* Department of Biology, National Taiwan Normal University, Taipei, Taiwan
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Department of Ecology and Evolution, University of Chicago
Correspondence: E-mail: ciwu{at}uchicago.edu.
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Abstract |
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Key Words: positive selection glycophorin malaria gene conversion rapid evolution
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Introduction |
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There are currently more than 500 published coding sequences from the Old World monkey (OWM) that can be inferred to be orthologous to a human gene. Among them, 280 meet a set of criteria (length, completeness, etc.; see Materials and Methods) to become the basis of our analysis. Of these 280 genes, 17 have been determined to be fast evolving. For each of these fast-evolving genes, we ask (1) if the gene has evolved especially rapidly in the human lineage; (2) if there are specific sites under positive selection; and (3) what may be the forces driving the rapid evolution.
In this data set, the fastest evolving genes in the human lineage are the glycophorins. There are three glycophorin loci in human, chimpanzee, and gorilla but only one in other primate species (Rearden et al. 1993; Blumenfeld et al. 1997). In human, glycophorin A (GPA) and B (GPB) code for antigens underlying the very common MN and Ss blood type polymorphisms, respectively. At least 40 other blood types are caused by the glycophorin variation (Blumenfeld and Huang 1995). Rearrangements by unequal recombination and/or gene conversion between glycophorin genes appear to be very common, and hot spots of recombination exist in a region of 4 kb encompassing the three extracellular exons (II, III, and IV) (Blumenfeld and Huang 1997).
While GPA constitutes the most abundant glycoproteins on the erythrocyte surface, an exceptional case of deletion homozygote for both GPA and GPB has been known to lead to normal adulthood (Schenkel-Brunner 2000). In human, GPA has been shown to be the receptor of a binding ligand, the 175-kD erythrocyte-binding antigen (EBA-175) of Plasmodium falciparum (Pasvol, Wainscoat, and Weatherall 1982; Sim et al. 1994). A recent study analyzed the evolution of GPA among higher primates (Baum, Ward, and Conway 2002) and suggested a "decoy" hypothesis for its rapid evolution. To further evaluate the possible forces driving the evolution of glycophorins, we sequenced the extracellular domain (exons II, III, and IV) of all three glycophorin genes from human, chimpanzee, and gorilla and the single gene from gibbon. We also analyzed published DNA sequences of P. falciparum in conjunction with the glycophorin sequences. An alternative "evasion" hypothesis is proposed to account for the overall patterns that are not easily discernible in the GPA sequences alone.
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Materials and Methods |
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Data Analysis
To calculate the sequence divergence in introns, Ki (Ki = number of nucleotide changes per intronic site), Kimura's two-parameter model was used (Kimura 1980). For coding regions, we used Li's (1993) method to calculate Ka and Ks as stated above. Ki in general may be a better representation of the neutral rate than Ks. In addition, there are far more intronic sites than the synonymous ones in this study. Because of the closeness between human and macaque, the results are essentially the same if other methods are used (Yang 1997; Yang and Bielawski 2000). For the phylogenetic tree of figure 3, we used the neighbor-joining method (Saitou and Nei 1987) based on Kimura's two-parameter model. Figure 4 shows evidence of gene conversion, which distorts the phylogenetic relationship.
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For the malaria parasite, the nine genes used for the comparison with EBA-175 are STARP, CSP, AMA-1, Pfs25, RAP-1, sporozoite antigen, MSP3, Pfg27/25, and Pfs48/45. For genes with two major alleles in P. falciparum, such as EBA-175 and MSP3, the one that is closer to the P. reichenowi sequence was selected for comparison.
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Results |
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In figure 1, Ka is plotted against Ks for the 280 genes from human and OWM. The data set likely has an overrepresentation of fast-evolving genes, perhaps due to a greater interest and effort at finding and publishing such genes by investigators. (The extrapolation from any data set to the whole genome will be plagued by possible biases in representation until the two respective genomes are nearly entirely sequenced and annotated.) In this data set, the average Ka is 2.67% and average Ks is 6.60%, their ratio being 0.405. The Ka/Ks value averaged across all 280 genes is 0.462. There is a slight and positive correlation (r = 0.262 and slope = 0.242) between Ka and Ks, as noticed by many authors in diverse taxonomic groups (Comeron and Kreitman 1998; Makalowski and Boguski 1998).
