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

Mary Elizabeth Mathyer,Emma Guttman-Yassky,Scot J Matkovich,John R Edwards,Cristina De Guzman Strong,Alina D Schmidt,Erin A Brettmann,Zane A Goodwin,Inez Y Oh,Eric Tycksen,Natasha Ramakrishnan,Ashley M Quiggle

doi:10.1038/s41467-021-22821-w

Mary Elizabeth Mathyer, Emma Guttman-Yassky + Show 10 more

Open Access

https://doi.org/10.1038/s41467-021-22821-w

Copy DOI

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.

Highlights

The genetic modules that contribute to human evolution are poorly understood
We find increased regulatory activity specific to CEU-IVL with an additive effect by the enhancer that includes predicted binding for IRF1 at enhancer rs4845327 and NFIC binding at promoter rs1854779
We sought to determine positive selection in the epidermal differentiation complex (EDC) using two independent algorithms, composite of multiple signals (CMS)[19,20] and the integrated selection of allele favored by evolution[21] (Fig. 1a)

Summary

Introduction

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). 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. We investigate human skin barrier adaptation by examining signatures of positive selection within the epidermal differentiation complex (EDC) locus from a diverse set of human genomes. We previously identified positive selection in the EDC for specific genes across the mammalian phylogeny, and in primates and humans[18] Motivated by these studies, we hypothesized ongoing evolution within the EDC for skin barrier adaptation among the geographically diverse group of modern-day human populations. Deletion of the enhancer in mice using CRISPR/Cas[9] genome editing results in a significant decrease in Ivl expression in cis We translate this new knowledge of the enhancer to regulate IVL in humans and examine human population-specific alleles for IVL. The findings highlight recent human skin barrier evolution for increased IVL expression and its enhancer, as humans migrated out-of-Africa

Methods

Results

Conclusion