Shades of complexity: New perspectives on the evolution and genetic architecture of human skin.

Like many highly variable human traits, more than a dozen genes are known to contribute to the full range of skin color. However, the historical bias in favor of genetic studies in European and European-derived populations has blinded us to the magnitude of pigmentation's complexity. As deliberate efforts are being made to better characterize diverse global populations and new sequencing technologies, better measurement tools, functional assessments, predictive modeling, and ancient DNA analyses become more widely accessible, we are beginning to appreciate how limited our understanding of the genetic bases of human skin color have been. Novel variants in genes not previously linked to pigmentation have been identified and evidence is mounting that there are hundreds more variants yet to be found. Even for genes that have been exhaustively characterized in European populations like MC1R, OCA2, and SLC24A5, research in previously understudied groups is leading to a new appreciation of the degree to which genetic diversity, epistatic interactions, pleiotropy, admixture, global and local adaptation, and cultural practices operate in population-specific ways to shape the genetic architecture of skin color. Furthermore, we are coming to terms with how factors like tanning response and barrier function may also have influenced selection on skin throughout human history. By examining how our knowledge of pigmentation genetics has shifted in the last decade, we can better appreciate how far we have come in understanding human diversity and the still long road ahead for understanding many complex human traits.

Evolutionary context of psoriatic immune skin response.

The skin is vital for protecting the body and perceiving external stimuli in the environment. Ability to adapt between environments is in part based on skin phenotypic plasticity, indicating evolved homeostasis between skin and environment. This homeostasis reflects the greater relationship between the body and the environment, and disruptions in this balance may lead to accumulation of susceptibility factors for autoimmune conditions like psoriasis. In this study, we examined the relationship between rapid, lineage-specific evolution of human skin and formation of psoriatic skin responses at the transcriptome level. We collected skin tissue biopsies from individuals with psoriasis and compared gene expression in psoriatic plaques to non-plaque psoriatic skin. We then compared these data with non-psoriatic skin transcriptome data from multiple primate species. We found 67 genes showing human-specific skin expression that are also differentially regulated in psoriatic skin; these genes are significantly enriched for skin barrier function, immunity and neuronal development. We identified six gene clusters with differential expression in the context of human evolution and psoriasis, suggesting underlying regulatory mechanisms in these loci. Human and psoriasis-specific enrichment of neuroimmune genes shows the importance of the ongoing evolved homeostatic relationship between skin and external environment. These results have implications for both evolutionary medicine and public health, using transcriptomic data to acknowledge the importance of an individual's surroundings on their overall health.

Filamentation Regulatory Pathways Control Adhesion-Dependent Surface Responses in Yeast.

Signaling pathways can regulate biological responses by the transcriptional regulation of target genes. In yeast, multiple signaling pathways control filamentous growth, a morphogenetic response that occurs in many species including fungal pathogens. Here, we examine the role of signaling pathways that control filamentous growth in regulating adhesion-dependent surface responses, including mat formation and colony patterning. Expression profiling and mutant phenotype analysis showed that the major pathways that regulate filamentous growth [filamentous growth MAPK (fMAPK), RAS, retrograde (RTG), RIM101, RPD3, ELP, SNF1, and PHO85] also regulated mat formation and colony patterning. The chromatin remodeling complex, SAGA, also regulated these responses. We also show that the RAS and RTG pathways coregulated a common set of target genes, and that SAGA regulated target genes known to be controlled by the fMAPK, RAS, and RTG pathways. Analysis of surface growth-specific targets identified genes that respond to low oxygen, high temperature, and desiccation stresses. We also explore the question of why cells make adhesive contacts in colonies. Cell adhesion contacts mediated by the coregulated target and adhesion molecule, Flo11p, deterred entry into colonies by macroscopic predators and impacted colony temperature regulation. The identification of new regulators (e.g., SAGA), and targets of surface growth in yeast may provide insights into fungal pathogenesis in settings where surface growth and adhesion contributes to virulence.