Complex signatures of natural selection at GYPA

Abstract

The human MN blood group antigens are isoforms of glycophorin A (GPA) encoded by the gene, GYPA, and are the most abundant erythrocyte sialoglycoproteins. The distribution of MN antigens has been widely studied in human populations yet the evolutionary and/or demographic factors affecting population variation remain elusive. While the primary function of GPA is yet to be discovered, it serves as the major binding site for the 175-kD erythrocyte-binding antigen (EB-175) of the malarial parasite, Plasmodium falciparum, a major selective pressure in recent human history. More specifically, exon two of GYPA encodes the receptor binding ligand to which P. falciparum binds. Accordingly, there has been keen interest in understanding what impact, if any, natural selection has had on the distribution of variation in GYPA and exon two in particular. To this end, we resequenced GYPA in individuals sampled from both P. falciparum endemic (sub-Saharan Africa and South India) and non-endemic (Europe and East Asia) regions of the world. Observed patterns of variation suggest that GYPA has been subject to balancing selection in populations living in malaria endemic areas and in Europeans, but no such evidence was found in samples from East Asia, Oceania, and the Americas. These results are consistent with malaria acting as a selective pressure on GYPA, but also suggest that another selective force has resulted in a similar pattern of variation in Europeans. Accordingly, GYPA has perhaps a more complex evolutionary history wherein on a global scale, spatially varying selective pressures have governed its natural history.

Detecting shared independent selection

“…The glycophorin cluster has primarily been associated with malarial resistance in African populations (Wang et al, 2003). The presence of signals around these genes in populations outside the malarial zone suggests independent selective pressure on immune characteristics at these loci, supporting previous work (Bigham et al, 2018). The most striking result is the presence of shared signals in both Asian and European populations, in which the beneficial haplotype is distinct not only from one another, but from the African haplotype as well.…”

How genetic disease risks can be misestimated across global populations

“…Specifically, we find that it matters whether populations have experienced a history of bottlenecks and founder effects. Knowing whether individual disease loci have experienced a history of natural section can lead to additional insights [42, 49,50]. That said, systematic allele frequency biases can be mistaken for directional selection, hindering tests of polygenic selection acting on GWAS traits [51].…”

The malaria-protective human glycophorin structural variant DUP4 shows somatic mosaicism and association with hemoglobin levels

“…This genomic region carrying this genes is known to undergo extensive copy number variation and gene conversion, and rearrangements that shuffle the coding regions of the three genes can generate rare blood group antigens in the Miltenberger series (19). This genomic region has also been highlighted as a region of balancing selection (20–23) and positive selection (24), though the effect of extensive gene conversion between the 120kb repeats on statistical measures of positive selection is not clear.…”

“…Recent work studying the host genetic contribution to severe malaria identified a SNV allele at a nearby non-repeated region in linkage disequilibrium with a complex structural variant at the glycophorin locus protective against severe malaria (5, 20). This structural variant, called DUP4, is restricted to East African populations, and is responsible for a glycophorin A - glycophorin B fusion gene product that is detected using serology as the blood group antigen Dantu NE+.…”