The major histocompatibility complex (MHC) is a core part of the adaptive immune system. As in other vertebrate taxa, it may also affect human chemical communication via odour-based mate preferences, with greater attraction towards MHC-dissimilar partners. However, despite some well-known findings, the available evidence is equivocal and made complicated by varied approaches to quantifying human mate choice. To address this, we here conduct comprehensive meta-analyses focusing on studies assessing: (i) genomic mate selection, (ii) relationship satisfaction, (iii) odour preference, and (iv) all studies combined. Analysis of genomic studies reveals no association between MHC-dissimilarity and mate choice in actual couples; however, MHC effects appear to be independent of the genomic background. The effect of MHC-dissimilarity on relationship satisfaction was not significant, and we found evidence for publication bias in studies on this area. There was also no significant association between MHC-dissimilarity and odour preferences. Finally, combining effect sizes from all genomic, relationship satisfaction, odour preference and previous mate choice studies into an overall estimate showed no overall significant effect of MHC-similarity on human mate selection. Based on these findings, we make a set of recommendations for future studies, focusing both on aspects that should be implemented immediately and those that lurk on the far horizon. We need larger samples with greater geographical and cultural diversity that control for genome-wide similarity. We also need more focus on mechanisms of MHC-associated odour preferences and on MHC-associated pregnancy loss. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

Department of Animal Behaviour Bielefeld University Bielefeld 33615 Germany

Department of Zoology Faculty of Science Charles University Viničná 7 128 42 Prague 2 Czech Republic

Division of Psychology University of Stirling Stirling FK9 4LA UK

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Flajnik MF, Kasahara M. 2001. Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15, 351–362. (10.1016/s1074-7613(01)00198-4) PubMed DOI

Horton R, et al. 2004. Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889–899. (10.1038/nrg1489) PubMed DOI

Persson G, Melsted WN, Nilsson LL, Hviid TVF. 2017. HLA class Ib in pregnancy and pregnancy-related disorders. Immunogenetics 69, 581–595. (10.1007/s00251-017-0988-4) PubMed DOI

Klein J, Saito A. 2000. The HLA system. N. Engl. J. Med. 343, 702–709. (10.1056/NEJM200009073431006) PubMed DOI

Winternitz J, Abbate J. 2015. Examining the evidence for major histocompatibility complex-dependent mate selection in humans and nonhuman primates. Res. Rep. Biol. 6, 73–88. (10.2147/RRB.S58514) DOI

Sanchez-Mazas A, Mack SJ, Single RM, Tsai Y, Lancaster AK, Solberg OD, Thomson G. 2008. Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. Hum. Immunol. 69, 443–464. (10.1016/j.humimm.2008.05.001) PubMed DOI PMC

Prugnolle F, Manica A, Charpentier M, Guégan JF, Guernier V, Balloux F. 2005. Pathogen-driven selection and worldwide HLA class I diversity. Curr. Biol. 15, 1022–1027. (10.1016/j.cub.2005.04.050) PubMed DOI

Hill AV, et al. 1991. Common West African HLA antigens are associated with protection from severe malaria. Nature 352, 595– 600 (10.1038/352595a0) PubMed DOI

Trachtenberg E, et al. 2003. Advantage of rare HLA supertype in HIV disease progression. Nat. Med. 9, 928–935. (10.1038/nm893) PubMed DOI

Sveinbjornsson G, et al. 2016. HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat. Genet. 48, 318–322. (10.1038/ng.3498) PubMed DOI PMC

Krause-Kyora B, et al. 2018. Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans. Nat. Commun. 9, 1569 (10.1038/s41467-018-03857-x) PubMed DOI PMC

Fumagalli M, Sironi M, Pozzoli U, Ferrer-Admettla A, Pattini L, Nielsen R. 2011. Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution. PLoS Genet. 7, e1002355 (10.1371/journal.pgen.1002355) PubMed DOI PMC

