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

Nature Ecology & Evolution volume 2, pages 367–376 (2018)Cite this article

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Abstract

Crescent-shaped red blood cells, the hallmark of sickle-cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without obvious pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown. Here, we determine the sequences of human β-globin orthologues in 15 deer species and use protein structural modelling to identify a sickling mechanism distinct from the human disease, coordinated by a derived valine (E22V) that is unique to sickling deer. Evidence for long-term maintenance of a trans-species sickling/non-sickling polymorphism suggests that sickling in deer is adaptive. Our results have implications for understanding the ecological regimes and molecular architectures that have promoted convergent evolution of sickling erythrocytes across vertebrates.

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Fig. 1: Mammalian adult β-globin peptide sequences in phylogenetic context.
Fig. 2: Structural basis for sicking of deer haemoglobin.
Fig. 3: Evidence for incomplete lineage sorting, gene conversion and a trans-species polymorphism in the evolutionary history of deer HBB A .

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Acknowledgements

We thank the Zoological Society of London Whipsnade Zoo (F. Molenaar), Bristol Zoological Society (S. Dow and K. Wyatt), the Royal Zoological Society of Scotland Highland Wildlife Park (J. Morse), the British Deer Society, the Penn State Deer Research Center (D. Wagner) and the Northeast Wildlife DNA Laboratory (N. Chinnici) for samples, the Medical Research Council London Institute of Medical Sciences Genomics Facility for DNA and RNA sequencing, B. N. Sacks, J. Mizzi and T. Brown for access to tule elk sequencing data, P. D. Butcher for discussions, and P. Sarkies, A. Brown and B. Lehner for comments on the manuscript. This work was supported by an Imperial College Interdisciplinary Cross-Campus Studentship to A.E., a Medical Research Council Career Development Award (MR/M02122X/1) to J.A.M., a Leverhulme Trust Fellowship to V.S., and Medical Research Council core funding and an Imperial College Junior Research Fellowship to T.W.

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Authors and Affiliations

  1. Molecular Systems Group, Medical Research Council London Institute of Medical Sciences, Du Cane Road, London, United Kingdom

    Alexander Esin & Tobias Warnecke

  2. Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, United Kingdom

    Alexander Esin & Tobias Warnecke

  3. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom

    L. Therese Bergendahl & Joseph A. Marsh

  4. Department of Life Sciences, Silwood Park Campus, Imperial College London, Ascot, United Kingdom

    Vincent Savolainen

  5. University of Johannesburg, Auckland Park, Johannesburg, South Africa

    Vincent Savolainen

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  1. Alexander Esin
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Contributions

A.E. performed the laboratory experiments and evolutionary analyses and contributed to the experimental design, data analysis and interpretation. L.T.B. and J.A.M. designed and performed the structural modelling and contributed to the data analysis and interpretation. V.S. contributed tissue samples. T.W. conceived the study, contributed to the experimental design, data analysis and interpretation, and wrote the manuscript with input from all authors.

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Correspondence to Tobias Warnecke.

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Supplementary Information

Supplementary Figures 1–11, Supplementary Table 1, Supplementary Discussion, Supplementary References.

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Supplementary Table 2

Confirmation of species identities by mitochondrial CytB sequencing.

Supplementary Data 1

Alignment of cervid HBB A and HBB F gene sequences (coding exons and internal introns) determined in this study.

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Esin, A., Bergendahl, L.T., Savolainen, V. et al. The genetic basis and evolution of red blood cell sickling in deer. Nat Ecol Evol 2, 367–376 (2018). https://doi.org/10.1038/s41559-017-0420-3

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