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

Abstract

The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/155903 doi: bioRxiv preprint first posted online Jun. 26, 2017; 3 Introduction 43 44Human sickling is caused by a single amino acid change (E6V) in the adult β-globin 45 (HBB) protein (1). Upon deoxygenation, steric changes in the haemoglobin tetramer 46 enable an interaction between 6V and a hydrophobic acceptor pocket (known as the 47 EF pocket) on the β-surface of a second tetramer (2, 3). This interaction promotes 48 polymerization of mutant haemoglobin (HbS) molecules, which ultimately coerces 49 red blood cells into the characteristic sickle shape. Heterozygote carriers of the HbS 50 allele are typically asymptomatic (4) whereas HbS homozygosity has severe 51 pathological consequences and is linked to shortened lifespan (5). Despite this, the 52HbS allele has been maintained in sub-Saharan Africa by balancing selection because 53 it confers -by incompletely understood means -a degree of protection against the 54 effects of Plasmodium infection and malaria (6). 55 56Sickling red blood cells were first described in 1840 -seventy years prior to their 57 discovery in humans (7) -when Gulliver (8) reported unusual erythrocyte shapes in 58 blood from white-tailed deer (Odocoileus virginianus). Subsequent research spanning 59 more than a century revealed that sickling, at least as an in vitro phenotype, is 60 widespread amongst deer species worldwide (8-11) (Fig. 1, Table S1). It is not, 61 however, universal: red blood cells from reindeer (Rangifer tarandus) and European 62 elk (Alces alces, known as moose in North America) do not sickle; neither do 63 erythrocytes from most North American wapiti [Cervus canadensis, 25 out of 27 64 sampled in (12); 5 out of 5 sampled in (11)]. Below, we will use the term moose for 65A. alces to avoid confusion, as wapiti are also commonly referred to as elk in North 66 America. 67. CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/155903 doi: bioRxiv preprint first posted online Jun. 26, 2017; 68Sickling deer erythrocytes are similar to human HbS cells with regard to their gross 69 morphology and the tubular ultrastructure of haemoglobin polymers (13)(14)(15)(16). 70Moreover, as in humans, sickling is reversible through modulation of oxygen supply 71 or pH (9, 17). As in humans, deer sickling is mediated by specific β-globin alleles 72 (18, 19), with both sickling and non-sickling alleles segregating in wild populations of 73 white-tailed deer (20). As in humans, foetal haemoglobin does not sickle under the 74 same conditions (19) and α-globin -two copies of which join two β-globin proteins 75 to form the haemoglobin tetramer -is not directly implicated in sickling etiology (18, 76 21). 77 78At the same time, a suit of striking differences emerged: whereas human sickling 79 occurs when oxygen tension is low, deer erythrocytes sickle under high pO 2 and at 80 alkali...