Full Paper

Genes and Immunity (2002) 3, 263–269. doi:10.1038/sj.gene.6363862

Increased heterozygosity for MHC class II lineages in newborn males

This study was supported by the Leukaemia Research Appeal for Wales (UK).

M T Dorak1,4, T Lawson2, H K G Machulla3, K I Mills1 and A K Burnett1

  1. 1Department of Haematology, University of Wales College of Medicine, Cardiff CF14 4XN, UK
  2. 2Department of Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
  3. 3Interbranch HLA Laboratory, Martin Luther University Medical School, Halle-Wittenberg, Germany
  4. 4Present address: Department of Epidemiology and International Health, School of Public Health, University of Alabama at Birmingham, AL 35294–0022, USA

Correspondence: MT Dorak, MD, PhD, Department of Epidemiology and International Health, School of Public Health, University of Alabama at Birmingham, AL 35294–0022, USA. E-mail: dorak@openlink.org

Received 8 November 2001; Revised 14 January 2002; Accepted 1 February 2002.

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Abstract

In plants, fungi and marine invertebrates, there are genetic compatibility systems to ensure diversity in the offspring. The importance of genetic compatibility in gametic union and selective abortion in vertebrate animals has also been appreciated recently. There have been suggestions that the major histocompatibility complex (HLA in humans) may be a compatibility system in vertebrates. HLA class II haplotypes often contain a second expressed DRB locus which can be either DRB3, DRB4 or DRB5. These encode the supertypical specificities and mark the ancestral lineages. The members of each lineage have related DNA sequences at the main class II locus HLA-DRB1. We analysed 415 newborns at all expressed DRB loci by PCR analysis to seek evidence for sex-specific prenatal selection events. While there was no significant change in heterozygosity rates between males and females at DRB1, the proportion of males carrying two DRB1 specificities from different ancestral lineages was significantly increased (53.7% in males vs 39.3% in females, P=0.003). The genotypes consisting of phylogenetically most distinct ones, namely the DRB3 and DRB4 haplotypes, showed the most striking difference between sexes (P=0.007). These results suggested a more favourable outcome for male concepti heterozygous for supertypical haplotypes. Heterozygosity for most divergent haplotypical families ensures the highest degree of functional heterozygosity at the main HLA class II locus DRB1 while increasing the likelihood of heterozygosity also at other MHC loci. Our observations agree with the previously reported heterozygote excess in male newborn rats and mice. Correlations between MHC class II heterozygosity and advertised male quality in deer and pheasant as well as increased reproductive success in MHC class II heterozygous male macaques are examples of postnatal benefits of heterozygosity in males that may be behind the development of prenatal selection mechanisms. The MHC-mediated prenatal selection of males may also be one of the selective events suggested by the very high primary (male-to-female) sex ratio at fertilization reaching close to unity at birth in humans. These results provide an appealing working hypothesis for further studies in humans and other vertebrates.

Keywords:

MHC; HLA-DRB lineages; prenatal selection; homozygosity; gender effect

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Introduction

A number of taxa have mechanisms for inbreeding avoidance and to increase genetic diversity in the offspring. The best-known examples are the self-incompatibility system of plants, fungal mating types and histocompatibility systems of marine invertebrates.1,2,3,4,5,6 In vertebrate animals, no such system is known but there is some evidence that the major histocompatibility complex (MHC) may be acting as a genetic compatibility system.6,7,8,9,10,11 The MHC is primarily involved in immunological functions but it is also very rich in genes with non-immunological and unknown functions.12

One remarkable feature of the MHC genes is their extreme polymorphism. This is attributed to natural selection acting on these loci.9,13,14 In addition to the allelic polymorphism, in the human MHC class II region, there is also structural polymorphism. HLA class II haplotypes vary in the number of HLA-DRB loci they carry and form three major groups.15,16 Each group is marked by the presence of a second expressed HLA-DRB gene in addition to the HLA-DRB1 gene encoding the classical HLA-DR alleles (Figure1). The classical DRB1 allele and the second expressed DRB locus, DRB3, DRB4 or DRB5, are in tight linkage disequilibrium so that the DRB1 and DRB3/4/5 haplotypes are stable without recombinants. The three haplotypical groups also correspond to the main evolutionary lineages.17,18 The second DRB gene in each one of the three lineages encodes what is conventionally called an HLA class II supertype: HLA-DR52, -DR53, or -DR51 encoded by the DRB3, DRB4, or DRB5 genes, respectively. The remaining haplotypes DRB1*01, *08 and *10 constitute a small fraction.16

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Expressed HLA-DRB gene content of HLA class II haplotypes. The second DRB gene determines the ancestral lineage.

