Resistance to malaria in humans: the impact of strong, recent selection

Hedrick Malaria Journal 2012, 11:349 http://www.malariajournal.com/content/11/1/349 REVIEW Open Access Resistance to malaria in humans: the impact of strong, recent selection Philip W Hedrick Abstract Malaria is one of the leading causes of death worldwide and has been suggested as the most potent type of selection in humans in recent millennia. As a result, genes involved in malaria resistance are excellent examples of recent, strong selection. In 1949, Haldane initially suggested that infectious disease could be a strong selective force in human populations. Evidence for the strong selective effect of malaria resistance includes the high frequency of a number of detrimental genetic diseases caused by the pleiotropic effects of these malaria resistance variants, many of which are “loss of function” mutants. Evidence that this selection is recent comes from the genetic dating of the age of a number of these malaria resistant alleles to less than 5,000 years before the present, generally much more recent than other human genetic variants. An approach to estimate selection coefficients from contemporary case–control data is presented. In the situations described here, selection is much greater than 1%, significantly higher than generally observed for other human genetic variation. With these selection coefficients, predictions are generated about the joint change of alleles S and C at the β-globin locus, and for α-thalassaemia haplotypes and S, variants that are unlinked but exhibit epistasis. Population genetics can be used to determine the amount and pattern of selection in the past and predict selection in the future for other malaria resistance variants as they are discovered. Keywords: Age of allele, Duffy, Epistasis, Sickle cell, Thalassaemia Background Malaria is one of the leading causes of death worldwide and has been suggested as the most potent type of selection in humans in recent millennia [1]. As a result, genes involved in malaria resistance are excellent examples of recent, strong selection. Perhaps best known is the sickle cell haemoglobin variant, which is often used as an example of heterozygote advantage. In addition, G6PD deficiency illustrates strong selection at an X-linked locus, β-globin variants S, C, and E and G6PD deficiency variants A-, Med, and Mahidol show how selective differences can be the result of a single-nucleotide change. Further, HLA-B53 illustrates how gene conversion can result in an adaptive allele, and α-thalassaemia shows how selection can operate on loci that have different copy numbers. Haldane, known as one of the three founders of population genetics, is often recognized with first suggesting that disease could be an important evolutionary force in Correspondence: School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA humans. Although his general review [2] is often cited for this concept, this hypothesis was presented in more detail in 1948 [3] where he suggested that β-thalassaemia heterozygotes had an increased fitness in the presence of malaria. Therefore, citation of [3] seems more correct for the hypothesis that malaria resistance in humans might be genetically determined and evolutionarily significant [4-6]. The first generally recognized evidence for genetic resistance to malaria in humans was in 1954 [7] for sicklecell haemoglobin heterozygotes AS. Overall, the “malaria hypothesis” of Haldane that some human diseases such as thalassaemia are polymorphisms and provide heterozygote advantage because of the trade-offs between the advantages of resistance to malaria and negative effects due to the disease, is now widely accepted but the exact means of disease resistance have often been difficult to elucidate. As documentation for the contemporary influence of malaria, in 2010 there were 216 million clinical cases and an estimated 863,000 deaths from malaria [8], © 2012 Hedrick; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hedrick Malaria Journal 2012, 11:349 http://www.malariajournal.com/content/11/1/349 making it one of the leading causes of death worldwide. Although these levels have declined globally 25% since 2000, another analysis estimated that the annual mortality may be much higher than this level at 1.24 million [9]. The impact of malaria is thought to have increased between 10,000 and 5,000 years ago when there were the beginnings of agriculture and consequently more human settlements. During this period, the numbers of both the human population and the mosquito vector increased, resulting in higher spread of malaria [10]. Recent molecular studies suggest that malaria in humans from Plasmodium falciparum may have originated from gorillas [11,12]. Using these data, an initial timeline for the origin of P. falciparum as a human pathogen suggests that it may be more recent than previously thought [13]. The past geographic extent of malaria and the distribution of malaria resistance variants broadly correspond [14-16]. For example, P. falciparum is found across Africa and Asia, as are the variants of haemoglobin and G6PD that provide malaria resistance. In regions of high endemic malaria, such as sub-Saharan tropical Africa and lowland Melanesia, there are often several variants. In contrast, variants do not exist in areas without past malaria, with the exception of ancestry from new immigrants [17]. To illustrate, the common malaria resistant alleles are not present in New World natives [18], presumably because their ancestors were unexposed to malaria and malaria only came to the Americas during the transatlantic slave trade between the 16th and 19th centuries [19]. Further, microgeographic variation of β-thalassaemia in Sardinia and the past presence of malaria are concordant [20] and α-thalassaemia and β-thalassaemia variation in Melanesia is associated with malaria presence [21,22]. Some resistance alleles for malaria are distinctive and others are very general. To illustrate, geographically separated Duffy alleles in Papua New Guinea and Africa result from changes at the same exact genomic location, 33 nucleotides upstream from the start codon. Similarly, the β-globin malaria resistance alleles S and C occur from different changes at the same codon. In contrast, there are many changes that modify levels of expression and provide malaria resistance for G6PD deficiency, α-thalassaemia, and β-thalassaemia. It is significant that malaria resistance genes are often extremely variable, for example, the malaria resistance genes ABO, G6PD, HLA, α-globin, and β-globin, are some of the most variable human genes. Such variation might be because disease resistance genes have high amounts of standing variation or because these genes have (...truncated)