Malaria was a weak selective force in ancient Europeans

Abstract

Malaria, caused by Plasmodium parasites, is thought to be one of the strongest selective forces that has shaped the genome of modern humans and was endemic in Europe until recent times. Due to its eradication around mid-twentieth century, the potential selective history of malaria in European populations is largely unknown. Here, we screen 224 ancient European genomes from the Upper Palaeolithic to the post-Roman period for 22 malaria-resistant alleles in twelve genes described in the literature. None of the most specific mutations for malaria resistance, like those at G6PD, HBB or Duffy blood group, have been detected among the available samples, while many other malaria-resistant alleles existed well before the advent of agriculture. We detected statistically significant differences between ancient and modern populations for the ATP2B4, FCGR2B and ABO genes and we found evidence of selection at IL-10 and ATP2B4 genes. However it is unclear whether malaria is the causative agent, because these genes are also involved in other immunological challenges. These results suggest that the selective force represented by malaria was relatively weak in Europe, a fact that could be associated to a recent historical introduction of the severe malaria pathogen.The malaria parasite Plasmodium falciparum is one of the main causes of child mortality worldwide, although other species from the same genus, P. vivax, P. malariae and P. ovale are also causative agents of the disease. Therefore, it is not surprising that malaria is one of the strongest known selective pressures that have recently shaped the human genome. Malaria is the evolutionary driving force behind sickle-cell disease (HbS), thalassemia, glucose-6-phosphatase deficiency (G6PD) and other erythrocyte defects that together comprise the most common Mendelian diseases of humankind. Remarkably, populations from different geographical areas have developed different genetic mechanisms adapted to malaria resistance; for instance, the HbS allele at the HBB gene is common in Africa but rare in Southeast Asia, whereas the HbE alelle shows a reversed pattern. Resistance to malaria includes primarily genes involved in immunological response, but also some involved in inflammation and cell adhesion and even genes related to metabolic pathways. The fact that different malaria-resistance alleles have arisen in different places suggests that this adaptation occurred relatively recent in human history, at least well after the Out of Africa migration 1 . P. falciparum may have rapidly spread from its African tropical origins to other tropical and subtropical regions of the world only within the last 6,000 years 2 . The recent origin of the worldwide P. falciparum populations, which are the most malignant of human malarial parasites, may account for its virulence 3 . Thus, haplotype analysis at the G6PD locus suggests that the African resistance allele to P. falciparum originated within the last 10,000 years 4 while a similar analysis at the HbE alleles (variants of the HBB gene) in...

Ancestry-Specific Analyses Reveal Differential Demographic Histories and Opposite Selective Pressures in Modern South Asian Populations

“…We compiled a list of phenotype-informative SNPs (Mathieson et al. 2015; Gelabert et al. 2017; van de Loosdrecht et al.…”

Three hallmarks of malaria-induced selection in human genomes

“…For example, Plasmodium has driven an Arrested Sweep on SLC4A1 in Southeast Asia (Paquette et al 2015), but these populations are poorly represented in the 1000 Genomes. Also, though ATP2B4 is globally associated with malaria (Malaria Genomic Epidemiology Network 2019), evidence for non-neutral evolution is mild and/or very geographically localized (Gelabert et al 2017; Gouveia et al 2019). Indeed, ATP2B4 was not a notable outlier in any test (, , ).…”

Genome-wide data from the Bubi of Bioko Island clarifies the Atlantic fringe of the Bantu dispersal

“…Relevant mutations associated with malaria resistance in 10 different genes (Additional file 1: Table S11) – as found in genome-wide association studies (GWAS) and other previous studies [31, 69] – were genotyped in Bubi and the 1000 Genomes African populations. Fisher’s exact test was used to determine the statistical significance of the observed differences ( p < 0.001).…”