Variation of skin in recent human evolution: Loss of function and structural variation affecting filaggrin gene

Filaggrin (FLG) gene is essential for natural skin-barrier function in humans. Multifaceted functions of FLG include natural moisturization of the skin, UV photoprotection and defense against ingression of pathogens and allergens into the body. Multiple FLG loss-of-function (LOF) variants have been associated with complex skin diseases such as ichthyosis vulgaris, atopic dermatitis, atopic asthma and comorbid allergies including food allergy. A recent study claims that FLG LOF variants have been positively selected to reach higher frequencies among northern Europeans to enhance vitamin D production by allowing more UV light penetrance. This idea parallels, but complicates the notion that skin color is the primary driver determining UV light penetration. Same study argues that the frequency distribution of LOF variants should follow a latitude gradient, increasing with distance to the equator. To further investigate and validate this argument, we have analyzed genetic variation in FLG among 2,504 samples. Strikingly, we found that the frequency of LOF variants do not correlate with latitude and the trends observed in previous study that suffered from ascertainment bias. We further genotyped copy number variation in the intragenic repeats of FLG among 100 samples, including an indigenous Alaskan population, using long-range PCR methods and revealed recurrent and population specific evolution of FLG size variation. Based on population genetic analysis, we concluded that the observed variation is best explained by reduced purifying selection, rather than directional positive selection.