Genes above the diagonal have a Ka/Ks ratio greater than 1, and there are 26 of them. Many of these genes have an unusually small Ks, rather than a large Ka. Because smaller genes tend to experience wider fluctuations in Ks, the Ka/Ks criterion may result in the overinclusion of small genes among the fast-evolving ones. We therefore suggest a different measure, = (Ka Ks)/
Ks) where
Ks is the standard deviation of Ks. When Ka/Ks > 1,
> 0. In table 1, 13 genes with
> 1 are listed in the descending order of
plus four other genes that have
< 1 but Ka > 0.08. The
statistic may have an advantage over the standard Ka/Ks presentation when portraying the rate of nonsynonymous substitution among small genes.
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In our study, we chose genes for further analysis on the basis of both a high Ka/Ks ratio and a high Ka value. GPA has the highest Ka among all the genes surveyed. Another gene with a comparably high Ka value is the protamine, which has been analyzed in detail already (Rooney, Zhang, and Nei 2000; Wyckoff, Wang, and Wu 2000).
Evolution of the Glycophorins
Figure 2 shows the canonical genomic structure of GPA, GPB, and GPE in human. These sequences are defined by sites previously recognized in serological analyses and by the exon-intron splicing patterns. However, the delineation of the A, B, and E loci applies only to human. In both chimpanzee and gorilla, their GPBs (like human GPA) do not skip exon III. In gorilla, GPA has a common allele that skips this exon (Huang et al. 1995; Xie et al. 1997). The reason that the locus designation does not agree among species is explored below.
Gene Conversion
The 29 sequences from humans consist of 10 GPA, nine GPB, and 10 GPE alleles. The nine sequences from chimpanzee and six sequences from gorilla cannot be categorized according to the canonical structure of figure 2. Figure 3 presents the phylogeny of the glycophorin sequences from human, chimpanzee, gorilla (h/c/g for short) and the outgroup, gibbon, based on the 2-kb region shown in figure 2. Since the gene triplication occurred before the speciation among the three species (Rearden et al. 1993; Blumenfeld et al. 1997), we had expected three clusters representing the A, B, and E locus, respectively (see the inset in figure 3). Instead, nine clusters were observed. Although each cluster likely represents alleles of a locus of one species, there is no clear phylogenetic relationship among the clusters. (The appearance of an E-locus cluster is deceiving as the distances between species are too high for orthologous genes.)
A simple way to see the phylogenetic incongruence with the expectation is given in table 2. The orthologous loci between human and chimpanzee and between these two species and gorilla should be around 1.2% and 1.5%, respectively (Chen and Li 2001). Instead, no two clusters are less than 2.4% apart, suggesting the absence of true orthology among these clusters. Because the distances between all nine clusters to gibbon are close to the genomic average (Sibley and Ahlquist 1987; Li 1997), mutation rate is not the source of incongruence.
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In general, the long-term consequence of gene conversion is homogenization among loci, but that is not the effect of our concern. The comparison we consider here is the level of genetic variation across multiple loci that undergo occasional gene conversion vis-à-vis the level of single-locus variation. The former should generally be higher than the latter. This elevated level of variation may be characterized as the "storage and retrieval" effect, which plays a central role in the "malaria evasion" hypothesis to be elaborated later.
Rate of Evolution
A result of frequent partial gene conversions is that all three loci would have evolved at a comparable rate. In figure 5a, the divergence between the single glycophorin of gibbon and those of all three loci of h/c/g is shown. Indeed, all h/c/g glycophorin sequences have evolved at an extraordinarily high rate. The average Ka is 0.143, three times as high as the average Ks (0.045). (In human, GPB and GPE appear to have slightly smaller Ka/Ks ratios than GPA, an observation that may be accounted for by the presence of pseudoexons in these two genes in human.) It is striking that ka, ranging from 0.101 to 0.196, does not overlap with ks (0.0310.073) in a total of 44 comparisons. The intron regions have evolved at an even slower rate than Ks, with Ki ranging from 0.038 to 0.049 (mean = 0.042).
