Molecular Evolution of GYPC: Evidence for Recent Structural Innovation and Positive Selection in Humans

Abstract

GYPC encodes two erythrocyte surface sialoglycoproteins in humans, glycophorin C and glycophorin D (GPC and GPD), via initiation of translation at two start codons on a single transcript. The malaria-causing parasite Plasmodium falciparum uses GPC as a means of invasion into the human red blood cell. Here, we examine the molecular evolution of GYPC among the Hominoidea (Greater and Lesser Apes) and also the pattern of polymorphism at the locus in a global human sample. We find an excess of nonsynonymous divergence among species that appears to be caused solely by accelerated evolution of GYPC in the human lineage. Moreover, we find that the ability of GYPC to encode both GPC and GPD is a uniquely human trait, caused by the evolution of the GPC start codon in the human lineage. The pattern of polymorphism among humans is consistent with a hitchhiking event at the locus, suggesting that positive natural selection affected GYPC in the relatively recent past. Because GPC is exploited by P. falciparum for invasion of the red blood cell, we hypothesize that selection for evasion of P. falciparum has caused accelerated evolution of GYPC in humans (relative to other primates) and that this positive selection has continued to act in the recent evolution of our species. These data suggest that malaria has played a powerful role in shaping molecules on the surface of the human red blood cell. In addition, our examination of GYPC reveals a novel mechanism of protein evolution: co-option of untranslated region (UTR) sequence following the formation of a new start codon. In the case of human GYPC, the ancestral protein (GPD) continues to be produced through leaky translation. Because leaky translation is a widespread phenomenon among genes and organisms, we suggest that co-option of UTR sequence may be an important source of protein innovation.

Pathogen-Driven Selection in the Human Genome

“…No direct involvement in immune response is also observed, for example, for glycophorins A and C (GYPC and GYPA), sialoglycoproteins abundantly expressed on the surface of red blood cells and exploited by Plasmodium falciparum for erythrocyte invasion [13, 14]. Both GYPC and GYPA have evolved adaptively in human populations, the underlying pressure being most likely accounted for by malaria [15–17]. Genetic variability at the GYPA and GYPC loci is responsible for the MNS and Gerbich blood group systems, respectively (Blood Group Antigen Gene Mutation Database (BGMUT) [18]).…”

High Expression of AHSP, EPB42, GYPC and HEMGN Predicts Favorable Prognosis in FLT3-ITD-Negative Acute Myeloid Leukemia

“…Second, its sequence is not homologous to any other gene, while glycophorin A ( GYPA ), glycophorin B ( GYPB ), and glycophorin E ( GYPE ) are all paralogous [46, 47]. Recent studies have shown that GYPC is a biomarker in breast cancer between high-risk and low-risk group using whole-genome methylation analysis [48] and is a major erythrocyte receptor for the rodent malaria parasite plasmodium berghei [49].…”

Readthrough errors purge deleterious cryptic sequences, facilitating the birth of coding sequences

“…One of the more surprising recent developments in molecular evolution is that adaptive protein-coding innovations sometimes arise out of DNA sequences that were previously non-coding. Sometimes only part of a protein arises in this way, via new or expanded coding exons (Sorek 2007), or via annexation of 3′ untranslated regions (UTRs) (Giacomelli, et al 2007;Vakhrusheva, et al 2011;Andreatta, et al 2015) or 5′ UTRs (Wilder, et al 2009) into an ORF. More dramatically, completely new protein-coding genes can also arise de novo (reviewed in McLysaght and Guerzoni 2015;Van Oss and Carvunis 2019).…”