Apanius V, Penn D, Slev PR, Ruff LR, Potts WK. 1997. The nature of selection on the major histocompatibility complex. Crit. Rev. Immunol. 37, 75–120. (10.1615/CritRevImmunol.v37.i2-6.10) PubMed DOI

Penn DJ, Damjanovich K, Potts WK. 2002. MHC heterozygosity confers a selective advantage against multiple-strain infections. Proc. Natl Acad. Sci. USA 99, 11 260–11 264. (10.1073/pnas.162006499) PubMed DOI PMC

Yamazaki K, Boyse EA, Miké V, Thaler HT, Mathieson BJ, Abbott J, Boyse J, Zayas ZA, Thomas L. 1976. Control of mating preferences in mice by genes in the major histocompatibility complex. J. Exp. Med. 144, 1324–1335. (10.1084/JEM.144.5.1324) PubMed DOI PMC

Bernatchez L, Landry C. 2003. MHC studies in nonmodel vertebrates: what have we learned about natural selection in 15 years? J. Evol. Biol. 16, 363–377. (10.1046/j.1420-9101.2003.00531.x) PubMed DOI

Kamiya T, O'Dwyer K, Westerdahl H, Senior A, Nakagawa S. 2014. A quantitative review of MHC-based mating preference: the role of diversity and dissimilarity. Mol. Ecol. 23, 5151–5163. (10.1111/mec.12934) PubMed DOI

Wedekind C, Seebeck T, Bettens F, Paepke AJ. 1995. MHC-dependent mate preference in humans. Proc. R. Soc. Lond. B 260, 245–249. (10.1098/rspb.1995.0087) PubMed DOI

Havlíček J, Roberts SC. 2009. MHC-correlated mate choice in humans: a review. Psychoneuroendocrinology 34, 497–512. (10.1016/j.psyneuen.2008.10.007) PubMed DOI

Winternitz J, Havlíček J, Garamszegi LZ, Huchard E, Abbate JL. 2017. Patterns of MHC-dependent mate selection in humans and nonhuman primates: a meta-analysis. Mol. Ecol. 26, 668–688. (10.1111/mec.13920) PubMed DOI

Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. 2006. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909. (10.1038/ng1847) PubMed DOI

Garver-Apgar CE, Gangestad SW, Thornhill R, Miller RD, Olp JJ. 2006. Major histocompatibility complex alleles, sexual responsivity, and unfaithfulness in romantic couples. Psychol. Sci. 17, 830–835. (10.1111/j.1467-9280.2006.01789.x) PubMed DOI

Zaidi AA, White JD, Mattern BC, Liebowitz CR, Puts DA, Claes P, Shriver MD. 2019. Facial masculinity does not appear to be a condition-dependent male ornament and does not reflect MHC heterozygosity in humans. Proc. Natl Acad. Sci. USA 116, 1633–1638. (10.1073/pnas.1808659116) PubMed DOI PMC

Khankhanian P, Gourraud P-A, Caillier SJ, Santaniello A, Hauser SL, Baranzini SE, Oksenberg JR. 2010. Genetic variation in the odorant receptors family 13 and the MHC loci influence mate selection in a multiple sclerosis dataset. BMC Genomics 11, 626 (10.1186/1471-2164-11-626) PubMed DOI PMC

Giphart MJ, D'Amaro J. 1983. HLA and reproduction? J. Immunogenet. 10, 25–29. (10.1111/j.1744-313X.1983.tb01013.x) PubMed DOI

Laurent R, Chaix R. 2012. MHC-dependent mate choice in humans: why genomic patterns from the HapMap European American dataset support the hypothesis. BioEssays 34, 267–271. (10.1002/bies.201100150) PubMed DOI

Nakagawa S, Cuthill IC. 2007. Effect size, confidence interval and statistical significance: a practical guide for biologists. Biol. Rev. 82, 591–605. (10.1111/j.1469-185X.2007.00027.x) PubMed DOI