The high rate of Ka does not depend on the choice of outgroup. Between the h/c/g sequences and that of the macaque, the average Ka/Ks ratio is 2.0, which increases to 3.56 if the outgroup is orangutan. It appears that the rate of amino acid substitution has accelerated since the apes separated from the OWMs. To address the possibility of recent acceleration in nonsynonymous substitutions, we compare the glycophorins among human, chimpanzee, and gorilla. Because each pairwise comparison represents a different genealogical depth, the Ka/Ks or Ka/Ki ratio was calculated for each of the 489 interspecific comparisons. In figure 5b, most of the Ka/Ks and Ka/Ki values are greater than 1, with an average of 4.0 and 2.61, respectively. These high ratios indicate that the selective pressure driving amino acid substitutions in glycophorins may have intensified since the time of African apes' common ancestor. It is significant that the increased selective pressure appears to be on all three loci.
Amino Acid Sites Under Selection
Given the large number of glycophorin coding sequences, we attempted to identify the putative amino acid residues under positive selection and estimate the strength of selection by the maximum likelihood method of (Yang et al. 2000). Using Model 8, we estimated that 78% of the residues have evolved under near neutrality with Ka/Ks1, and 22% have been driven by positive selection. According to this model, the average Ka/Ks ratio for these selectively driven sites is as high as 7.7. These fast-evolving sites are distinct from the glycosylation sites, which are relatively conserved among primate species (Baum, Ward, and Conway 2002). These sites are listed in Supplementary Material online.
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Discussion |
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The Decoy Hypothesis
In this hypothesis, GPA serves as a "decoy" to distract viruses and bacteria away from other vital organs (Baum, Ward, and Conway 2002). In general, one might not expect a decoy to evolve rapidly as it should be made easy to find. To explain the rapid evolution of GPA, the hypothesis posits that a decoy behaves like the immunoglobulins, which diversify rapidly to cope with a wide array of antigens. Glycophorins, however, have a rather different evolutionary dynamics than the immunoglobulins. Although they have been evolving rapidly, the heterozygosity in GPA in any individual is quite unremarkable, other than the common MN polymorphism. The low abundance of GPB, which underlies the Ss polymorphism, and the undetectable expression of GPE also seem incompatible with the postulate of diversity enhancement. In addition, since there are many sialic proteins specifically encoded on the erythrocyte surface (e.g., Kell, GPC, and Duffy [Schenkel-Brunner 2000]), they might be adequate decoys as well. Why then have they not been evolving rapidly like the glycophorins? Under the decoy hypothesis, pathogenic antigens must themselves be changing rapidly, so the decoy has to keep up the pace. Without identifying the candidate pathogens for which the decoy serves to distract, the hypothesis at the moment is not testable.
Alternatively, rapid evolution between loci and low diversity within locus may suggest evasion. The many incidences of interlocus conversions would also mean frequent and abrupt changes in the receptor structure. The evasion hypothesis below is very specific about the candidate pathogen and can be falsified with proper experimental setups.
The Evasion (from P. falciparum) Hypothesis
In human, both GPA and GPB have been shown to be the receptors of the malaria parasite, P. falciparum (Pasvol, Wainscoat, and Weatherall 1982; Dolan et al. 1994). The malaria ligand binding to human GPA has been identified to be the 175-kD erythrocyte-binding antigen (EBA-175). Its binding to GPA has been shown to be the primary pathway by which P. falciparum invades human erythrocytes (Sim et al. 1994). The proposed hypothesis is that GPA has been evolving rapidly to evade the malaria parasite. Both mutations and interlocus conversions are means of evasion; hence, the GPB and GPE sequences have been impacted by malaria as well. It should be noted that, under the evasion hypothesis, binding to EBA-175 is considered a negative pleiotropic effect of GPA. The normal function(s) of the glycophorins currently remain(s) unknown.
In parallel, EBA-175 may have been tracking the evolution of the glycophorins and, if true, should be evolving just as rapidly as the glycophorins. All these fast-evolving molecules should bear a strong signature of positive selection. In this section, we shall outline the evidence to show that the hypothesis is a viable one and deserves to be seriously tested. (The scope of the actual testing is, however, beyond the goals of the present study.)
