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

Mathyer, Mary Elizabeth; Brettmann, Erin A.; Schmidt, Alina; Goodwin, Z.; Oh, Inez Y.; Quiggle, A.; Tycksen, Eric; Ramakrishnan, Natasha; Matkovich, Scot J.; Guttman‐Yassky, Emma; Edwards, John; Strong, Cristina de Guzman

doi:10.1038/s41467-021-22821-w

Cited by 6 publications

(2 citation statements)

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“…8,33,34 Given that chronic inflammation is a hallmark of iSGS, these data suggest that the observed increased expression of CE proteins may be secondary to inflammatory microenvironment. However, a recent report of a positive selection of polymorphisms of IVL and other genes in the epidermal differentiation complex region of chromosome 1 in Northern European populations 35 and the fact that the women affected by iSGS are of Northern European descent suggest an alternative potential role of genetic variances.…”

Section: Discussionmentioning

confidence: 99%

Idiopathic Subglottic Stenosis Is Associated With More Frequent and Abnormal Squamous Metaplasia

Tchoukalova,

Phung,

Kennedy

et al. 2023

Ann Otol Rhinol Laryngol

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Objectives: Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients. Methods: RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors. Results: We found 7 upregulated genes in the subglottic region of iSGS patients relative to both the tracheal mucosa and subglottic region of controls. A gene ontology enrichment analysis found that the epithelial cell differentiation and cornification pathways are significant, involving specifically 3 of the genes: involucrin ( IVL), small proline rich protein 1B ( SPRR1B), and keratin 16 ( KRT16). Involvement of these pathways suggests squamous metaplasia of the epithelium. Histological analyses of epithelium in subglottic mucosal biopsies revealed squamous metaplasia in 41% of the samples from iSGS patients and in 25% from controls. Immunohistochemical evaluation of the samples presented with squamous epithelium revealed increased expression of the protein encoded by SPRR1B, hyperproliferative basal cells, shedding of apical layers, and accompanying lesions in iSGS compared to CTRL. Cultured primary subglottic epithelial cells from iSGS patients had higher proliferation rates compared to healthy donors and squamous metaplastic differentiation formed thinner epithelia with increased expression proteins encoded by INV, SPRR1B, and KRT16, suggesting intrinsic dysfunction of basal cells in iSGS. Conclusions: Abnormal squamous differentiation of epithelial cells may contribute to the pathogenesis of iSGS. Patients having metaplastic epithelial phenotype may be sensitive to drugs that reverse it to a normal phenotype.

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Section: Discussionmentioning

confidence: 99%

Idiopathic Subglottic Stenosis Is Associated With More Frequent and Abnormal Squamous Metaplasia

Tchoukalova,

Phung,

Kennedy

et al. 2023

Ann Otol Rhinol Laryngol

View full text Add to dashboard Cite

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“…There is no equivalent to this statistic for CREs. Positive selection in CREs has been identified using tests for selective sweeps and divergence in substitution rate in specific regions across taxa [36,83,84]. In principle, future work on CRE evolution could also leverage analysis of motif composition in a similar way to synonymous and nonsynonymous changes to…”

Section: Detecting Positive Selectionmentioning

confidence: 99%