Derti A, Cenik C, Kraft P, Roth FP. 2010. Absence of evidence for MHC-dependent mate selection within HapMap populations. PLoS Genet. 6, e1000925 (10.1371/journal.pgen.1000925) PubMed DOI PMC

Dandine-Roulland C, Laurent R, Dall'Ara I, Toupance B, Chaix R. 2019. Genomic evidence for MHC disassortative mating in humans. Proc. R. Soc. B 286, 20182664 (10.1098/rspb.2018.2664) PubMed DOI PMC

Viechtbauer W. 2015. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 1–48. (10.18637/jss.v036.i03) DOI

Cohen J. 1988 Statistical power analysis for the behavioral sciences, 2nd edn Hillsdale, NJ: L. Erlbaum.

Moller AP, Jennions MD, Møller A. 2002. How much variance can be explained by ecologists and evolutionary biologists? Oecologia 132, 492–500. (10.1007/s00442-002-0952-2) PubMed DOI

Egger M, Davey Smith G, Schneider M, Minder C. 1997. Bias in meta-analysis detected by a simple, graphical test. Brit. Med. J. 315, 629–634. (10.1136/bmj.315.7109.629) PubMed DOI PMC

Duval S, Tweedie R. 2000. A nonparametric ‘trim and fill’ method of accounting for publication bias in meta-analysis. J. Am. Stat. Assoc. 95, 89–98. (10.1080/01621459.2000.10473905) DOI

Duval S, Tweedie R. 2000. Trim and fill: a simple funnel-plot-based method. Biometrics 56, 455–463. (10.1111/j.0006-341X.2000.00455.x) PubMed DOI

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. 2003. Measuring inconsistency in meta-analyses. Brit. Med. J. 327, 557–560. (10.1136/bmj.327.7414.557) PubMed DOI PMC

R Core Team. 2015. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. See https://www.R-project.org/.

Wickham H. 2016. ggplot2: elegant graphics for data analysis. New York, NY: Springer.

Kassambara A. 2018. ggpubr: ‘ggplot2’ based publication ready plots. R package, version 0.2. See https://CRAN.R-project.org/package=ggpubr. PubMed

Henry L, Wickham H, Chang W. 2018. ggstance: horizontal ‘ggplot2’ components. R package, version 0.3.1 See https://CRAN.R-project.org/package=ggstance.

Sun C.2016. erer: empirical research in economics with R. R package, version 2.5. See https://CRAN.R-project.org/package=erer .

Wickham H. 2019. stringr: simple, consistent wrappers for common string operations. R package, version 1.4.0. See https://CRAN.R-project.org/package=stringr.

Becker RA, Wilks A, Brownrigg R, Minka T, Deckmyn A. 2018. maps: draw geographical maps. R package, version 3.3.0. See https://CRAN.R-project.org/package=maps.

Bivand R, Keitt T, Rowlingson B. 2019. rgdal: bindings for the ‘geospatial’ data abstraction library. R package, version 1.4-3. See https://CRAN.R-project.org/package=rgdal.

Mersmann O, Trautmann H, Steuer D, Bornkamp B. 2018. truncnorm: truncated normal distribution. R package, version 1.0-8. See https://CRAN.R-project.org/package=truncnorm.

Ram K, Wickham H. 2018. wesanderson: a Wes Anderson palette generator. R package, version 0.3.6. See https://CRAN.R-project.org/package=wesanderson.

Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. 2007. Performance of the trim and fill method in the presence of publication bias and between-study heterogenity. Stat. Med. 26, 4544–4562. (10.1002/sim.2889) PubMed DOI

Qiao Z, Powell JE, Evans DM. 2018. MHC-dependent mate selection within 872 spousal pairs of European ancestry from the Health and Retirement Study. Genes (Basel) 9, 53. (10.3390/genes9010053) PubMed DOI PMC

Nordlander C, Hammarström L, Lindblom B, Smith CI. 1983. No role of HLA in mate selection. Immunogenetics 18, 429–431. (10.1007/BF00372474) PubMed DOI

