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Atopic Dermatitis Susceptibility Variants in Filaggrin Hitchhike Hornerin Selective Sweep
Muthukrishnan Eaaswarkhanth1, Duo Xu1, Colin Flanagan1
1Department of Biological Sciences, University at Buffalo, The State University of New York at Buffalo, Buffalo, NY.
Genome Biology and Evolution
|September 29, 2016
Summary
Human skin evolution shows filaggrin (FLG) gene variation. Loss-of-function mutations in FLG are not adaptive in low UV light, but a selective sweep in Asia suggests HRNR gene function was the target.
Area of Science:
- Human evolutionary genetics
- Population genetics
- Dermatology
Background:
- The filaggrin (FLG) gene is crucial for skin barrier function and its variations are linked to atopic dermatitis.
- Previous research suggested FLG loss-of-function mutations might be adaptive in low ultraviolet (UV) light environments.
Purpose of the Study:
- To investigate the evolutionary trajectory of the FLG gene and its associated genetic variations.
- To re-evaluate the adaptive significance of FLG loss-of-function mutations in human populations.
Main Methods:
- Analysis of 2,504 human genomes to study FLG gene evolution.
- Genotyping of filaggrin repeat copy number variation in 126 individuals from diverse ancestries.
- Haplotype analysis to detect signatures of natural selection.
Main Results:
- Evidence suggests FLG genetic variations, including loss-of-function variants, have minimal impact on human fitness.
- A recent selective sweep in Asian populations was identified, increasing the frequency of the Huxian haplogroup.
- The Huxian haplogroup contains functional variants in both FLG and hornerin (HRNR) genes, impacting atopic dermatitis susceptibility and skin microbiome diversity.
Conclusions:
- The adaptive sweep likely targeted the hornerin (HRNR) gene, not FLG.
- Clinically relevant FLG variants associated with atopic dermatitis may have hitchhiked during the HRNR-targeted selective sweep.
- This study reveals complex evolutionary dynamics at a locus with significant clinical relevance.
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