review article trans-species polymorphism in immune...

Review ArticleTrans-Species Polymorphism in Immune GenesGeneral Pattern or MHC-Restricted Phenomenon

Martin Tjšickyacute and Michal Vinkler

Charles University in Prague Faculty of Science Department of Zoology Vinicna 7 128 44 Praha Czech Republic

Correspondence should be addressed to Michal Vinkler michalvinklernaturcunicz

Received 25 March 2015 Accepted 4 May 2015

Academic Editor Nejat K Egilmez

Copyright copy 2015 M Tesicky and M Vinkler This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Immunity exhibits extraordinarily high levels of variation Evolution of the immune system in response to host-pathogeninteractions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the geneticvariability Many studies have documented that immunologically relevant polymorphism observed today may be tens of millionsyears old and may predate the emergence of present species This pattern can be explained by the concept of trans-speciespolymorphism (TSP) predicting themaintenance and sharing of favourable functionally important alleles of immune-related genesbetween species due to ongoing balancing selection Despite the generality of this concept explaining the long-lasting adaptivevariation inherited from ancestors current research in TSP has vastly focused only on major histocompatibility complex (MHC)In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern Further research should clearly pay more attention to the investigation of TSP in innate immunegenes and especially pattern recognition receptors which are promising candidates for this type of evolution More effort shouldalso bemade to distinguish TSP from convergent evolution and adaptive introgression Identification of balanced TSP variants mayrepresent an accurate approach in evolutionary medicine to recognise disease-resistance alleles

1 Introduction

Immune function is highly heritable [1ndash4] governed froma large proportion by combination of alleles encoding func-tionally relevant immune-relatedmolecules [5ndash7]The allelesof immune genes coevolve in interaction with pathogensattacking the organism [8] According to the Red Queenhypothesis pathogens form constant pressure on host popu-lation selecting in many cases on variability within immunegenes [9] Genetic variability underlying the selected hetero-geneity in the immune function is observable in the host asallelic polymorphism that is a long-lasting occurrence of twoor more genotypes in a population in frequencies that cannotbe attributed to a recurrent mutation [10] Long-lastingpolymorphism may be maintained in the human and animalhost populations by balancing selection [11ndash13] Intriguinglythis polymorphism maintained by selection may be sharedacross species and even between higher evolutionary lineagessuch as genera or rarely families [14ndash18] This sharing ofimmunologically important genetic variation may have then

profound effects on the interspecific similarity of naturallyoccurring ranges of immune responsiveness upon specificantigen stimulation

Trans-species polymorphism (TSP) refers to the occur-rence of identical or similar alleles in related species exclud-ing instances where the similarity arose by convergence orintrogression [19 20] By definition TSP alleles in relatedspecies aremore similar in their sequences than are the alleleswithin individual species TSP arises from the passage ofalleles from ancestral species to descendant species by incom-plete lineage sorting [19ndash21] (see also in Figure 1) Generallywe distinguish two forms of TSP neutral TSP and balancedTSP Neutral (transient) TSP is frequent in closely relatednewly diverged species and gradually disappears [19] Thusneutral TSP has a tendency to be widespread across loci onlyin a short window of time after the speciation event [22 23]In contrast balanced TSP is functionally much more impor-tant [20] This type of TSP results from balancing selectionthat is selection for variability maintenance Balanced TSPis typically long-lasting and may be maintained in immune

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2015 Article ID 838035 10 pageshttpdxdoiorg1011552015838035

2 Journal of Immunology Research

Ancestral species

Species A

Speciation

Speciation

Species B Species C2 1 1

9984001 3 1

99840039984001 2

Figure 1 Mechanisms explaining polymorphism shared betweentaxa (based on [19 112]) The three proposed mechanisms aredepicted in allelesrsquo genealogy (1) trans-species polymorphism TSP(incomplete lineage sorting allelic lineages predate speciation andare passed to descendent species) (2) convergence (allelic lineagesevolve similar features independently in separate lineages) and(3) introgression (allelic lineages are horizontally transferred eitherfrom recipient species to donor species or in both directions)Each row depicts a gene pool of one generation each circlesquarean allele of specific features Different colours highlight individ-ual allelic lineages where interconnecting lines mark antecedent-descendent relationships Green and purple dashed arrows representdirections of introgression

genes for millions or even tens of millions of years [24ndash26] Identification of balanced TSP variants is therefore apowerful approach to identify naturally occurring resistancealleles with application potential in human medicine as wellas in animal breeding and nature conservation

TheTSP conceptwas proposed three decades ago byKlein[27] who supported its existence by comparative evidencein major histocompatibility complex (MHC H2 antigen) inmice [28] Until present MHC alleles from many mutuallyrelated species were sequenced and the TSP phenomenonwas reported in numbers of studies in all sorts of taxa (seeSupplement 1 in Supplementary Material available onlineat httpdxdoiorg1011552015838035) Surprisingly ourknowledge on TSP in other immune gene classes is onlylimited Is TSP unique to MHC or does it represent a generalevolutionary pattern masked by little endeavour paid toits investigation outside the MHC family In the presentreview we compile present evidence on TSP in human andanimal immune genes and outlinemain directions for furtherevolutionary immunogenetic research

2 Evolutionary Mechanisms MaintainingBalanced TSP in Immune Genes

Long-lasting TSP in immune genes is dependent on bal-ancing selection This type of selection maintains geneticvariation in populations for extensive periods of time based

on three possible mechanisms (1) heterozygote advantage[29 30] (2) negative frequency-dependent selection [3132] and (3) spatio-temporally fluctuating selection [33 34]Heterozygote advantage (also termed overdominance) ariseswhen individuals heterozygous in a particular gene are able toresist the pathogen infection better than both homozygotesIn this case polymorphism is maintained by selection for het-erozygosity Overdominance is well described forMHCgenesin a number of species where the benefits of heterozygosityin certain loci depend on the degree of overlap in bindingspecificity of individual alleles [30 35] Negative frequency-dependent selection in contrast represents a mechanismwhere only particular genotypes provide resistance advantagein a given time This advantage is nevertheless negativelylinked to the allele frequencies in a population [31] It has beenrepeatedly shown that pathogens tend to infect and adaptto the most common genotypes of the host in a populationleaving out rare genotypes [36] Rare alleles are thereforefavoured and increase in frequency until they reach a specificequilibrium beyond which they start to be selected againstFrequencies of the alleles thus oscillate in time and balancedpolymorphism ismaintained [12 30] Empiric supports comefrom associations of MHC alleles of susceptibility to diseases[30 35 36] Finally fluctuating selection is based on variationin selective pressures in space and time Most pathogens arepresent in a limited area of distribution and their abundancechange in time (spatio-temporal fluctuations) This createsdistinct and changing selective pressures on different hostpopulations that may be nonetheless linked by migration[33 34] In contrast to the negative frequency-dependentselection in fluctuating selection the fitness value changesas a function of particular pathogen abundance and notas a function of the allele frequency itself [33] Althoughthere is still serious lack in empirical evidence supportingthe existence of fluctuating selection theoretical approachessuggest that this mechanism is admissible for instance forthe maintenance of the MHC polymorphism [12] The threemechanisms of balancing selection are notmutually exclusiveand in all perceivable combinations all may be involved in themaintenance of the balanced TSP