Rosenberg LT, Cooperman D, Payne R. 1983. HLA and mate selection. Immunogenetics 17, 89–93. (10.1007/BF00364292) PubMed DOI

Israeli M, Kristt D, Nardi Y, Klein T. 2014. Genetic considerations in human sex-mate selection: partners share human leukocyte antigen but not short-tandem-repeat identity markers. Am. J. Reprod. Immunol. 71, 467–471. (10.1111/aji.12213) PubMed DOI

Bittles AH, Black ML. 2010. Consanguinity, human evolution, and complex diseases. Proc. Natl Acad. Sci. USA 107, 1779–1786. (10.1073/pnas.0906079106) PubMed DOI PMC

Elhaik E, et al. 2014. Geographic population structure analysis of worldwide human populations infers their biogeographical origins. Nat. Commun. 5, 1–13. (10.1038/ncomms4513) PubMed DOI PMC

Roberts SC, Gosling LM. 2003. Genetic similarity and quality interact in mate choice decisions by female mice. Nat. Genet. 35, 103–106. (10.1038/ng1231) PubMed DOI

Reichard M, Spence R, Bryjová A, Bryja J, Smith C. 2012. Female rose bitterling prefer MHC-dissimilar males: experimental evidence. PLoS ONE 7, e40780 (10.1371/journal.pone.0040780) PubMed DOI PMC

Olsson M, Madsen T, Nordby J, Wapstra E, Ujvari B, Wittsell H. 2003. Major histocompatibility complex and mate choice in sand lizards. Proc. R. Soc. Lond. B 270, 254–256. (10.1098/rsbl.2003.0079) PubMed DOI PMC

Hellenthal G, Falush D, Myers S, Busby GBJ, Band G, Wilson JF, Capelli C. 2014. A genetic atlas of human admixture history. Science 747, 747–751. (10.1126/science.1243518) PubMed DOI PMC

Hedrick PW, Black FL. 1997. HLA and mate selection: no evidence in South Amerindians. Am. J. Hum. Genet. 61, 505–511. (10.1086/515519) PubMed DOI PMC

Štěrbová Z, Valentová JV. 2012. Influence of homogamy, complementarity, and sexual imprinting on mate choice. Anthropologie L/1, 47–59.

Barrai I, Scapoli C, Beretta M, Nesti C, Mamolini E. 1996. Isonymy and the genetic structure of Switzerland. I. The distributions of surnames. Ann. Hum. Biol. 23, 431–455. (10.1080/03014469600004672) PubMed DOI

Milinski M, Wedekind C. 2001. Evidence for MHC-correlated perfume preferences in humans. Behav. Ecol. 12, 140–149. (10.1093/beheco/12.2.140) DOI

Hämmerli A, Schweisgut C, Kaegi M, Kacgi M. 2012. Population genetic segmentation of MHC-correlated perfume preferences. Int. J. Cosmet. Sci. 34, 161–168. (10.1111/j.1468-2494.2011.00696.x) PubMed DOI

Lenochová P, Vohnoutová P, Roberts SC, Oberzaucher E, Grammer K, Havlíček J. 2012. Psychology of fragrance use: perception of individual odor and perfume blends reveals a mechanism for idiosyncratic fragrance choice. PLoS ONE 7, e33810 (10.1371/journal.pone.0033810) PubMed DOI PMC

Fletcher GJO, Simpson JA, Thomas G, Giles L. 1999. Ideals in intimate relationships. J. Pers. Soc. Psychol. 76, 72 (10.1037/0022-3514.76.1.72) PubMed DOI

Csajbók Z, Berkics M. 2017. Factor, factor, on the whole, who's the best fitting of all?: factors of mate preferences in a large sample. Pers. Individ. Dif. 114, 92–102. (10.1016/j.paid.2017.03.044) DOI

Zietsch BP, Verweij KJH, Heath AC, Martin NG. 2011. Variation in human mate choice: simultaneously investigating heritability, parental influence, sexual imprinting, and assortative mating. Am. Nat. 177, 605–616. (10.1086/659629) PubMed DOI PMC

