title: Understanding the contrasting spatial haplotype patterns of malaria-protective β-globin polymorphisms.
abstract: The malaria-protective β-globin polymorphisms, sickle-cell (β(S)) and β(0)-thalassaemia, are canonical examples of human adaptation to infectious disease. Occurring on distinct genetic backgrounds, they vary markedly in their patterns of linked genetic variation at the population level, suggesting different evolutionary histories. β(S) is associated with five classical restriction fragment length polymorphism haplotypes that exhibit remarkable specificity in their geographical distributions; by contrast, β(0)-thalassaemia mutations are found on haplotypes whose distributions overlap considerably. Here, we explore why these two polymorphisms display contrasting spatial haplotypic distributions, despite having malaria as a common selective pressure. We present a meta-population genetic model, incorporating individual-based processes, which tracks the evolution of β-globin polymorphisms on different haplotypic backgrounds. Our simulations reveal that, depending on the rate of mutation, a large population size and/or high population growth rate are required for both the β(S)- and the β(0)-thalassaemia-like patterns. However, whilst the β(S)-like pattern is more likely when population subdivision is high, migration low and long-distance migration absent, the opposite is true for β(0)-thalassaemia. Including gene conversion has little effect on the overall probability of each pattern; however, when inter-haplotype fitness variation exists, gene conversion is more likely to have contributed to the diversity of haplotypes actually present in the population. Our findings highlight how the contrasting spatial haplotype patterns exhibited by β(S) and β(0)-thalassaemia may provide important indications as to the evolution of these adaptive alleles and the demographic history of the populations in which they have evolved.
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK. Electronic address: carinna.hockham@zoo.ox.ac.uk.
authors.forename: Carinna
authors.initials: C
authors.lastname: Hockham
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK. Electronic address: fred.piel@zoo.ox.ac.uk.
authors.forename: Frédéric B
authors.initials: FB
authors.lastname: Piel
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK. Electronic address: sunetra.gupta@zoo.ox.ac.uk.
authors.forename: Sunetra
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK. Electronic address: bridget.penman@zoo.ox.ac.uk.
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Penman
mesh_terms: D000349:Africa; D056084:Genetic Fitness / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008288:Malaria / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012805:Sickle Cell Trait / Q000235:genetics*; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D055544:beta-Globins
keywords: Gene conversion; Haplotype distribution; Malaria; Sickle-cell; β-Thalassaemia