Atopic dermatitis susceptibility variants in filaggrin hitchhike hornerin selective sweep

Muthukrishnan Eaaswarkhanth, Duo Xu, Colin Flanagan, Margarita Rzhetskaya, M. Geoffrey Hayes, Ran Blekhman, Nina G. Jablonski, Omer Gokcumen

Research output: Contribution to journalArticle

17 Citations (Scopus)


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 andmicrobiome 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.

Original languageEnglish
Pages (from-to)3240-3255
Number of pages16
JournalGenome Biology and Evolution
Issue number10
Publication statusPublished - 1 Jan 2016


  • Copy number variation
  • Positive selection
  • Skin evolution
  • Structural variants
  • Tandem repeats

Fingerprint Dive into the research topics of 'Atopic dermatitis susceptibility variants in filaggrin hitchhike hornerin selective sweep'. Together they form a unique fingerprint.

  • Activities

    • 1 Participating in a conference, workshop, ...

    Seventh Annual UB Postdoc Research Symposium

    Muthukrishnan Eaaswarkhanth (Participant)

    5 Jun 2015

    Activity: Participating in or organising an event typesParticipating in a conference, workshop, ...

    Cite this

    Eaaswarkhanth, M., Xu, D., Flanagan, C., Rzhetskaya, M., Hayes, M. G., Blekhman, R., Jablonski, N. G., & Gokcumen, O. (2016). Atopic dermatitis susceptibility variants in filaggrin hitchhike hornerin selective sweep. Genome Biology and Evolution, 8(10), 3240-3255.