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Manaphy Full Art How Does Genetic Drift Impact the Frequency of Blood Types in Different People

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Bioessays. 2013 Oct; 35(10): 862–867.

Ancestry runs deeper than blood: The evolutionary history of ABO points to cryptic variation of functional importance

Laure Ségurel

oneDepartment of Human Genetics, University of Chicago, Chicago, IL, USA

twoDepartment of Ecology and Development, University of Chicago, Chicago, IL, Us

3Howard Hughes Medical Found, University of Chicago, Chicago, IL, Us

Ziyue Gao

2Department of Ecology and Development, University of Chicago, Chicago, IL, U.s.

4Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA

Molly Przeworski

1Department of Man Genetics, Academy of Chicago, Chicago, IL, United states

2Department of Environmental and Evolution, University of Chicago, Chicago, IL, USA

3Howard Hughes Medical Constitute, University of Chicago, Chicago, IL, USA

Abstract

The ABO histo-blood group, commencement discovered over a century ago, is plant not but in humans merely also in many other primate species, with the same genetic variants maintained for at to the lowest degree 20 million years. Polymorphisms in ABO have been associated with susceptibility to a large number of man diseases, from gastric cancers to immune or artery diseases, but the adaptive phenotypes to which the polymorphism contributes remain unclear. Nosotros propose that variation in ABO has been maintained past frequency-dependent or fluctuating choice pressures, potentially arising from co-development with gut pathogens. We further hypothesize that the histo-blood grouping labels A, B, AB, and O do not offer a total description of variants maintained by natural selection, implying that in that location are unrecognized, functionally of import, antigens beyond the ABO group in humans and other primates.

Keywords: ABO, balancing option, evolution, host-pathogen interaction, population genetics, primates

Long-term maintenance of the ABO histo-blood group in primates

The ABO histo-blood groups, encoded by the A, B, and O alleles at the ABO gene 1, was the first polymorphism to exist discovered in humans. Genetic multifariousness at the ABO gene is unusually loftier, suggesting that distinct claret groups have persisted due to balancing pick, a grade of adaptation that maintains variety in a species in the confront of genetic drift (the chance fluctuations in allele frequencies that occur in finite populations). Why ABO blood groups might be under balancing selection has been debated for close to a century 2.

Strikingly, A and B are both found in at least 17 other primate species (see Fig. 1A), and the genetic differences betwixt the A and B alleles consist of the same two amino acid changes in exon 7 of ABO 3 , 4. In contrast, at that place are a number of distinct loss-of-function (O) alleles, which are not shared among species v. We recently showed that the A/B polymorphism emerged at least around 20 millions years ago and persisted in some primate species until the present 6. Notably, humans and gibbons inherited A and B types from a common ancestor at the origin of apes 6. The maintenance of a polymorphism for that long is exceedingly unlikely by chance solitary, providing compelling evidence that variants in ABO have been maintained by ancient balancing selection and thus must accept of import furnishings on individual fitness 7.

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A: Phylogenetic information about the A/B polymorphism for primate species in which it has been characterized (meet 6 and references therein), along side 2 examples of overlapping geographical ranges for pairs of species that differ in their ABO phenotype. The calibration is in Millions of years. Geographical ranges are from the IUCN Carmine Listing maps (http://world wide web.iucnredlist.org/). B: Expression pattern of ABO in dissimilar tissues and primate species 22.

Other examples of ancient balancing choice in primates include the major histocompatibility complex (MHC), which plays a disquisitional role in allowed response 8, and the opsin polymorphism in New World Monkeys that underlies trichromatic color vision 9. In contrast to these two approved cases, the adaptive phenotype to which ABO contributes is less articulate 10 , 11. It was originally suggested that ABO was under selection considering of its protective role with regard to fetal-maternal Rhesus incompatibility 12. Since then, ABO variation has been associated with susceptibility to a large number of human diseases, from gastric cancers to immune or artery diseases ten , 11 , 13. However, because these associations correspond to multiple, potentially unrelated phenotypes, it remains unknown which of them are responsible for the persistence of ABO types in multiple primate species. Here, we advise that variation in ABO is maintained by frequency-dependent or fluctuating choice, possibly in response to gut pathogens, and that at that place exists functionally important cryptic variation in the factor yet to exist uncovered.

Fluctuating pick in response to gut pathogens?

Balancing selection is often equated with heterozygote advantage, typified past the (evolutionarily young) sickle jail cell polymorphism in humans 14. ABO variation in primates is unlikely to be maintained by this machinery, however, given that there be haplotypes encoding the AB phenotype ("cis-AB" alleles), which are fixed in Mus musculus for case 15, and yet these are found just at very low frequencies in humans and have not been reported in other primates 6. More by and large, heterozygote advantage is thought to represent a transient solution that can be relatively apace resolved past the evolution of greater phenotypic plasticity or by duplication xvi, as appears to have happened at least twice for the opsin polymorphism 9.

