Evolutionary Biology

, Volume 41, Issue 3, pp 388–396 | Cite as

Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production

  • Jacob P. Thyssen
  • Daniel D. Bikle
  • Peter M. Elias
Synthesis Paper


Skin pigmentation lightened progressively to a variable extent, as modern humans emigrated out of Africa, but extreme lightening occurred only in northern Europeans. Yet, loss of pigmentation alone cannot suffice to sustain cutaneous vitamin D3 (VD3) formation at the high latitudes of northern Europe. We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence of FLG mutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differences in circulating 25-OH-VD3 levels in these same populations. By allowing additional UV-B penetration and intracutaneous VD3 formation, the latitude-dependent gradient in FLG mutations, likely together with other concurrent mutations in VD3 metabolic pathways, provide a non-pigment-based mechanism that sustains higher levels of circulating VD3 in northern Europeans. At the time that FLG mutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase in FLG mutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades.


Filaggrin Human evolution Pigmentation Skin color Vitamin D3 







Thousand years ago


Trans-urocanic acid




Vitamin D3



Ms. Joan S. Wakefield provided superb editorial and administrative assistance. These studies were supported by the San Francisco Veterans Affairs Medical Center, a grant from the Department of Defense (CA110338), and NIH Grants, AR057752 and AR050023. These contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAMS, NIH, DOD or VA. Jacob P. Thyssen is a Lundbeck Foundation Fellow, supported by an unrestricted grant.

Conflict of interest

The authors have no competing interests as defined by Evolutionary Biology, or other interests that might be perceived to influence the interpretation of the article.

Supplementary material

11692_2014_9282_MOESM1_ESM.doc (298 kb)
Supplementary material 1 (DOC 298 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jacob P. Thyssen
    • 1
  • Daniel D. Bikle
    • 2
  • Peter M. Elias
    • 3
  1. 1.Department of Dermato-Allergology, National Allergy Research Centre, Gentofte University HospitalUniversity of CopenhagenHellerupDenmark
  2. 2.Endocrinology Service, Veterans Affairs Medical Center, and Department of MedicineUC San FranciscoSan FranciscoUSA
  3. 3.Dermatology Service, Veterans Affairs Medical Center, and Department of DermatologyUC San FranciscoSan FranciscoUSA

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