Kromer J, Hummel T, Pietrowski D, Giani AS, Sauter J, Ehninger G, Schmidt AH, Croy I. 2016. Influence of HLA on human partnership and sexual satisfaction. Sci. Rep. 6, 6–11. (10.1038/srep32550) PubMed DOI PMC

Saphire-Bernstein S, Larson CM, Gildersleeve KA, Fales MR, Pillsworth EG, Haselton MG. 2017. Genetic compatibility in long-term intimate relationships: partner similarity at major histocompatibility complex (MHC) genes may reduce in-pair attraction. Evol. Hum. Behav. 38, 190–196. (10.1016/j.evolhumbehav.2016.09.003) DOI

Roberts SC, Klapilová K, Little AC, Burriss RP, Jones BC, DeBruine LM, Petrie M, Havlíček J. 2012. Relationship satisfaction and outcome in women who meet their partner while using oral contraception. Proc. R. Soc. B 279, 1430–1436. (10.1098/rspb.2011.1647) PubMed DOI PMC

Roberts SC, Little AC, Burriss RP, Cobey KD, Klapilová K, Havlíček J, Jones BC, DeBruine L, Petrie M. 2014. Partner choice, relationship satisfaction, and oral contraception: the congruency hypothesis. Psychol. Sci. 25, 1497–1503. (10.1177/0956797614532295) PubMed DOI

Leinders-Zufall T, et al. 2004. MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306, 1033–1037. (10.1126/science.1102818) PubMed DOI

Spehr M, Kelliher KR, Li XH, Boehm T, Leinders-Zufall T, Zufall F. 2006. Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J. Neurosci. 26, 1961–1970. (10.1523/JNEUROSCI.4939-05.2006) PubMed DOI PMC

Sturm T, Leinders-zufall T, Mac B, Zufall F, Overath P, Rammensee H. 2013. Mouse urinary peptides provide a molecular basis for genotype discrimination by nasal sensory neurons. Nat. Commun. 4, 1616 (10.1038/ncomms2610) PubMed DOI

Milinski M, Griffiths S, Wegner KM, Reusch TBH, Haas-Assenbaum A, Boehm T. 2005. Mate choice decisions of stickleback females predictably modified by MHC peptide ligands. Proc. Natl Acad. Sci. USA 102, 4414–4418. (10.1073/pnas.0408264102) PubMed DOI PMC

Milinski M, Croy I, Hummel T, Boehm T. 2013. Major histocompatibility complex peptide ligands as olfactory cues in human body odour assessment. Proc. R. Soc. B 280, 20122889 (10.1098/rspb.2012.2889) PubMed DOI PMC

Natsch A, Emter R. 2020. The specific biochemistry of human axilla odour formation viewed in an evolutionary context. Phil. Trans. R. Soc. B 375, 20190269 (10.1098/rstb.2019.0269) PubMed DOI PMC

Natsch A. 2013. A human chemosensory modality to detect peptides in the nose? Proc. R Soc. B 280, 20131678 (10.1098/rspb.2013.1678) PubMed DOI PMC

Thomas ML, Harger JH, Wagener DE, Rabin BS, Gill TJ. 1985. HLA sharing and spontaneous abortion in humans. Am. J. Obstet. Gynecol. 151, 1053–1058. (10.1016/0002-9378(85)90379-5) PubMed DOI

Ober C. 1999. Studies of HLA, fertility and mate choice in a human isolate. Hum. Reprod. Update 5, 103–107. (10.1093/humupd/5.2.103) PubMed DOI

Kishore R, Agarwal S, Halder A, Das V, Shukla BRK, Agarwal S. 1996. HLA sharing, anti-paternal cytotoxic antibodies and MLR blocking factors in women with recurrent spontaneous abortion. J. Obstet. Gynaecol. Res. 22, 177–183. (10.1111/j.1447-0756.1996.tb00962.x) PubMed DOI