Genetic variation tin also be maintained in the population by negative frequency-dependent selection, in which rare types accept a fettle advantage (as in cocky-incompatibility loci in plants 17). 1 scenario by which this might occur, proposed for ABO xviii, is when pathogens exploit specific host proteins to initiate infection and train on the more than mutual types in the population. Host and pathogen co-development tin can besides lead to the maintenance of variation when information technology induces temporally fluctuating selective pressures, equally tin ascend when there is an interaction between the genotypes of the host and that of the pathogen and both virulence and resistance are costly 21. Consistent with these models, many of the well-characterized examples of long-term balancing pick are related to host immunity (due east.g. xix).

For ABO specifically, multiple lines of evidence suggest that host-pathogen interactions are responsible for the maintenance of the polymorphism. Showtime, variation in ABO antigens has been associated with susceptibility to a number of infectious diseases 10 , 13, and an interaction between ABO types and specificity of binding has been found in strains of Norwalk virus 20. Second, the limerick of Helicobacter pylori appears to have evolved in response to changes in human ABO histo-blood group frequencies: the frequency of strains able to demark to the A claret group is greatly decreased in the Native Amerindian populations that are fixed for O 21. Thus, at to the lowest degree some of the weather condition for frequency-dependent or fluctuating selection arising from host-pathogen co-evolution appear to be met.

The phylogenetic distribution of ABO provides additional hints virtually the source of balancing selection pressures. In apes, ABO antigens are expressed at the surface of red blood cells and on the vascular endothelium as well equally in body fluids, mucus secretions and diverse epithelial tissues (in humans, simply in "secretor" individuals who deport an intact FUT2; encounter Fig. 1B). In contrast, in Old World Monkeys, ABO antigens are absent on red claret cells, and in New Globe Monkeys, they are likewise absent-minded from the vascular endothelium (meet Fig. 1B 22). This observation strongly suggests that the balancing option pressures did not arise from the presence of ABO antigens on blood cells alone, and for example, that the influence of ABO on rosetting 23, the binding of crimson blood cells infected by Plasmodium falciparum to uninfected cells, could not explain the ABO polymorphism outside of apes. The adaptive phenotype must exist due instead, at to the lowest degree originally, to its more ancestral expression pattern on the surface of epithelial cells. Notably, in all primates, ABO antigens are present on the digestive tract, which is an important site of infection, due east.g. for H. pylori and Norwalk virus. Interestingly, H. pylori is known to infect macaques and New Earth Monkeys 24 , 25. Thus, the interaction between variation at ABO and gut pathogens could impose a shared selective pressure amidst primates.

As well enlightening are findings virtually B4galnt2 in mice. A cis-regulatory region of this gene appears to be under long-term balancing option, with the 2 highly diverged haplotypes controlling a tissue-specific switch betwixt expression in gut and blood 26. Intriguingly, variation in this regulatory region is associated both to the presence of Helicobacter species in the mice gut 27 and to VWF levels in the blood (a protein involved in blood clotting), two phenotypes also associated with ABO histo-blood groups in humans 11 , 21. These parallels seem unlikely to exist purely casual, and suggest that the association with Helicobacter species – or a trade-off between roles in different tissues – may be important in the maintenance of variation at ABO.

Unrecognized variation of functional relevance?

Another potentially informative phylogenetic pattern is the loss of ABO histo-blood groups in some species. Amid 41 primate species for which data are available, ten species practice non present the B allele/phenotype and 11 do not present the A allele/phenotype vi. In apes, notably, chimpanzees and bonobos lack B, while gorillas lack A. The differences amongst species could reflect the loss of A, B, or O by chance (i.due east. genetic drift) if they have undergone a marked reduction in population size 28. For example, although the variants in the MHC have been maintained for millions of years in mammals (and other vertebrates), MHC variability is greatly decreased in species that have experienced potent, recent bottlenecks 29. To examination this possibility, we examined whether primates with smaller effective population sizes (every bit measured by putatively neutral diverseness levels) tend to take lost A or B. For the 11 species for which reliable genetic diverseness estimates were available 30, there is no discernable correlation (phylogenetic least-square regression, p-value = 0.28).

Another explanation for the loss of ABO types might be that species confront different selective pressures, for example because of differences in pathogen community composition. While this hypothesis seems sensible, the loss of allelic classes occurred in locations in which other species have maintained all ABO histo-claret groups: for case, Symphalangus syndactylus and Hylobates agilis are in sympatry on the Sumatra isle and the Malay peninsula, yet one is fixed for B and the second presents both A and B (see Fig. aneA). A similar ascertainment holds for Ateles chamek and Saimiri boliviensis, which are both found in parts of Brazil, Bolivia, and Peru (with the important caveat that they may occupy different ecological niches within those geographic areas; Fig. iA).

