Atopic Dermatitis Susceptibility Variants in Filaggrin Hitchhike Hornerin Selective Sweep.
Human skin has evolved rapidly, leaving evolutionary signatures in the genome. The filaggrin (FLG) gene is widely studied for its skin-barrier function in humans. The extensive genetic variation in this gene, especially common loss-of-function (LoF) mutations, has been established as primary risk factors for atopic dermatitis. To investigate the evolution of this gene, we analyzed 2,504 human genomes and genotyped the copy number variation of filaggrin repeats within FLG in 126 individuals from diverse ancestral backgrounds. We were unable to replicate a recent study claiming that LoF of FLG is adaptive in northern latitudes with lower ultraviolet light exposure. Instead, we present multiple lines of evidence suggesting that FLG genetic variation, including LoF variants, have little or no effect on fitness in modern humans. Haplotype-level scrutinization of the locus revealed signatures of a recent selective sweep in Asia, which increased the allele frequency of a haplotype group (Huxian haplogroup) in Asian populations. Functionally, we found that the Huxian haplogroup carries dozens of functional variants in FLG and hornerin (HRNR) genes, including those that are associated with atopic dermatitis susceptibility, HRNR expression levels and microbiome diversity on the skin. Our results suggest that the target of the adaptive sweep is HRNR gene function, and the functional FLG variants that involve susceptibility to atopic dermatitis, seem to hitchhike the selective sweep on HRNR. Our study presents a novel case of a locus that harbors clinically relevant common genetic variation with complex evolutionary trajectories.
Department of Biological Sciences, University at Buffalo, The State University of New York at Buffalo, Buffalo, NY.
Muthukrishnan
M
Eaaswarkhanth
Department of Biological Sciences, University at Buffalo, The State University of New York at Buffalo, Buffalo, NY.
Duo
D
Xu
Department of Biological Sciences, University at Buffalo, The State University of New York at Buffalo, Buffalo, NY.
Colin
C
Flanagan
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
Margarita
M
Rzhetskaya
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
M Geoffrey
MG
Hayes
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN.
Ran
R
Blekhman
Department of Anthropology, Pennsylvania State University, University Park, PA.
Nina G
NG
Jablonski
Department of Biological Sciences, University at Buffalo, The State University of New York at Buffalo, Buffalo, NY omergokc@buffalo.edu.
Omer
O
Gokcumen
D002135:Calcium-Binding Proteins / Q000235:genetics*; D056915:DNA Copy Number Variations; D003876:Dermatitis, Atopic / Q000235:genetics*; D019143:Evolution, Molecular; D000091344:Filaggrin Proteins; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D012641:Selection, Genetic
D002135:Calcium-Binding Proteins; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C503908:HRNR protein, human; D007381:Intermediate Filament Proteins
copy number variation; positive selection; skin evolution; structural variants; tandem repeats
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