Van Oosterhout, C

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van Oosterhout, Cock

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, 20122501, published online 8 January 2013280 2013 Proc. R. Soc. B Cock van Oosterhout selfing vertebrate is no evidence for overdominant selectionMaintenance of major histocompatibility supertype variation in  Referenceshttp://rspb.royalsocietypublishing.org/content/280/1754/20122501.full.html#related-urls Article cited in: http://rspb.royalsocietypublishing.org/content/280/1754/20122501.full.html#ref-list-1 This article cites 10 articles, 4 of which can be accessed freeSubject collections (49 articles)genetics    (1371 articles)evolution    Articles on similar topics can be found in the following collectionsEmail alerting service hereright-hand corner of the article or click Receive free email alerts when new articles cite this article - sign up in the box at the top http://rspb.royalsocietypublishing.org/subscriptions go to: Proc. R. Soc. BTo subscribe to  on January 10, 2013rspb.royalsocietypublishing.orgDownloaded from  on January 10, 2013rspb.royalsocietypublishing.orgDownloaded from rspb.royalsocietypublishing.orgCommentCite this article: van Oosterhout C. 2013Maintenance of major histocompatibilitysupertype variation in selfing vertebrate is noevidence for overdominant selection. Proc RSoc B 280: 20122501.http://dx.doi.org/10.1098/rspb.2012.2501Received: 19 October 2012Accepted: 13 November 2012Author for correspondence:Cock van Oosterhoute-mail: c.van-oosterhout@uea.ac.ukThe accompanying reply can be viewed athttp://dx.doi.org/10.1098/rspb.2012.2854.& 2013 The Author(s) Published by the Royal Society. All rights reserved.Maintenance of major histocompatibilitysupertype variation in selfing vertebrate isno evidence for overdominant selectionCock van OosterhoutSchool of Environmental Science, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UKA principal challenge in evolutionary studies is that the evolutionary forces (i.e.mutation, recombination, gene flow, drift and selection) are rarely observeddirectly, but that they must be inferred from their effects on fitness, phenotype,behaviour, demography or genetic variation. Evolutionary biology thereforerelies heavily on deductive logic, whereby premises are linked with con-clusions. For example, one premise is that high parasite biodiversity willselect for a genetically diverse immune system. Observing a positive correlationbetween parasite diversity and immunogenetic variation does not, however,imply causality, as there may be additional processes (e.g. population sizeand migration) that affect both of these variables. For instance, among primates,parasite species richness is lowest among the threatened species [1], and giventhat small population size and isolation will affect both genetic variation andparasite biodiversity, a spurious correlation may exist between both variables.For that reason, many population genetic studies on immune genes employneutral genetic markers to account for the effects of population demography.Ellison et al. [2] studied both microsatellite loci and major histocompatibility(MHC) immune genes, analysing how inbreeding affects the variation at bothtypes of loci in the self-fertilizing fish, Kryptolebias marmoratus. In addition,they studied how pathogen resistance is affected by genetic variation, analysingthe relative contribution of both microsatellite and MHC variation on para-site loads in natural and laboratory populations with different degrees ofinbreeding. This is a strong experimental design, because measuring the lossin microsatellite variation over successive generations of selfing quantifiesthe effect of random genetic drift, and parasite load is directly linked to anindividual’s genotype.Ellison et al. [2] found that both MHC and neutral variation were lost afterseveral generations of selfing, an observation that is consistent with the effectsof drift. However, MHC alleles were not lost at random, and, intriguingly,the most divergent alleles appeared to be maintained. In their analysis, theygroup alleles into MHC supertypes, which are defined based on the moleculebinding properties of the positively selected sites. This is considered to be agood approximation of the functional differences [3], and given that thelocus affiliation of MHC sequences was not known, this approach makes bio-logical sense without losing too much information. The authors suggest thatthe maintenance of several divergent functional MHC supertypes in individ-uals with low microsatellite heterozygosity is indicative of overdominantselection. Given that individuals with a higher MHC diversity showed alower parasite load, the authors hypothesize that overdominant selectioncould play a role in the maintenance of functional MHC diversity inK. marmoratus.However, there is an alternative explanation for the maintenance of highlydivergent MHC alleles that does not involve overdominant selection. The MHCis a multi-gene family often consisting of several duplicated class I and class IIimmune genes. These genes are generally highly polymorphic, and currentlythe paradigm is that (a combination of) parasite-mediated selection [4], pre-and post-copulatory sexual selection [5], and selection on the mutational loadaccumulated in the surrounding MHC region [6] are the selective forcesrspb.royalsocietypublishing.orgProcRSocB280:201225012 on January 10, 2013rspb.royalsocietypublishing.orgDownloaded from maintaining this MHC polymorphism. The conclusion, there-fore, that the MHC polymorphism of K. marmoratus expressedin the number of MHC supertypes is maintained by parasite-mediated overdominant selection seems to fit the currentparadigm. However, in this species, the authors observethat each fish possesses between 1 and 11 MHC alleles andbetween 1 and 8 supertypes. This suggests that some individ-uals have at least six MHC loci, which is consistent