The genetic basis and evolution of red blood cell sickling in deer

Alexander Esin, L. Therese Bergendahl, Vincent Savolainen, Joseph A. Marsh, Tobias Warnecke
2017 Nature Ecology & Evolution  
Crescent-shaped red blood cells, the hallmark of sickle cell disease, present a 19 striking departure from the biconcave disc shape normally found in mammals. 20 Characterized by increased mechanical fragility, sickled cells promote 21 haemolytic anaemia and vaso-occlusions and contribute directly to disease in 22 humans. Remarkably, a similar sickle-shaped morphology has been observed in 23 erythrocytes from several deer species, without pathological consequences. The 24 genetic basis of
more » ... ocyte sickling in deer, however, remains unknown, limiting 25 the utility of deer as comparative models for sickling. Here, we determine the 26 sequences of human β-globin orthologs in 15 deer species and identify a set of co-27 evolving, structurally related residues that distinguish sickling from non-sickling 28 deer. Protein structural modelling indicates a sickling mechanism distinct from 29 human sickle cell disease, coordinated by a derived valine (E22V) in the second 30 alpha helix of the β-globin protein. The evolutionary history of deer β-globins is 31 characterized by incomplete lineage sorting, episodes of gene conversion between 32 adult and foetal β-globin paralogs, and the presence of a trans-species 33 polymorphism that is best explained by long-term balancing selection, suggesting 34 that sickling in deer is adaptive. Our results reveal structural and evolutionary 35 parallels and differences in erythrocyte sickling between human and deer, with 36 implications for understanding the ecological regimes and molecular 37 architectures that favour the evolution of this dramatic change in erythrocyte 38 shape. 39 40 41 42
doi:10.1038/s41559-017-0420-3 pmid:29255300 pmcid:PMC5777626 fatcat:wklm74l3qzbadkqjzktzxgawoy