Meuleman T, Lashley LELO, Dekkers OM, Van Lith JMM, Claas FHJ, Bloemenkamp KWM. 2015. HLA associations and HLA sharing in recurrent miscarriage: a systematic review and meta-analysis. Hum. Immunol. 76, 362–373. (10.1016/j.humimm.2015.02.004) PubMed DOI

Rull K, Nagirnaja L, Laan M. 2012. Genetics of recurrent miscarriage: challenges, current knowledge, future directions. Front. Genet. 3, 1–13. (10.3389/fgene.2012.00034) PubMed DOI PMC

Meuleman T, Haasnoot GW, Van Lith JMM, Bloemenkamp VKWM, Claas FHJ. 2018. Paternal HLA-C is a risk factor in unexplained recurrent miscarriage. Am. J. Reprod. Immunol. 79, e12797 (10.1111/aji.12797) PubMed DOI

Tripathi P, Naik S, Agrawal S. 2006. HLA-E and immunobiology of pregnancy. Tissue Antigens 67, 207–213. (10.1111/j.1399-0039.2005.00550.x) PubMed DOI

Kanai T, et al. 2001. Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without. Am. J. Reprod. Immunol. 45, 168–173. (10.1111/j.8755-8920.2001.450308.x) PubMed DOI

Pfeiffer KA, Fimmers R, Engels G, Van Der Ven H, Van Der Ven K. 2001. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol. Hum. Reprod. 7, 373–378. (10.1093/molehr/7.4.373) PubMed DOI

Hviid TV, Hylenius S, Hoegh AM, Kruse C, Christiansen OB. 2002. HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens 60, 122–132. (10.1034/j.1399-0039.2002.600202.x) PubMed DOI

Fan W, Li S, Huang Z, Chen Q. 2014. Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: a meta-analysis of non-family-based studies. J. Assist. Reprod. Genet. 31, 173–184. (10.1007/s10815-013-0155-2) PubMed DOI PMC

Jurisicova A, Casper RF, Maclusky NJ, Millst GB, Librach CL. 1996. HLA-G expression during preimplantation human embryo development. Proc. Natl Acad. Sci. USA 93, 161–165. (10.1073/pnas.93.1.161) PubMed DOI PMC

Wang Q, Zhuang G, Zhou C, Li T, Li J, Xu Y, Gu X, Li Y. 2009. Expression of certain HLA-I types in cleavage-stage embryos. Reprod. Biomed. Online 18, 244–250. (10.1016/S1472-6483(10)60262-3) PubMed DOI

Wyatt TD. 2020. Reproducible research into human chemical communication by cues and pheromones: learning from psychology's renaissance. Phil. Trans. R Soc. B 375, 20190262 (10.1098/rstb.2019.0262) PubMed DOI PMC

Ferdenzi C, Richard Ortegón S, Delplanque S, Baldovini N, Bensafi M. 2020. Interdisciplinary challenges for elucidating human olfactory attractiveness. Phil. Trans. R. Soc. B 375, 20190268 (10.1098/rstb.2019.0268) PubMed DOI PMC

Penn D, Potts W. 1998. MHC-disassortative mating preferences reversed by cross-fostering. Proc. R. Soc. Lond. B 265, 1299–1306. (10.1098/rspb.1998.0433) PubMed DOI PMC

Henrich J, Heine SJ, Norenzayan A. 2010. Most people are not WEIRD. Nature 466, 29 (10.1038/466029a) PubMed DOI

Dwan K, Gamble C, Williamson PR, Kirkham JJ. 2013. Systematic review of the empirical evidence of study publication bias and outcome reporting bias—an updated review. PLoS ONE 8, e66844 (10.1371/journal.pone.0066844) PubMed DOI PMC

Testing effects of partner support and use of oral contraception during relationship formation on severity of nausea and vomiting in pregnancy

Marriage does not relate to major histocompatibility complex: a genetic analysis based on 3691 couples

Human olfactory communication: current challenges and future prospects

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