3 TSP in Major HistocompatibilityGenes (MHC)

MHC groups several extremely polymorphic and dynami-cally evolving members of the immunoglobulin superfamilyplaying a crucial role in the adaptive immune defence againstpathogens in jawed vertebrates [29 37] MHC genes encodecytoplasm-membrane-bound glycoproteins which presentendogenous and exogenous oligopeptides to T cells [38]Although the strength of the association between MHCpolymorphism and resistance to infectious diseases variesbetween species and populations [39 40] the capability ofcertain alleles to bind certain pathogen-derived peptides isundoubtedly essential for individual survival [30] The typeof the selection responsible for the variability maintenancelinked to disease resistance may however not only be naturalselection but also sexual selection [31 41] since the twomech-anisms are not mutually exclusive and both can contribute to

Journal of Immunology Research 3

Table 1 Number of published research articles dealing with TSP in vertebrate immune genes available on Web of Science final update 19March 2015 For details see Supplement 1

Gene group Gene Number of references

Major histocompatibility complex (MHC)

Classical MHC I HLA-A -B -C MHC Ia undifferentiated 27Non-classical MHC I HLA-E -G 2

MHC IIA DPA DRA DQA DAA MHC IIA undifferentiated 36MHC IIB DPB DRB DQB DAB DRB-like MHC IIB undifferentiated 80

Non-MHC immunoglobulinsPSMB8 (LMP7) 4

IGVH 2C Alfa gene 2

Host defence peptides AvBD12 22-5A synthetase family OAS1b 2Tripartite motif protein family TRIM5alfa 2

balanced parasite-mediated polymorphism The MHC genefamily can be generally divided into two classes MHC classI and MHC class II [39] Owing to their importance in theimmune response and a high variability on both interspecificand intraspecific levels traditionally most studies dealingwith TSP have focused on MHC class I and MHC class IIgenes and their peptide binding regions (PBRs) in particular(summarized in Table 1 and Figure 2)

MHC class I proteins consist of a transmembrane 120572-chain composed of 120572

1 1205722 1205723domains and 120573

2-microglobulin

[29 30 38] PBR is coded by exon 2 (1205721-domain) and exon

3 (1205722-domain) and binds shorter oligopeptide fragments

(approximately 8ndash11 amino acids in length) originating froman intracellular pathogen or endogenous peptides Com-plexes of MHC class I molecules with their peptides arerecognized by T-cell receptors (TCRs) of CD8+ T cells MHCclass II molecules in contrast consist of two noncovalentlyassociated chains 120572 chains (120572

1 1205722) and 120573 chains (120573

1 1205732)

encoded by two different genes termed MHC IIA and MHCIIB [30 32] The MHC class II PBR is formed by N-terminaldomains of these moleculesmdash120572

1(exon 2) and 120573

1(exon 2)

Opened binding groove of MHC class II allows binding oflonger peptides (approximately 11ndash17 amino acids in length)originating from extracellular pathogens or intracellularpathogens inhabiting vesicular systems [29 30] Complexesof MHC class II molecules with their peptides are recognizedby CD4+ T cells [29 38] However cross presentation ofantigenic peptides enables the exposure of someMHC-class-II-type exogenous peptides on the binding surface of MHCclass I molecules and vice versa [38 42]

In MHC genes TSP encompasses mainly variable exonsencoding PBRs (inMHCclass I exons 2 and 3 inMHCclass IIexon 2 of bothMHC IIA andMHC IIB genes) that have beenthe targets of strong diversifying (increasing allele numbers)and positive (adapting the alleles to pathogenic peptides)selection followed by balancing selection modifying allelefrequencies [19 43] There are highly variable and divergentalleles which can persist as identical or nearly identical alleleswithin millions of years [16] and as allelic lineages up to tensof millions of years [19] In contrast to PBR non-PBR MHCdomains are usually evolutionary conserved often underpurifying selectionwithout orwithminimal TSP [26 44ndash46]

0102030405060708090

Num

ber o

f ref

eren

ces

MH

C II

B

MH

C IIA

MH

C Ia

PSM

B8

MH

C Ib

IGV

H

C A

lfa g

ene

AvBD

12

OA

S1b

TRIM

5al

fa

Figure 2 Number of published research articles dealingwith TSP invertebrate immune genes available on Web of Science final update19 March 2015 For details see Supplement 1

Although evidence for TSP has been gathered from severalMHC loci in mammals birds reptiles amphibians and fishindicating that TSP is a general phenomenon in MHC thevast majority of studies focused on genotyping only themost variable exon 2 of the MHC IIB genes (Table 1 andFigure 2) In MHC IIA loci the lower number of studiesreporting TSP may be explained by the general belief of theirmore conserved nature when compared to MHC IIB genes[24 47 48] Furthermore despite the broad range of taxainvestigated most evidence on TSP is limited to mammals(especially primates rodents and even-toed ungulates seeSupplement 1)

Time persistence of allelic lineages in mammalian clas-sical MHC class I genes is assumed to be generally shorterthan in classical MHC class II genes [19 49 50] For instancein primates MHC class I allelic lineages HLA-A -B -C areprobably younger than 22 million years [19 49] In contrastsome allelic lineages in primate MHC class II appear to beolder than 30 million years [51] In Lemuriformes identicalMHC class II alleles of DRB exon 2 persist for more than37ndash42 million years [17] Similarly in DQA genes in rodentsthe oldest alleles are maintained for at least 48 million years[52] Interestingly TSP ismaintained in fish amphibians and


reptiles onmuch longer timescales than inmammals [45 53ndash55] For instance the oldest allelic lineages of exon 2 MHC Iathat are shared between Salmoniformes and Cypriniformesprecede the taxa divergence and persist for more than 145million years [56] The oldest reported TSP then concernsantigen presenting MHC class I within Acipenseriformeswith time persistence of 187 million years [57]

4 Trans-Species Polymorphism inOther Immune Genes

41 Non-MHC Immunoglobulins TSP has also beendescribed in members of the immunoglobulin superfamilyother than MHC The existence of high genetic variabilityand TSP in heavy chains of immunoglobulins in rabbitsand hares has been predicted by serological cross reactivityamong serotypes as early as in 1980s [58] Heavy chainsof immunoglobulins are encoded by the immunoglobulinvariable region heavy chain (IgVH) genes [59] Variabilityin these genes may affect the binding specificity of antigenbinding sites of antibodies Apart from IgVH genes directlyinvolved in VDJ arrangements other IgVH genes includingpseudogenes can serve as a source of variation for geneconversion [60] It has been shown that the IgVH TSP in theLeporid lineage concerns the VH1VHa gene and predatesthe rabbit and hare divergence and persists for at least16ndash24 million years perhaps as long as for 50 million years[58 60 61] Another example of TSP in the immunoglobulinsuperfamily has been reported among eight macaque speciesin exon 2 of the C120572 constant region of IgA heavy chain[62 63] Although previously considered as conservativehigh interspecific as well as intraspecific variability has beendiscovered in primates [62ndash64] Exon 2 encodes the hingeregion which lies at the base of the heavy chain regions ofimmunoglobulin [62 63] Variability in the hinge regionassociated with variation in flexibility of the molecule mightaffect the spectrum of antigens recognised by the antigenbinding site of the IgA antibody [62] or allow avoidance ofthe attacks of bacterial proteases in this region [62 65]

