cost of altering EN1 expression in the brain. In addition to the identification of the first reported enhancers that control mammalian EN1 expression, research supported by this award identified SP1 and DEAF1 as the first transcription factors, DNA binding proteins that are directly engaged in the regulation of gene expression, that are required to activate EN1 expression in the skin and thus promote the formation of eccrine glands during development.  

The studies supported by this award combined comparative genomics with functional testing in transgenic and genome edited mice. Importantly, because human eccrine gland development occurs exclusively during the fetal period and there are no in vitro models for eccrine gland formation, the genetically tractable mouse experimental models we generated were critical for functionally testing the EN1 enhancers we identified and for uncovering their importance in generating eccrine glands. Accordingly, the molecular tools to study skin enhancer activity and mouse models developed as part of this proposal are unique resources that will be leveraged by other researchers investigating eccrine gland and skin derived organ development more broadly.

The broader implications of the experimental outcomes derived from this award are multifold. Our findings stand as the first example of explaining a full human evolutionary trait from the single base pair all the way to complete adaptive phenotype, providing an evidence-based case for demonstrating and teaching students and the broader public about the impact of evolution on generating the human phenotype. Moreover, our findings provide evidence that the balance between enhancer pleiotropy and specificity shapes the mechanism by which a phenotype evolves, which will impact the search for the genetic basis of other adaptive human traits. Finally, the biological network we derived for the formation of eccrine glands can be directly applied towards future efforts to develop therapeutic platforms for eccrine gland regeneration, a critical unmet need in skin reconstructive medicine.

 


Last Modified: 02/27/2024
Modified by: Yana G Kamberov

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