Revisiting the malaria hypothesis: accounting for polygenicity and pleiotropy

Abstract

The malaria hypothesis predicts local, balancing selection of deleterious alleles that confer strong protection from malaria. Three protective variants, recently discovered in red cell genes, are indeed more common in African than European populations. Still, up to 89% of the heritability of severe malaria is attributed to many genome-wide loci with individually small effects. Recent analyses of hundreds of genome-wide association studies (GWAS) in humans suggest that most functional, polygenic variation is pleiotropic for multiple traits. Interestingly, GWAS alleles and red cell traits associated with small reductions in malaria risk are not enriched in African populations. We propose that other selective and neutral forces, in addition to malaria prevalence, explain the global distribution of most genetic variation impacting malaria risk.

Keywords: evolution; malaria; pleiotropy; polygenic; red blood cells.

Figure 1, Key Figure.. The main polygenic component of malaria resistance is not enriched in African populations.

(A) 89% of the estimated heritability of severe malaria risk is attributed to variants with effects too small to be confidently detected by GWAS. Reproduced from [7]. (B) SNP-heritability of severe malaria risk is distributed across chromosomes proportional to their length. Replotted from [36]. (C) Strongly associated (large-effect) alleles from a GWAS for severe malaria risk occur at higher frequencies in African populations, compared to European populations (red oval). Smaller-effect alleles, which are less confidently associated, are equally likely to be more frequent in European populations (blue oval). Rank_EUR is the conditional rank of the allele in European populations, given African allele count; values greater than/less than 50% indicate that the allele is more common in Europe/Africa. Reproduced from [7]. (D) Alleles from healthy RBCs associated with reduced P. falciparum growth rate in vitro are not enriched for higher frequencies in African populations (blue oval). Polarized F_ST indicates the differentiation in allele frequencies between African and European populations in 1000 Genomes; values greater than/less than 0 indicate that the allele is more common in Europe/Africa. Replotted from [15]. (E) In donors who lack large-effect alleles for malaria resistance, red cell osmotic fragility is negatively related to exome-wide African ancestry. Replotted from [15]. (F) In donors who lack large-effect alleles for malaria resistance, higher red cell osmotic fragility predicts slower P. falciparum growth in vitro. Replotted from [15]. Panels A and C are reproduced with minor modifications under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).

Figure I. Most common human alleles have a broad geographic distribution.

Data are summarized across ~92 million bi-allelic variants from 1000 Genomes. Within each cell, C = common (>5% frequency), R = rare (<5%), u= unobserved (0%). The number and proportion of variants with a given geographical distribution is indicated by the text on the right, as well as the height of the row. AFR=African, EUR=European, SAS=South Asian, EAS=East Asian, AMR=Admixed American. Reproduced from [10].