42 PSMB8 PSMB8 (proteasome subunit 120573-type 8 geneLMP7) encodes immunoproteasomal catalytic subunit of 120573-ring which is involved in the cleavage of peptides processedfor presentation on MHC class I molecules [66] This geneis located in MHC class I gene cluster and together withanother proteasomal genePSMB9 its expression is interferon-induced Polymorphism in this gene involves amino acidposition 31 that affects the catalytic function of the subunitTwo functionally distinct allelic lineages differing at this posi-tion have been distinguished in various vertebrate lineages[67] (1) A-type PSMB8 having AlaVal at the position 31with a larger and opened S-pocket allowing the cleavage ofaromatic amino acids with the chymotrypsin activity and(2) F-type PSMB8 having PheTyr at the position of 31with a narrower S-pocket suitable for elastase cleavage ofsmall hydrophobic amino acids [67] This type of TSP hasbeen reported in PSMB8 in bony fish of the Oryzias genus[68] where two highly diverged allelic lineages differing in

the sequence encoding the S-pocket (called here PSMB8Nand PSMB8d) persist for at least 30ndash60 million years Asimilar pattern has also been reported among clawed frog(Xenopus) species [69] suggesting the existence of similarindependent TSP allelic lineages in amphibians for 80millionyears Intriguingly allelic dichotomy in PSMB8 gene betweenCypriniformes and Salmoniformes (PSMB8F and PSMBA)suggests extremely long-term transorder polymorphismmaintained for more than 300 million years [67] To con-clude these examples demonstrate long-term TSP in lowertaxonomic units (Oryzias Xenopus and between Salmoni-formes and Cypriniformes) in genetic traits that most proba-bly converged between major vertebrate lineages [67 70]

43 Host Defence Peptides Host defence peptides (HDPsalso known as antimicrobial proteins) are small diverse andevolutionary conserved effector molecules involved mainlyin pathogen killing [71 72] but also in immunomodulationwound healing cell development and so forth [73 74]Thereare many types of HDPs in all sorts of organisms [75]and HDP intraspecific sequence variability maintained bybalancing selection has been reported [76 77] In HDPs TSPhas been documented so far only in avian 120573-defensin AvBD12gene [78] 120573-defensins are amphipathic cationic cysteine-richpeptides [72] In humans intraspecific polymorphism in 120573-defensin genes affects susceptibility to pathogens such asHIV [79] In AvBD12 gene TSP was described in exon 3 intwo passerine species blue tits and great tits [78] Given thelimited sampling effort more widespread occurrence of TSPin HDPs cannot be excluded

44 TRIM5120572 TRIM5120572 (tripartite motif protein 5 120572-isoform) is the longest isoform of a viral restriction factorwhich interacts with viral capsid proteins in cytosol duringretrovirus infection and thus prevents reverse transcription[80 81] Similarly to MHC genes TRIM genes are highlypolymorphic and their evolution has been driven bygene loss pseudogenization duplication and punctuatedpositive selection [80 82] TRIM5120572 consists of C-terminalSPRYB302 domain RING domain and B-box2a andcoiled-coil (CC) TSP is documented among macaquesin the SPRYB302 domain and among biting midges(Ceratopogonidae) in the CC domain [82] The variability inSPRYB302 domain determinates restriction specificity [80]while the functional significance of the polymorphism in CCdomain still remains unresolved [80 82] In addition to theTSP in coding region of the gene TSP has also been detectedin intron 1 apparently maintained between humans andchimpanzees by balancing selection for 4ndash7 million years[83] This TSP may affect transcriptional activity of the gene

45 Oligoadenylate Synthetase Oligoadenylate synthetases(OASs) are interferon-inducible enzymes with pleiotropicfunctions involved in the organism protection against retro-viral infections [84] After activation by interferons the RNA-dependent 2101584051015840-OAS synthesizes 2101584051015840-oligoadenylates fromadenosine triphosphate which activates latent endoribonu-clease RNase L leading to degradation of dsRNA and inhibi-tion of viral replication [84] In mice the variability in gene


OAS1b has functional consequences on variation in resistanceagainst flavivirus infections for example to West Nile virus[85 86] Species of Palearctic mice share two deeply divergedallelic lineages of OAS1b predating the split of house mouse(Mus musculus) and servant mouse (M famulus) 28 millionyears ago Both groups of allelic lineages provide resistance toflavivirus infections however the lineage of ldquomajor resistanceallelesrdquo protects against a broader spectrum of flavivirusgenotypes compared to ldquominors resistance allelesrdquo [87] ThisTSP appears to involve only the C-terminal domain of OAS1bwhich is responsible for the enzyme tetramerization andprotein-protein binding [87] In contrast the OAS1 TSPknown in humans chimpanzees and gorillas concerns theN-terminal RNA-binding region [88]

5 Future Directions

TSP is a crucial evolutionary mechanism responsible forsharing adaptive genetic variation across taxa Althoughpresently most studies dealing with TSP have concentratedonly on the MHC loci (MHC I and MHC II and theirpeptide binding regions in particular) the few examplesdescribed in other immune genes suggest that TSP is a com-mon and general evolutionary phenomenon Indeed besidesimmune genes the TSP has been documented for examplein self-incompatibility loci preventing self-fertilization inAngiosperms [89ndash91] in mating loci in fungi [92ndash94] inABO blood system in primates [95ndash97] or in complementarysex determiner gene in Hymenoptera [98 99] Investigationof TSP predominantly in association withMHC thus appearsto be a historically given stereotype which might have sloweddown the rate of similar investigation in other families ofimmune genes It has been recently proposed for humans-chimpanzees that TSP is especially common in membraneglycoproteins [100] As shown in the present review TSPmaybe present in genes encoding effector molecules as well asimmune receptorsTheproducts of both gene types physicallyinteract with pathogen molecules and are therefore morelikely than others to evolve under balancing selection

Further research should clearly focus more intensivelyon investigation of TSP patterns in innate immune genesIt has been proposed recently that at least approximatelyhalf of the genetic variability for resistance to infection isattributable to non-MHC genes [101]We suggest that besidesantimicrobial peptides oligoadenylate synthetases or viralrestriction factors where the first evidence of TSP has beenreported further effort should be made to reveal TSP in pat-tern recognition receptors (PRRs) PRRs are innate immunityreceptors that recognize pathogen-associated molecular pat-terns (PAMPs) that serve as danger signals [102] Consideringthe direct physical association between PRRs and PAMPsin triggering the immune response [103] in concordancewith the Red Queen hypothesis we may predict strong evolu-tionary pressures maintaining balanced frequencies of PRRalleles There are many families of PRRs toll-like receptors(TLRs) C-type lectin receptor (CLRs) RIG-like receptors(RLSs retinoic acid-inducible gene-I-like receptors) NOD-like receptors (NLRs nucleotide-binding oligomerization

domain receptors) and others [102 104] Despite the factthat PRRs are evolutionary relatively conserved considerablenonsynonymous polymorphism with predicted functionalsignificance has been recently documented in the bindingsites of these receptors both on interspecific and intraspecificlevels [105ndash109] Recent comparison of human populationsalso revealed that balancing selection is the main forceshaping the evolution of many innate immunity genes [110]PRRs hence appear as suitable candidate genes for TSPinvestigation

Although commonly assessed in gene coding regionsTSP may also be maintained in other functionally importantparts of the genome such as for example the promoterregulatory sequences of individual genes It has been reportedin primates that TSP may preferentially involve transcriptionfactor binding sites regulating gene expression [100 111]Our knowledge on TSP in noncoding regions is currentlyinsufficient and further research is needed to show howwidespread this type of TSP is