A third (not mutually exclusive) hypothesis is that at that place are more allelic classes at ABO than the three normally defined A, B, and O, and so that natural selection might actually be maintaining a larger number of variants equally part of a multi-allelic balanced polymorphism. In that regard, we note that the A, B, AB, and O blood groups are categories defined based on hemaglutination patterns subsequently mixing of blood. Given that shared selective pressures among primate species cannot be the event of the presence of ABO on reddish blood cells, in that location is no reason to assume that the A, B, and O labels fully describe the spectrum of variants distinguished by natural choice. Thus, species apparently monomorphic for one category, eastward.g. for the A class, may really exist harboring variation amongst A alleles of functional importance. If so, we would misclassify these species as monomorphic and underestimate the number of relevant functional classes. In support of this hypothesis, functional variation is known to be within histo-blood types in humans: for case, A1 and A2 alleles, while equivalent for transfusion purposes, differ in quality and quantity of antigens 31. These sub-groups accept been shown to have an effect on levels of VWF 11, merely tend not to have been tested systematically in studies of disease phenotypes, so that we know petty well-nigh their furnishings on allowed or other phenotypes. Intriguingly, these phenotypic sub-groups have also been observed in chimpanzees, gibbons, and orangutans 32.

Additional back up for the 3rd hypothesis comes from population genetic analyses: surveys of variation at ABO in humans have revealed unusually old variants not only in exon seven, where changes distinguish A and B types, merely also in exon 4 and intron one (see Fig. 2); these polymorphisms are not in linkage disequilibrium with those in exon 7, raising the possibility of boosted targets of aboriginal balancing selection along the ABO factor 33. Moreover, we recently discovered that two polymorphisms around intron 4 of ABO are found in both humans and chimpanzees 34 (see Fig. two) and appear to be former 33 , 34 and unrelated to the balancing selection interim on exon vii (unpublished simulation results). This sharing betwixt humans and chimpanzees is unexpected if the but functionally important variation distinguishes A and B types, equally chimpanzees lack the B type and therefore should non share ancestral polymorphisms with humans. Similarly, in exon seven, there is a non-synonymous variant (position 703, Gly235Ser) shared between humans, orangutans, and gibbons, species that are all polymorphic for A and B, as well equally with gorillas, which lack A 6 (run across Fig. 2). In humans, alleles with the Gly at this site on a B groundwork accept reduced B activity and small-scale amounts of A activity (B(A) allele) 31, suggesting that some gorillas may in fact take small levels of A activity rather than beingness fixed for B. Regulatory variation well-nigh ABO may too exist of import: notably, differences in the number of repeats spring by the CCAAT-binding factor NF-Y take been associated with ABO expression differences in humans 31 and polymorphisms for the number of binding motifs are also plant in chimpanzees (Thompson and Ober, personal advice). Thus, the variation patterns beyond species point to currently unrecognized polymorphisms of selective (and hence functional) importance in ABO.

An external file that holds a picture, illustration, etc. Object name is bies0035-0862-f2.jpg

Structure of ABO and nucleotide diverseness in humans (pinnacle) and chimpanzees (bottom) for sliding windows of one kb, using information for Yoruban individuals in the 1000 Genomes Project 35 and information for Western chimpanzees from the PanMap project 36. The location of the molecular changes distinguishing A and B types are indicated, every bit are a subset of the polymorphisms shared between ape species. The average genome-wide diversity is shown for YRI and for Western chimpanzees xxx, respectively.

Futurity directions

The evolutionary history of ABO indicates that balancing selection has maintained a polymorphism at this locus for many millions of years, and hence that these variants are of import to the fitness of humans and other primates. The mechanism of balancing selection is withal yet unknown, only more probable to exist fluctuating or frequency-dependent selection than heterozygote advantage. The adaptive phenotypes to which ABO contributes are also unclear, but its phylogenetic distribution strongly suggests that they do not stalk from its role in blood solitary just rather could exist due to shared gut pathogens. This consideration, in turn, implies that the histo-blood grouping categories (A, B, AB, and O) may non fully describe the variation in ABO antigens, and raises the possibility of a larger number of allelic classes of relevance for natural selection. The case of ABO thus illustrates how the analysis of evolutionary pressures can help to reveal variation of biological importance.

The evolutionary analyses also serve to motivate further functional studies. For instance, genetic variation data for the unabridged ABO gene in additional primates (notably New World Monkeys) would let one to test whether regions with unusually high variety are observed exterior of exon seven, and could lead to the identification of additional targets of ancient balancing pick. Such variants could so be examined for their effects on enzymatic activity. To evaluate whether at that place is cryptic variation of functional importance in ABO, it may be particularly interesting to focus on activeness levels of ABO in species idea to be lacking 1 of the main histo-blood groups (e.g. gorillas or chimpanzees). In parallel, phenotypic associations might be conducted to test the effect of histo-claret blazon subgroups and secretor status on susceptibility to infectious diseases and other plausible phenotypes. This information could and so be integrated with information on population frequencies at ABO and local pathogen customs limerick to larn more well-nigh the selection mechanism underlying the remarkable evolution of this gene.

Acknowledgments

We thank Emma E. Thompson and Carole Ober for permission to cite their unpublished information and for sparking our interest in ABO, Joachim Hermisson, Ellen Leffler and Guy Sella for helpful discussions, and 2 anonymous reviewers and the editor for comments. This piece of work was supported by NIH GM72861 to M. P. Thousand. P. is a Howard Hughes Early on Career Scientist.

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