with aprevious study of this fish that suggested there are 13 MHCclass I loci [7]. Furthermore, Ellison et al. [2] report that nofish had more than two alleles of each supertype, whichimplies that alleles of distinct supertypes segregate at differ-ent loci. The evolutionary genetic implication of this is thateven when alleles become fixed, supertype diversity willnot be depleted because this variation is preserved acrossdifferent loci. This could explain why, even after more than10 generations of selfing, the average diversity of MHCsupertypes per individual in the laboratory lines was similarto that found in the natural K. marmoratus population.Inbreeding can erode the within-locus variation when analternative allele of the same supertype is lost. However,while inbred individuals possess fewer alleles, the remainingalleles are distinct from one another because they are fromdifferent supertypes. This explains why the observed meanamino acid difference is higher for (inbred) individualswith fewer MHC alleles (fig. 3 of [2]).Even in the absence of overdominant selection, individ-uals can continue to possess multiple MHC supertypes inthe form of a completely homozygous multi-locus genotype.This is what evidently happened in the R strain of Ellisonet al.’s [2] study, in which all fish possessed the same geno-type. The alternative explanation—that all selfing individualsare heterozygous for exactly the same alleles across all oftheir loci—simply defies the laws of probability. Anadditional problem with this explanation is that if all 13unlinked class I MHC loci had to be kept heterozygous byoverdominant selection, the segregation load would be sohigh that only one out of 8192 offspring (i.e. 12213) producedby selfing would have a fitness (or immunocompetence)equal to that of the parental fish.The presence of distinct MHC supertypes at different gen-etic loci would offer an important adaptive evolutionaryadvantage to a selfing species such as K. marmoratus, becausevital immunogenetic variation will be preserved even in theface of the most severe inbreeding. This significantly reducesthe costs of natural selection [8], and solves Haldane’sDilemma for selfing (and inbreeding-prone) species inwhich individuals rely on an immune system with multiplesupertypes. Species that have not adapted to inbreedingmay have the same allelic copy (or supertype) present at mul-tiple loci, such as the guppy, Poecilia reticulata, in whichindividuals carried up to five almost identical MHC class IIallele copies in their genome [9]. In such cases, inbreedingcould exacerbate the loss of allelic variation by fixing thesame copy across multiple loci, as was observed in the greaterprairie chicken, Tympanuchus cupido [10].From the valid premise that selfing K. marmoratus individ-uals have a genetically diverse immune system, one cannotlogically conclude that this is maintained by overdominantselection. Conversely, the argument presented here does notdiscount the possibility that some form of balancing selectionis operating on the MHC of these fish. In particular, balancingselection could act on haplotype variation and favour haplo-types with several diverse MHC supertypes. Indeed, this isconsistent with the negative correlation between parasiteload and the number of MHC supertypes. In other words, bal-ancing selection ismore likely to act on the variation across lociwithin haplotypes, rather than on the within-locus variation,which is prone to drift. So, while I disagree with Ellisonet al.’s [2] conclusion that the study supports the hypothesisof immune-related overdominance in K. marmoratus, I concurthat parasite-mediated balancing selection may play a role inthis system. However, such selection is more likely to act onthe variation present across rather than within MHC loci.References1. Altizer S, Nunn CL, Lindenfors P. 2007 Dothreatened hosts have fewer parasites? Acomparative study in primates. J. Anim. Ecol.76, 304–314. (doi:10.1111/j.1365-2656.2007.01214.x)2. Ellison A, Allainguillaume J, Girdwood S, Pachebat J,Peat KM, Wright P, Consuegra S. 2012 Maintainingfunctional major histocompatibility complexdiversity under inbreeding: the case of a selfingvertebrate. Proc. R. Soc. B 279, 5004–5013.(doi:10.1098/rspb.2012.1929)3. Naugler C, Liwski R. 2008 An evolutionary approachto major histocompatibility diversity based on allelesupertypes. Med. Hypotheses 70, 933–937.(doi:10.1016/j.mehy.2007.09.015)4. Spurgin LG, Richardson DS. 2010 How pathogensdrive genetic diversity: MHC, mechanisms andmisunderstandings. Proc. R. Soc. B 277, 979–988.(doi:10.1098/rspb.2009.2084)5. Edwards SV, Hedrick PW. 1998 Evolution andecology of MHC molecules: from genomics to sexualselection. Trends Ecol. Evol. 13, 305–311. (doi:10.1016/S0169-5347(98)01416-5)6. van Oosterhout C. 2009 A new theory of MHC evolution:beyond selection on the immune genes. Proc. R. Soc. B276, 657–665. (doi:10.1098/rspb.2008.1299)7. Sato A, Satta Y, Figueroa F, Mayer WE, Zaleska-Rutczynska Z, Toyosawa S, Travis J, Klein J. 2002Persistence of Mhc heterozygosity in homozygousclonal killifish, Rivulus marmoratus: implications forthe origin of hermaphroditism. Genetics 162,1791–1803.8. Haldane JBS. 1957 The cost of natural selection.J. Genet. 55, 511–524. (doi:10.1007/BF02984069)9. Llaurens V, McMullan M, van Oosterhout C. 2012Cryptic MHC polymorphism revealed but notexplained by selection on the class IIB peptide-binding region. Mol. Biol. Evol. 29, 1631–1644.(doi:10.1093/molbev/mss012)10. Eimes JA, Bollmer JL, Whittingham LA, Johnson JA,van Oosterhout C, Dunn PO. 2011 Rapid loss of MHCclass II variation in a bottlenecked population isexplained by drift and loss of copy numbervariation. J. Evol. Biol. 24, 1847–1856. (doi:10.1111/j.1420-9101.2011.02311.x)

Maintenance of major histocompatibility supertype variation in selfing vertebrate is no evidence for overdominant selection

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