When studying patterns of polymorphism on inter-specific level some caution is also needed before TSP isassigned and reported Several evolutionary mechanismsother than balanced TSP were also proposed to explainthe existence of shared polymorphism in several relatedtaxa These are namely (1) incomplete lineage sorting bychance (sometimes described as neutral or transient TSP asdescribed in the introduction) (2) convergent evolution and(3) genetic introgression Distinguishing these mechanismsfrom TSP is one of the greatest challenges in the presentTSP research [112 113] (see also Figure 1) In contrast tobalanced TSP and incomplete lineage sorting by chance(which is a state expected mainly in newly diverged species)convergent evolution is a process whereby organisms (relatedor not) independently evolve similar traits as a result ofadaptation to similar environments or ecological niches [2032] Although presumably common in immune genes [3251 114] convergence has been shown difficult to detectConvergent evolution usually operates in short functionallyimportant motifs and may be therefore distinguished fromTSP by specific coding resemblance only in these key regions[32] Comparison of phylogenetic trees constructed based onregions with a distinct function (eg peptide-binding regionPBR sequence and non-PBR sequence ofMHC)may be usedto differentiate between TSP and convergence [26 51 114]Also the third mechanism that may be mistaken with TSPthat is hybridization with subsequent adaptive introgressionmay be far more common than generally assumed [112]Introgression occurs mainly in evolutionary young radiatedor closely related species with incomplete reproductive iso-lation mechanisms which further complicates its differen-tiation from TSP Mixing alleles of the both trans-specificand hybrid origin (that are barely distinguishable) have beenreported in adaptive radiated species in Darwin finches[115 116] or cichlid fish of Haplochromis species flock of EastAfrican lakes [23] Furthermore hybridization can also occurin relatively diverged taxa Almost one-tenth of bird speciesmay hybridize [117] There is still lack of evidence to showhow common is the hybridization-linked adaptive introgres-sion in immune genes (but see eg [14 112 113 118ndash120])


One of the possible ways to distinguish between adaptiveintrogression and TSP is to compare the relative size ofthe haplotype blocks of the shared polymorphism In caseof TSP we expect these blocks to be smaller than in caseof the gene introgression [113 118 119] Combining largedata sets with novel genomic approaches such as the highlydense SNP chips or next-generation sequencing may beuseful in doing so Not only basic evolutionary research butalso human and veterinary medical research may benefitfrom precise identification of TSP In addition to the clearpotential of TSP to identify functionally important variationin human and animal genomes (that may be associatedwith disease susceptibility or resistance) TSP alleles mayalso be linked to deleterious mutations accumulated in theneighbourhood of the sites maintained by the balancingselection [121] Identification of beneficial and deleteriousvariability in genomes is essential precondition allowingcomplex personalised medicine in the future

6 Conclusion

Taken all together despite its importance and general applica-bility in recent research the TSP concept is being commonlyassociated only with MHC trans-specific genetic variationThis research stereotype is unfortunate since lacking evi-dence on TSP in other types of immune genes precludesour understanding of the mechanisms shaping the presentgenetic variability maintained by host-pathogen coevolutionBesides focusing on TSP in innate immunity genes (andmainly PRRs) more effort should also bemade to distinguishtrue TSP from TSP-like patterns Although originally aquestion of an academic interest TSP investigationmay bringpractically relevant results Identification of TSP variants isa powerful approach to identification of naturally occurringresistance alleles with application potential in human andveterinary medicine animal breeding and nature conserva-tion Recent advance of genomics in immunology allows ussystematic research of TSP in all sorts of immune genes andperceiving the TSP concept as a MHC-linked mechanismwould jeopardise the interpretational potential of the currentimmunogenetic research

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors are grateful to Lenka Kubıckova and KarelKodejs and three anonymous reviewers for their helpfulcomments on the paper andDagmar Vinklerova for languagecorrections This study was supported by the Czech ScienceFoundation (Grant no P50615-11782S) by the Grant Agencyof the Charles University (Grant no 540214) and through theInstitutional Research Support (SVV-260 2082015)

References

[1] A J M de Craen D Posthuma E J Remarque A H J van denBiggelaar R G JWestendorp andD I Boomsma ldquoHeritabilityestimates of innate immunity an extended twin studyrdquo Genesand Immunity vol 6 no 2 pp 167ndash170 2005

[2] V Orru M Steri G Sole et al ldquoXGenetic variants regulatingimmune cell levels in health and diseaserdquo Cell vol 155 no 1pp X242ndashX256 2013

[3] G Sorci A P Moslashller and T Boulinier ldquoGenetics of host-parasite interactionsrdquo Trends in Ecology amp Evolution vol 12 no5 pp 196ndash200 1997

[4] G S Cooke and A V S Hill ldquoGenetics of susceptibility tohuman infectious diseaserdquo Nature Reviews Genetics vol 2 no12 pp 967ndash977 2001

[5] S Buhler and A Sanchez-Mazas ldquoHLA DNA sequence varia-tion among human populations molecular signatures of demo-graphic and selective eventsrdquo PLoS ONE vol 6 no 2 Article IDe14643 16 pages 2011

[6] P A Reche and E L Reinherz ldquoSequence variability analysisof human class I and class II MHC molecules functional andstructural correlates of amino acid polymorphismsrdquo Journal ofMolecular Biology vol 331 no 3 pp 623ndash641 2003

[7] A Sanchez-Mazas and D Meyer ldquoThe relevance of HLAsequencing in population genetics studiesrdquo Journal of Immunol-ogy Research vol 2014 Article ID 971818 12 pages 2014

[8] P Schmid-Hempel Evolutionary Parasitology The IntegratedStudy of Infections Immunology Ecology and Genetics OxfordUniversity Press New York NY USA 2011

[9] M E J Woolhouse J P Webster E Domingo B Charlesworthand B R Levin ldquoBiological and biomedical implications of theco-evolution of pathogens and their hostsrdquoNature Genetics vol32 no 4 pp 569ndash577 2002

[10] R C King W D Stansfield and P K Mulligan A Dictionaryof Genetics Oxford University Press Oxford UK 7th edition2006

[11] N Takahata ldquoA simple genealogical structure of stronglybalanced allelic lines and trans-species evolution of polymor-phismrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 87 no 7 pp 2419ndash2423 1990

[12] P W Hedrick ldquoPathogen resistance and genetic variation atMHC locirdquo Evolution vol 56 no 10 pp 1902ndash1908 2002

[13] F M Key J C Teixeira C de Filippo and A M AndresldquoAdvantageous diversity maintained by balancing selection inhumansrdquo Current Opinion in Genetics amp Development vol 29pp 45ndash51 2014

[14] S X Xu W H Ren S Z Li F W Wei K Y Zhou and GYang ldquoSequence polymorphism and evolution of three cetaceanMHC genesrdquo Journal of Molecular Evolution vol 69 no 3 pp260ndash275 2009

[15] H Kupfermann W E Mayer C OrsquohUigin D Klein andJ Klein ldquoShared polymorphism between gorilla and humanmajor histocompatibility complex DRB locirdquoHuman Immunol-ogy vol 34 no 4 pp 267ndash278 1992

[16] NOttingNGDeGrootGGMDoxiadis andR E BontropldquoExtensive Mhc-DQB variation in humans and non-humanprimate speciesrdquo Immunogenetics vol 54 no 4 pp 230ndash2392002

