Piezo1 Genetic Variants: Impact on Red Blood Cell Physiology and Human Evolution

Background

The 2022 Nobel Prize in Physiology or Medicine was awarded, among other achievements, for the sequencing of the Neanderthal genome. Remarkably, comparison of the red blood cell proteomes of modern humans and Neanderthals reveals only two protein differences, corresponding to variants of α-spectrin and the mechanosensitive ion channel PIEZO1. This striking degree of conservation underscores the fundamental importance of red blood cell function throughout human evolution and identifies PIEZO1 as a potential contributor to physiological adaptation and natural selection.

Evidence-Based Hypothesis on the Role of a Piezo1 Variant in Red Blood Cells in the Extinction of Neanderthals (https://doi.org/10.1101/2025.09.29.679417)

Current Work

Our current research aims to establish a mechanistic link between genetic variation in the mechanosensitive ion channel PIEZO1 and tissue oxygenation. We hypothesize that present-day PIEZO1 variants differ from ancestral Neanderthal variants in their channel properties, resulting in altered red blood cell function and oxygen delivery. We employ genome editing of human induced pluripotent stem cells (hiPSCs) to generate red blood cells expressing archaic PIEZO1 variants. These cells are systematically compared with red blood cells carrying modern human variants to assess their electrophysiological, rheological, and functional properties. In parallel, we investigate the influence of PIEZO1 activity on tissue oxygenation in vivo using a novel non-invasive approach in patients with hereditary xerocytosis and matched healthy controls. Experimental findings are integrated with large-scale genetic and phenotypic datasets to reconstruct the demographic history of PIEZO1 polymorphisms and to model the environmental factors that may have shaped the distribution and persistence of present-day PIEZO1 variants. Together, this multidisciplinary approach combines cell biology, physiology, clinical research, and evolutionary modeling to elucidate the role of PIEZO1 in human adaptation and red blood cell physiology.

Funding: DFG-Weave Project

Project Website