Interspecific Divergence in EBA-175 and Other Loci
We first examined the nucleotide substitution rate of EBA-175 vis-à-vis those of other genes between P. falciparum and P. reichenowi, the latter infecting chimpanzee (Ozwara et al. 2001). The entire EBA-175 (4,359 bp) has a Ka value of 0.095 (SE = 0.009) and a Ks value of 0.074 (SE = 0.015). The difference is significant (P < 0.01), as determined by the simulation method of Wyckoff, Wang, and Wu (2000). EBA-175 has apparently been under positive selection since the speciation between the two Plasmodia (and, presumably, their hosts, human and chimpanzee). We also compute the Ka and Ks values for nine other antigen-coding loci (table 3). The value ranges from 0.014 to 0.058 for Ka and 0.027 to 0.152 for Ks. Many of these antigens, including AMA-1, CSP, MSP-3, and Pfs48/45, are themselves under positive selection (Hughes and Hughes 1995; Escalante, Lal, and Ayala 1998), but none has a higher Ka value than EBA-175.
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In comparison, the level of nonsynonymous variation is too high to be attributed to demographical influences. More revealing is the population frequencies of these nonsynonymous changes. The frequency spectrum of the derived mutations is shown in figure 6. Against the neutral equilibrium (blank bar), there is an excess of high-frequency mutations by Fay and Wu's H statistic (Fay and Wu 2000) (P < 0.05), a sign of positive selection (Ewens 1979). Because P. falciparum is believed to have experienced a recent loss in neutral variation and should have an excess of rare mutations over the neutral equilibrium (Tajima 1989; Fu 1994), the excess in high-frequency mutations in figure 6 is even more noteworthy. Such an excess in region II can best be accounted for by either global positive selection (Ewens 1972; Fay and Wu 2000) or local selection leading to population differentiation (Fu 1994; Slatkin and Wiehe 1998). (Again, the lack of differentiation at the synonymous sites rules out the possibility of neutral population subdivision.)
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From structural considerations, many glycophorin variants common in regions of malaria endemics may be poor receptors for EBA-175. The He variant is a GPB epitope converted in part by GPA but with several additional mutations. The He epitope, which may make GPA GPB-like or vice versa, occurs very rarely in Caucasians and Asians but is prevalent among Africans (2% to 10%) from malaria endemic regions (Race and Sanger 1975; Mourant, Domaniewska-Sobczak, and Kopeâc 1976). In contrast, the variant Sta can reach 5% to 10% in some East Asian populations but are extremely rare among Africans and Caucasians. Sta is mostly a GPA allele that skips exon III and thus resembles GPB in the extracellular domain (Huang, Chen, and Blumenfeld 2000). A most interesting case may be the Mi-III variant, a GPB allele partially converted by GPA. The conversion restores the expression of the pseudoexon III (fig. 1), making GPB more like a variant GPA (Huang and Blumenfeld 1991). Whereas Mi-III accounts for less than 1% among Caucasians and 3% among ethnic Han Chinese, it represents 30% to 90% of GPB in several large dominant aborigines groups. These groups, especially the Ami tribe, occupied the lower elevation in Taiwan, where malaria was common in the past (Broadberry and Lin 1996).
In addition to such structural variants, many populations in regions of malaria endemics harbor unusual glycophorin variants, often in unusual frequencies. The Hunter variant can reach 22% in West Africa but is rare among Caucasians (0.5%) (Blumenfeld et al. 1997). In New Guinea, the frequency of N antigen is higher than 90%, whereas it is generally about 50% (30% to 70%) elsewhere in the world (Mourant, Domaniewska-Sobczak, and Kopeâc 1976).
Conclusions
Unlike other genetic alterations, such as sickle cell anemia or G6PD deficiency (Tishkoff et al. 2001), that confer resistance to malaria, mutations in the glycophorins would not have been debilitating even in homozygotes (Schenkel-Brunner 2000). Moreover, a reservoir of GPB and GPE variants retrievable by gene conversion or unequal exchange may produce novel GPA variants and provide human and African apes a means to evade the pursuit of pathogens. In this scenario, the advantage of gene duplication may be the ability to "store and retrieve" genetic variations. Whether (and how) glycophorins and Plasmodium genes interact and coevolve will have implications in public health and evolutionary theories. If this hypothesis turns out to be correct, human and ape ancestors must have been battling malaria for over 10 million years.
Pooling the evidence, we consider it plausible that the evolution of human glycophorins is at least partially driven by P. falciparum. It may be fruitful to systematically document the invasion efficiency of P. falciparum strains that carry different EBA-175 alleles. Such efficiency should be assayed against human erythrocytes carrying different glycophorin variants.
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Supplementary Material |
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Acknowledgements |
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Footnotes |
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