[17] Y Go Y Satta Y Kawamoto et al ldquoMhc-DRB genes evolutionin lemursrdquo Immunogenetics vol 54 no 6 pp 403ndash417 2002


[18] W E Mayer M Jonker D Klein P Ivanyi G van Seventerand J Klein ldquoNucleotide sequences of chimpanzee MHC classI alleles evidence for trans-species mode of evolutionrdquo TheEMBO Journal vol 7 no 9 pp 2765ndash2774 1988

[19] J Klein A Sato S Nagl and C OrsquoHuigın ldquoMolecular trans-species polymorphismrdquo Annual Review of Ecology and System-atics vol 29 pp 1ndash21 1998

[20] J Klein A Sato and N Nikolaidis ldquoMHC TSP and the originof species from immunogenetics to evolutionary geneticsrdquoAnnual Review of Genetics vol 41 pp 281ndash304 2007

[21] J Klein ldquoOrigin of major histocompatibility complex polymor-phism the trans-species hypothesisrdquo Human Immunology vol19 no 3 pp 155ndash162 1987

[22] S Nagl H Tichy W E Mayer N Takahata and J KleinldquoPersistence of neutral polymorphisms in Lake Victoria cichlidfishrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 95 no 24 pp 14238ndash14243 1998

[23] I E Samonte Y Satta A Sato H Tichy N Takahata andJ Klein ldquoGene flow between species of Lake Victoria hap-lochromine fishesrdquoMolecular Biology and Evolution vol 24 no9 pp 2069ndash2080 2007

[24] P L Kamath andW M Getz ldquoAdaptive molecular evolution ofthe Major Histocompatibility Complex genes DRA and DQAin the genus Equusrdquo BMC Evolutionary Biology vol 11 no 1article 128 2011

[25] A Aguilar and J C Garza ldquoPatterns of historical balancingselection on the salmonid major histocompatibility complexclass II 120573 generdquo Journal of Molecular Evolution vol 65 no 1pp 34ndash43 2007

[26] L Li X P Zhou and X L Chen ldquoCharacterization andevolution of MHC class II B genes in ardeid birdsrdquo Journal ofMolecular Evolution vol 72 no 5-6 pp 474ndash483 2011

[27] J Klein ldquoGeneration of diversity at MHC loci implications forT-cell receptor repertoiresrdquo in Immunology 80M Fougerau andJ Dausset Eds pp 239ndash253 Academic Press London UK1980

[28] B Arden and J Klein ldquoBiochemical comparison of majorhistocompatibility complexmolecules fromdifferent subspeciesof Mus musculus evidence for trans-specific evolution ofallelesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 79 no 7 pp 2342ndash2346 1982

[29] A L Hughes and M Yeager ldquoNatural selection at majorhistocompatibility complex loci of vertebratesrdquo Annual Reviewof Genetics vol 32 pp 415ndash435 1998

[30] K J M Jeffery and C R M Bangham ldquoDo infectious diseasesdrive MHC diversityrdquoMicrobes and Infection vol 2 no 11 pp1335ndash1341 2000

[31] M Milinski ldquoThe major histocompatibility complex sexualselection and mate choicerdquo Annual Review of Ecology Evolu-tion and Systematics vol 37 pp 159ndash186 2006

[32] M Yeager and A L Hughes ldquoEvolution of the mammalianMHC natural selection recombination and convergent evolu-tionrdquo Immunological Reviews vol 167 pp 45ndash58 1999

[33] D Meyer and G Thomson ldquoHow selection shapes variation ofthe humanmajor histocompatibility complex a reviewrdquo Annalsof Human Genetics vol 65 pp 1ndash26 2001

[34] L G Spurgin and D S Richardson ldquoHow pathogens drivegenetic diversity MHC mechanisms and misunderstandingsrdquoProceedings of the Royal Society B Biological Sciences vol 277no 1684 pp 979ndash988 2010

[35] K M Wegner M Kalbe H Schaschl and T B H ReuschldquoParasites and individual major histocompatibility complexdiversitymdashan optimal choicerdquo Microbes and Infection vol 6no 12 pp 1110ndash1116 2004

[36] S Sommer ldquoThe importance of immune gene variability(MHC) in evolutionary ecology and conservationrdquo Frontiers inZoology vol 2 article 16 2005

[37] S V Edwards and P W Hedrick ldquoEvolution and ecology ofMHC molecules from genomics to sexual selectionrdquo Trends inEcology amp Evolution vol 13 no 8 pp 305ndash311 1998

[38] J Neefjes M L M Jongsma P Paul and O Bakke ldquoTowardsa systems understanding of MHC class I and MHC class IIantigen presentationrdquo Nature Reviews Immunology vol 11 no12 pp 823ndash836 2011

[39] J Trowsdale ldquoThe MHC disease and selectionrdquo ImmunologyLetters vol 137 no 1-2 pp 1ndash8 2011

[40] H-J Wallny D Avila L G Hunt et al ldquoPeptide motifs ofthe single dominantly expressed class I molecule explain thestriking MHC-determined response to Rous sarcoma virus inchickensrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 103 no 5 pp 1434ndash1439 2006

[41] D J Penn andW K Potts ldquoThe evolution ofmating preferencesand major histocompatibility complex genesrdquo American Natu-ralist vol 153 no 2 pp 145ndash164 1999

[42] J M Vyas A G van der Veen and H L Ploegh ldquoThe knownunknowns of antigen processing and presentationrdquo NatureReviews Immunology vol 8 no 8 pp 607ndash618 2008

[43] L Bernatchez and C Landry ldquoMHC studies in nonmodelvertebrates what have we learned about natural selection in 15yearsrdquo Journal of Evolutionary Biology vol 16 no 3 pp 363ndash377 2003

[44] E Ottova A Simkova J-F Martin et al ldquoEvolution and trans-species polymorphism ofMHC class II120573 genes in cyprinid fishrdquoFish amp Shellfish Immunology vol 18 no 3 pp 199ndash222 2005

[45] D H Bos and B Waldman ldquoEvolution by recombination andtransspecies polymorphism in theMHC class I gene ofXenopuslaevisrdquo Molecular Biology and Evolution vol 23 no 1 pp 137ndash143 2006

[46] S Glaberman and A Caccone ldquoSpecies-specific evolution ofclass I MHC genes in iguanas (Order Squamata SubfamilyIguaninae)rdquo Immunogenetics vol 60 no 7 pp 371ndash382 2008

[47] K T Ballingall M S Rocchi D J McKeever and F WrightldquoTrans-species polymorphism and selection in the MHC classIIDRAgenes of domestic sheeprdquoPLoSONE vol 5 no 6 ArticleID e11402 2010

[48] E Janova J Matiasovic J Vahala R Vodicka E van Dykand P Horin ldquoPolymorphism and selection in the majorhistocompatibility complex DRA and DQA genes in the familyEquidaerdquo Immunogenetics vol 61 no 7 pp 513ndash527 2009

[49] H Piontkivska and M Nei ldquoBirth-and-death evolution in pri-mate MHC class I genes divergence time estimatesrdquoMolecularBiology and Evolution vol 20 no 4 pp 601ndash609 2003

[50] K Takahashi A P Rooney andMNei ldquoOrigins and divergencetimes of mammalian class II MHC gene clustersrdquo Journal ofHeredity vol 91 no 3 pp 198ndash204 2000

[51] K Kriener C OrsquohUigin and J Klein ldquoIndependent origin offunctional MHC class II genes in humans and New Worldmonkeysrdquo Human Immunology vol 62 no 1 pp 1ndash14 2001

