Selective sweep for an enhancer involucrin allele identifies skin barrier adaptation out of Africa

Mary Elizabeth Mathyer, Erin A. Brettmann, Alina D. Schmidt, Zane A. Goodwin, Inez Y. Oh, Ashley M. Quiggle, Eric Tycksen, Natasha Ramakrishnan, Scot J. Matkovich, Emma Guttman-Yassky, John R. Edwards and Cristina de Guzman Strong ()
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Mary Elizabeth Mathyer: Washington University in St. Louis School of Medicine
Erin A. Brettmann: Washington University in St. Louis School of Medicine
Alina D. Schmidt: Washington University in St. Louis School of Medicine
Zane A. Goodwin: Washington University in St. Louis School of Medicine
Inez Y. Oh: Washington University in St. Louis School of Medicine
Ashley M. Quiggle: Washington University in St. Louis School of Medicine
Eric Tycksen: Washington University in St. Louis School of Medicine
Natasha Ramakrishnan: Washington University in St. Louis School of Medicine
Scot J. Matkovich: Washington University in St. Louis School of Medicine
Emma Guttman-Yassky: Icahn School of Medicine at Mt. Sinai
John R. Edwards: Washington University in St. Louis School of Medicine
Cristina de Guzman Strong: Washington University in St. Louis School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The genetic modules that contribute to human evolution are poorly understood. Here we investigate positive selection in the Epidermal Differentiation Complex locus for skin barrier adaptation in diverse HapMap human populations (CEU, JPT/CHB, and YRI). Using Composite of Multiple Signals and iSAFE, we identify selective sweeps for LCE1A-SMCP and involucrin (IVL) haplotypes associated with human migration out-of-Africa, reaching near fixation in European populations. CEU-IVL is associated with increased IVL expression and a known epidermis-specific enhancer. CRISPR/Cas9 deletion of the orthologous mouse enhancer in vivo reveals a functional requirement for the enhancer to regulate Ivl expression in cis. Reporter assays confirm increased regulatory and additive enhancer effects of CEU-specific polymorphisms identified at predicted IRF1 and NFIC binding sites in the IVL enhancer (rs4845327) and its promoter (rs1854779). Together, our results identify a selective sweep for a cis regulatory module for CEU-IVL, highlighting human skin barrier evolution for increased IVL expression out-of-Africa.

Date: 2021
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DOI: 10.1038/s41467-021-22821-w

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