[52] S Kundu and C G Faulkes ldquoA tangled history patterns ofmajor histocompatibility complex evolution in the Africanmole-rats (Family Bathyergidae)rdquo Biological Journal of theLinnean Society vol 91 no 3 pp 493ndash503 2007


[53] M Zhao Y Wang H Shen et al ldquoEvolution by selectionrecombination and gene duplication in MHC class I genes oftwo Rhacophoridae speciesrdquo BMC Evolutionary Biology vol 13no 1 article 113 2013

[54] W Jaratlerdsiri S R Isberg D P Higgins et al ldquoEvolution ofMHC class I in the order crocodyliardquo Immunogenetics vol 66no 1 pp 53ndash65 2014

[55] W Jaratlerdsiri S R Isberg D P Higgins L G Miles andJ Gongora ldquoSelection and trans-species polymorphism ofmajor histocompatibility complex class II genes in the ordercrocodyliardquo PLoS ONE vol 9 no 2 Article ID e87534 2014

[56] I Kiryu JMDijkstra R I Sarder A Fujiwara Y Yoshiura andM Ototake ldquoNew MHC class Ia domain lineages in rainbowtrout (Oncorhynchus mykiss) which are shared with other fishspeciesrdquo Fishamp Shellfish Immunology vol 18 no 3 pp 243ndash2542005

[57] D Wang L Zhong Q Wei X Gan and S He ldquoEvolution ofMHC class I genes in two ancient fish paddlefish (Polyodonspathula) and Chinese sturgeon (Acipenser sinensis)rdquo FEBSLetters vol 584 no 15 pp 3331ndash3339 2010

[58] W J Horing E Papagiannes S Dray and L S Rodkey ldquoExpres-sion of cross-reacting determinants of the immunoglobulinheavy chain variable region a3 allotype in Oryctolagus andLepusrdquoMolecular Immunology vol 17 no 1 pp 111ndash117 1980

[59] A Pinheiro D Lanning P C Alves et al ldquoMolecular basesof genetic diversity and evolution of the immunoglobulinheavy chain variable region (IGHV) gene locus in leporidsrdquoImmunogenetics vol 63 no 7 pp 397ndash408 2011

[60] C Su and M Nei ldquoFifty-million-year-old polymorphism atan immunoglobulin variable region gene locus in the rabbitevolutionary lineagerdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 17 pp 9710ndash9715 1999

[61] P J Esteves D Lanning N Ferrand K L Knight S K Zhaiand W Van Der Loo ldquoThe evolution of the immunoglobulinheavy chain variable region (IgV H) in Leporids an unusualcase of transspecies polymorphismrdquo Immunogenetics vol 57no 11 pp 874ndash882 2005

[62] K Sumiyama S Kawamura O Takenaka and S Ueda ldquoA highsequence variety in the immunoglobulin C-alpha hinge regionamong old world monkeysrdquo Anthropological Science vol 106no 1 pp 31ndash39 1998

[63] K Sumiyama N Saitou and S Ueda ldquoAdaptive evolution of theIgA hinge region in primatesrdquoMolecular Biology and Evolutionvol 19 no 7 pp 1093ndash1099 2002

[64] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[65] C J Male ldquoImmunoglobulin A1 protease production byHaemophilus influenzae and Streptococcus pneumoniaerdquo Infec-tion and Immunity vol 26 no 1 pp 254ndash261 1979

[66] H J FehlingW Swat C Laplace et al ldquoMHC class I expressionin mice lacking the proteasome subunit LMP-7rdquo Science vol265 no 5176 pp 1234ndash1237 1994

[67] K Tsukamoto F Miura N T Fujito G Yoshizaki and MNonaka ldquoLong-lived dichotomous lineages of the proteasomesubunit beta type 8 (PSMB8) gene surviving more than 500million years as alleles or paralogsrdquo Molecular Biology andEvolution vol 29 no 10 pp 3071ndash3079 2012

[68] F Miura K Tsukamoto R B Mehta K Naruse W Magtoonand M Nonaka ldquoTransspecies dimorphic allelic lineages of

the proteasome subunit 120573-type 8 gene (PSMB8) in the teleostgenus Oryziasrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 107 no 50 pp 21599ndash216042010

[69] M Nonaka C Yamada-Namikawa M F Flajnik and L DuPasquier ldquoTrans-species polymorphism of themajor histocom-patibility complex-encoded proteasome subunit LMP7 in anamphibian genus Xenopusrdquo Immunogenetics vol 51 no 3 pp186ndash192 2000

[70] M Noro and M Nonaka ldquoEvolution of dimorphisms of theproteasome subunit beta type 8 gene (PSMB8) in basal ray-finned fishrdquo Immunogenetics vol 66 no 5 pp 325ndash334 2014

[71] T Ganz ldquoDefensins antimicrobial peptides of innate immu-nityrdquo Nature Reviews Immunology vol 3 no 9 pp 710ndash7202003

[72] T Cuperus M Coorens A van Dijk and H P HaagsmanldquoAvian host defense peptidesrdquo Developmental and ComparativeImmunology vol 41 no 3 pp 352ndash369 2013

[73] S C Mansour O M Pena and R E Hancock ldquoHost defensepeptides front-line immunomodulatorsrdquo Trends in Immunol-ogy vol 35 no 9 pp 443ndash450 2014

[74] D M E Bowdish D J Davidson and R E W Hancock ldquoA re-evaluation of the role of host defence peptides in mammalianimmunityrdquo Current Protein amp Peptide Science vol 6 no 1 pp35ndash51 2005

[75] G S Wang X Li and Z Wang ldquoAPD2 the updated antimi-crobial peptide database and its application in peptide designrdquoNucleic Acids Research vol 37 no 1 pp D933ndashD937 2009

[76] J A Tennessen and M S Blouin ldquoBalancing selection at afrog antimicrobial peptide locus fluctuating immune effectorallelesrdquo Molecular Biology and Evolution vol 25 no 12 pp2669ndash2680 2008

[77] E J Hollox and J A L Armour ldquoDirectional and balancingselection in human beta-defensinsrdquo BMC Evolutionary Biologyvol 8 article 113 2008

[78] O Hellgren and B C Sheldon ldquoLocus-specific protocol fornine different innate immune genes (antimicrobial peptides 120573-defensins) across passerine bird species reveals within-speciescoding variation and a case of trans-species polymorphismsrdquoMolecular Ecology Resources vol 11 no 4 pp 686ndash692 2011

[79] L Braida M Boniotto A Pontillo P A Tovo A Amoroso andS Crovella ldquoA single-nucleotide polymorphism in the humanbeta-defensin 1 gene as associated with HIV-1 infection inItalian childrenrdquo AIDS vol 18 no 11 pp 1598ndash1600 2004

[80] W E Johnson and S L Sawyer ldquoMolecular evolution of theantiretroviral TRIM5 generdquo Immunogenetics vol 61 no 3 pp163ndash176 2009

[81] M Stremlau C M Owens M J Perron M Kiessling PAutissier and J Sodroski ldquoThe cytoplasmic body componentTRIM5alpha restricts HIV-1 infection in Old World monkeysrdquoNature vol 427 no 6977 pp 848ndash853 2004

[82] R M Newman L Hall M Connole et al ldquoBalancing selectionand the evolution of functional polymorphism in Old Worldmonkey TRIM5120572rdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 50 pp19134ndash19139 2006

[83] R Cagliani M Fumagalli M Biasin et al ldquoLong-term bal-ancing selectionmaintains trans-specific polymorphisms in thehuman TRIM5 generdquo Human Genetics vol 128 no 6 pp 577ndash588 2010


[84] A G Hovanessian and J Justesen ldquoThe human 21015840-51015840 oligoad-enylate synthetase family unique interferon-inducible enzymescatalyzing 21015840-51015840 instead of 31015840-51015840 phosphodiester bond forma-tionrdquo Biochimie vol 89 no 6-7 pp 779ndash788 2007

[85] T Mashimo M Lucas D Simon-Chazottes et al ldquoA non-sense mutation in the gene encoding 21015840-51015840-oligoadenylate syn-thetaseL1 isoform is associated with West Nile virus suscepti-bility in laboratory micerdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 17 pp11311ndash11316 2002

[86] A A Perelygin S V Scherbik I B Zhulin B M StockmanY Li and M A Brinton ldquoPositional cloning of the murineflavivirus resistance generdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 14 pp9322ndash9327 2002

[87] W Ferguson S Dvora J Gallo A Orth and S BoissinotldquoLong-termbalancing selection at theWestNile virus resistancegene Oas1b maintains transspecific polymorphisms in thehouse mouserdquo Molecular Biology and Evolution vol 25 no 8pp 1609ndash1618 2008

[88] W Ferguson S Dvora RW Fikes A C Stone and S BoissinotldquoLong-term balancing selection at the antiviral gene OAS1 incentral African chimpanzeesrdquoMolecular Biology and Evolutionvol 29 no 4 pp 1093ndash1103 2012

[89] T R Ioerger A G Clark and T-H Kao ldquoPolymorphism at theself-incompatibility locus in Solanaceae predates speciationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 87 no 24 pp 9732ndash9735 1990

[90] A D Richman M K Uyenoyama and J R Kohn ldquoAllelicdiversity and gene genealogy at the self-incompatibility locus inthe solanaceaerdquo Science vol 273 no 5279 pp 1212ndash1216 1996

[91] K G Dwyer M A Balent J B Nasrallah and M E NasrallahldquoDNA sequences of self-incompatibility genes from Brassicacampestris and B oleracea polymorphism predating specia-tionrdquo Plant Molecular Biology vol 16 no 3 pp 481ndash486 1991

[92] L Lukens H Yicun and G May ldquoCorrelation of genetic andphysical maps at the Amating-type locus of Coprinus cinereusrdquoGenetics vol 144 no 4 pp 1471ndash1477 1996

[93] C A Muirhead N Louise Glass and M Slatkin ldquoMultilocusself-recognition systems in fungi as a cause of trans-speciespolymorphismrdquo Genetics vol 161 no 2 pp 633ndash641 2002

[94] L T A van Diepen A Olson K Ihrmark J Stenlid and TY James ldquoExtensive trans-specific polymorphism at the matingtype locus of the root decay fungus heterobasidionrdquo MolecularBiology and Evolution vol 30 no 10 pp 2286ndash2301 2013

[95] N Kermarrec F Roubinet P-A Apoil and A BlancherldquoComparison of allele O sequences of the human and non-human primate ABO systemrdquo Immunogenetics vol 49 no 6pp 517ndash526 1999

[96] J M Martinko V Vincek D Klein and J Klein ldquoPrimateABO glycosyltransferases evidence for trans-species evolu-tionrdquo Immunogenetics vol 37 no 4 pp 274ndash278 1993

[97] L Segurel E E Thompson T Flutre et al ldquoThe ABO bloodgroup is a trans-species polymorphism in primatesrdquoProceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 45 pp 18493ndash18498 2012

[98] S Lechner L Ferretti C Schoning W Kinuthia D Willem-sen and M Hasselmann ldquoNucleotide variability at its limitInsights into the number and evolutionary dynamics of thesex-determining specificities of the honey bee apis melliferardquoMolecular Biology and Evolution vol 31 no 2 pp 272ndash287 2014

[99] G E Heimpel and J G de Boer ldquoSex determination in thehymenopterardquo Annual Review of Entomology vol 53 pp 209ndash230 2008

[100] E M Leffler Z Gao S Pfeifer et al ldquoMultiple instancesof ancient balancing selection shared between humans andchimpanzeesrdquo Science vol 340 no 6127 pp 1578ndash1582 2013

[101] K Acevedo-Whitehouse and A A Cunningham ldquoIs MHCenough for understanding wildlife immunogeneticsrdquo Trends inEcology and Evolution vol 21 no 8 pp 433ndash438 2006

[102] T H Mogensen ldquoPathogen recognition and inflammatorysignaling in innate immune defensesrdquo Clinical MicrobiologyReviews vol 22 no 2 pp 240ndash273 2009

[103] M S Lee and Y J Kim ldquoSignaling pathways downstreamof pattern-recognition receptors and their cross talkrdquo AnnualReview of Biochemistry vol 76 pp 447ndash480 2007

[104] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[105] M Vinkler H Bainova and J Bryja ldquoProtein evolution of Toll-like receptors 4 5 and 7 within Galloanserae birdsrdquo GeneticsSelection Evolution vol 46 article 72 2014

[106] A Fornuskova J Bryja M Vinkler M Macholan and JPialek ldquoContrasting patterns of polymorphism and selectionin bacterial-sensing toll-like receptor 4 in two house mousesubspeciesrdquo Ecology and Evolution vol 4 no 14 pp 2931ndash29442014

[107] M Alcaide and S V Edwards ldquoMolecular evolution of the toll-like receptor multigene family in birdsrdquo Molecular Biology andEvolution vol 28 no 5 pp 1703ndash1715 2011

[108] B Ferwerda M B B McCall S Alonso et al ldquoTLR4 polymor-phisms infectious diseases and evolutionary pressure duringmigration of modern humansrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no42 pp 16645ndash16650 2007

[109] M Vinkler H Bainova A Bryjova O Tomasek T Albrechtand J Bryja ldquoCharacterisation of Toll-like receptors 4 5 and 7and their genetic variation in the grey partridgerdquo Genetica vol143 no 1 pp 101ndash112 2015

[110] A Ferrer-Admetlla E Bosch M Sikora et al ldquoBalancingselection is the main force shaping the evolution of innateimmunity genesrdquo Journal of Immunology vol 181 no 2 pp1315ndash1322 2008

[111] D A Loisel M V Rockman G A Wray J Altmann and S CAlberts ldquoAncient polymorphism and functional variation in theprimate MHC-DQA1 51015840 cis-regulatory regionrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 44 pp 16331ndash16336 2006

[112] PWHedrick ldquoAdaptive introgression in animals examples andcomparison to new mutation and standing variation as sourcesof adaptive variationrdquo Molecular Ecology vol 22 no 18 pp4606ndash4618 2013

[113] K M Wegner and C Eizaguirre ldquoNew(t)s and views fromhybridizingMHCgenes introgression rather than trans-speciespolymorphism may shape allelic repertoiresrdquo Molecular Ecol-ogy vol 21 no 4 pp 779ndash781 2012

[114] K Kriener C OrsquohUigin H Tichy and J Klein ldquoConvergentevolution of major histocompatibility complex molecules inhumans and NewWorld monkeysrdquo Immunogenetics vol 51 no3 pp 169ndash178 2000

[115] V Vincek C OrsquoHuigin Y Satta et al ldquoHow large was thefounding population of Darwinrsquos finchesrdquo Proceedings of theRoyal Society B Biological Sciences vol 264 no 1378 pp 111ndash118 1997


[116] A Sato H Tichy P R Grant B R Grant T Sato and COrsquoHuigin ldquoSpectrum of MHC class II variability in Darwinrsquosfinches and their close relativesrdquo Molecular Biology and Evolu-tion vol 28 no 6 pp 1943ndash1956 2011

[117] P R Grant and B R Grant ldquoHybridization of bird speciesrdquoScience vol 256 no 5054 pp 193ndash197 1992

[118] C Grossen L Keller I Biebach D Croll and InternationalGoat Genome Consortium ldquoIntrogression from domestic goatgenerated variation at the major histocompatibility complex ofalpine ibexrdquo PLoS Genetics vol 10 no 6 Article ID e10044382014

[119] K Nadachowska-Brzyska P Zielinski J Radwan andW BabikldquoInterspecific hybridization increases MHC class II diversity intwo sister species of newtsrdquoMolecular Ecology vol 21 no 4 pp887ndash906 2012

[120] A Simkova K Civanova L Gettova and A Gilles ldquoGenomicporosity between invasiveChondrostoma nasus and endangeredendemic Parachondrostoma toxostoma (Cyprinidae) the evolu-tion of MHC IIB genesrdquo PLoS ONE vol 8 no 6 Article IDe65883 2013

[121] C Van Oosterhout ldquoA new theory of MHC evolution beyondselection on the immune genesrdquo Proceedings of the Royal SocietyB Biological Sciences vol 276 no 1657 pp 657ndash665 2009

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Ancestral species

Species A

Speciation

Speciation

Species B Species C2 1 1

9984001 3 1

99840039984001 2

Figure 1 Mechanisms explaining polymorphism shared betweentaxa (based on [19 112]) The three proposed mechanisms aredepicted in allelesrsquo genealogy (1) trans-species polymorphism TSP(incomplete lineage sorting allelic lineages predate speciation andare passed to descendent species) (2) convergence (allelic lineagesevolve similar features independently in separate lineages) and(3) introgression (allelic lineages are horizontally transferred eitherfrom recipient species to donor species or in both directions)Each row depicts a gene pool of one generation each circlesquarean allele of specific features Different colours highlight individ-ual allelic lineages where interconnecting lines mark antecedent-descendent relationships Green and purple dashed arrows representdirections of introgression

genes for millions or even tens of millions of years [24ndash26] Identification of balanced TSP variants is therefore apowerful approach to identify naturally occurring resistancealleles with application potential in human medicine as wellas in animal breeding and nature conservation

TheTSP conceptwas proposed three decades ago byKlein[27] who supported its existence by comparative evidencein major histocompatibility complex (MHC H2 antigen) inmice [28] Until present MHC alleles from many mutuallyrelated species were sequenced and the TSP phenomenonwas reported in numbers of studies in all sorts of taxa (seeSupplement 1 in Supplementary Material available onlineat httpdxdoiorg1011552015838035) Surprisingly ourknowledge on TSP in other immune gene classes is onlylimited Is TSP unique to MHC or does it represent a generalevolutionary pattern masked by little endeavour paid toits investigation outside the MHC family In the presentreview we compile present evidence on TSP in human andanimal immune genes and outlinemain directions for furtherevolutionary immunogenetic research

2 Evolutionary Mechanisms MaintainingBalanced TSP in Immune Genes

Long-lasting TSP in immune genes is dependent on bal-ancing selection This type of selection maintains geneticvariation in populations for extensive periods of time based

on three possible mechanisms (1) heterozygote advantage[29 30] (2) negative frequency-dependent selection [3132] and (3) spatio-temporally fluctuating selection [33 34]Heterozygote advantage (also termed overdominance) ariseswhen individuals heterozygous in a particular gene are able toresist the pathogen infection better than both homozygotesIn this case polymorphism is maintained by selection for het-erozygosity Overdominance is well described forMHCgenesin a number of species where the benefits of heterozygosityin certain loci depend on the degree of overlap in bindingspecificity of individual alleles [30 35] Negative frequency-dependent selection in contrast represents a mechanismwhere only particular genotypes provide resistance advantagein a given time This advantage is nevertheless negativelylinked to the allele frequencies in a population [31] It has beenrepeatedly shown that pathogens tend to infect and adaptto the most common genotypes of the host in a populationleaving out rare genotypes [36] Rare alleles are thereforefavoured and increase in frequency until they reach a specificequilibrium beyond which they start to be selected againstFrequencies of the alleles thus oscillate in time and balancedpolymorphism ismaintained [12 30] Empiric supports comefrom associations of MHC alleles of susceptibility to diseases[30 35 36] Finally fluctuating selection is based on variationin selective pressures in space and time Most pathogens arepresent in a limited area of distribution and their abundancechange in time (spatio-temporal fluctuations) This createsdistinct and changing selective pressures on different hostpopulations that may be nonetheless linked by migration[33 34] In contrast to the negative frequency-dependentselection in fluctuating selection the fitness value changesas a function of particular pathogen abundance and notas a function of the allele frequency itself [33] Althoughthere is still serious lack in empirical evidence supportingthe existence of fluctuating selection theoretical approachessuggest that this mechanism is admissible for instance forthe maintenance of the MHC polymorphism [12] The threemechanisms of balancing selection are notmutually exclusiveand in all perceivable combinations all may be involved in themaintenance of the balanced TSP

3 TSP in Major HistocompatibilityGenes (MHC)

MHC groups several extremely polymorphic and dynami-cally evolving members of the immunoglobulin superfamilyplaying a crucial role in the adaptive immune defence againstpathogens in jawed vertebrates [29 37] MHC genes encodecytoplasm-membrane-bound glycoproteins which presentendogenous and exogenous oligopeptides to T cells [38]Although the strength of the association between MHCpolymorphism and resistance to infectious diseases variesbetween species and populations [39 40] the capability ofcertain alleles to bind certain pathogen-derived peptides isundoubtedly essential for individual survival [30] The typeof the selection responsible for the variability maintenancelinked to disease resistance may however not only be naturalselection but also sexual selection [31 41] since the twomech-anisms are not mutually exclusive and both can contribute to








IGVH 2C Alfa gene 2




1 1205722 1205723domains and 120573

2-microglobulin




1 1205722) and 120573 chains (120573

1 1205732)


1(exon 2) and 120573

1(exon 2)



0102030405060708090

Num

ber o

f ref

eren

ces

MH

C II

B

MH

C IIA

MH

C Ia

PSM

B8

MH

C Ib

IGV

H

C A

lfa g

ene

AvBD

12

OA

S1b

TRIM

5al

fa















5 Future Directions








6 Conclusion




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























IGVH 2C Alfa gene 2




1 1205722 1205723domains and 120573

2-microglobulin




1 1205722) and 120573 chains (120573

1 1205732)


1(exon 2) and 120573

1(exon 2)



0102030405060708090

Num

ber o

f ref

eren

ces

MH

C II

B

MH

C IIA

MH

C Ia

PSM

B8

MH

C Ib

IGV

H

C A

lfa g

ene

AvBD

12

OA

S1b

TRIM

5al

fa















5 Future Directions








6 Conclusion




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























5 Future Directions








6 Conclusion




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















6 Conclusion




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article trans-species polymorphism in immune...

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