Full figure and legend (31K)

The form of selection acting on MHC loci has been shown to be balancing selection.9,19,20,21,22,23 One type of balancing selection in heterozygote advantage in which homozygotes are negatively selected whereas heterozygotes are favoured because of the advantage conferred by heterozygosity. Data have recently emerged on postnatal selection of MHC alleles in the form of heterozygote advantage even in single infectious diseases.24,25,26 Direct demonstration of prenatal, non-pathogen-based selection in outbred populations is still lacking. The available data on prenatal selection of homozygotes for MHC alleles are restricted to isolated populations and examination of parental MHC sharing. Finding evidence in favour of selection against homozygotes in outbred populations has proven difficult because of the great degree of polymorphism of MHC alleles and relatively modest selection coefficients.9,19,22

Despite a large number of studies on classical HLA loci A, B, C and DR in reproductive failure and homozygous deficiency, no study examined the ancestral lineages. In the light of our continuing observations on the relevance of one of these lineages in male-specific susceptibility to childhood leukaemia27,28 and the epidemiological association between childhood leukaemia and foetal loss,29,30 we analysed the HLA-DRB1/3/4/5 genotypes in newborns to examine the hypothesis regarding the male-specificity of MHC-mediated prenatal selection.

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Results

Allele frequencies

The allele frequencies for all expressed HLA-DRB loci are presented in Table 1. There was no significant difference between male- and female-specific frequencies for any allele. To confirm the assumption that both males and females have come from the same population, the genetic identity between them was quantitated using DRB1 and ancestral lineage genotypes. For both, Nei’s unbiased genetic identity estimates were above 99%, reiterating the lack of a significant difference in the allele frequencies between male and female newborns.


Genotype frequencies

The overall homozygosity rates for HLA-DRB1 alleles and the sum of homozygosity for supertypical loci are presented in Table2. Overall homozygosity in the whole group was not different from the expected value. When overall homozygosity at the HLA-DRB1 locus was compared between the sexes, males had non-significantly lower homozygosity compared to females (11.44% vs 12.62%).


The HLA class II supertypical homozygosity rates were, however, lower in newborn boys compared to girls (P=0.03). Consequently, the overall heterozygosity for supertypical haplotypes (ie, DRB3/DRB4, DRB3/DRB5, DRB4/DRB5) was increased in boys (53.73% vs 39.25%, P=0.003, 95% CI for the difference: 4.9 to 24.1%). As shown in Table3, there was a difference in the overall distribution of genotypes between male and female newborns (P=0.03). The greatest impact to the overall difference came from two of the supertypical genotypes: decreased homozygosity for HLA-DRB3 and increased heterozygosity for DRB3/DRB4 haplotypes together with a trend towards decreased homozygosity for DRB4 haplotypes in boys (P=0.007 for the 3×2 comparison of the frequencies of these three genotypes in males and females). This is the expected pattern for overdominant selection of the DRB3 and DRB4 supertypical groups.


The contributions of other combinations of supertypical haplotypes to the global distortion of genotype frequencies were also examined. An overdominant selection model involving one heterozygous and two homozygous genotypes for the DRB3 and DRB5 haplotypes yielded a P value of 0.03, and a P value of 0.16 for the DRB4 and DRB5 haplotypes. The lack of a striking selection for HLA-DRB4/DRB5 was interesting in that the HLA-DRB1 alleles of these families have more closely related sequences31,32 (see Discussion). The presence of evidence for selection of DRB3/DRB4 and DRB3/DRB5 but not for DRB4/DRB5 suggested that even among the supertypical haplotypes only heterozygosity for the most distinct ones selected strongly enough to be detected in a sample of this size.

An additional analysis was carried out to confirm the conclusion drawn from the supertypical genotype analysis. The heterozygosity rate for HLA-DRB1 within the group of newborns bearing only DRB3 haplotypes was not increased in boys (8.96% in boys and 12.62% in girls; NS). The same comparison in newborns with only HLA-DRB4 haplotypes yielded a decrease in boys (2.99% vs 7.94%; P=0.03). Thus, while heterozygosity for supertypical haplotypes was increased in boys, heterozygosity for DRB1 alleles belonging to the same lineage was not (due to supertypical homozygosity). These results confirmed that unless accompanied by supertypical heterozygosity, heterozygosity at HLA-DRB1 did not confer an advantage to male concepti in prenatal selection.

As shown in Table3, there was no difference between the observed and expected frequencies (based on the assumption of Hardy-Weinberg equilibrium) in the overall group. Thus, increased heterozygosity was not a general feature but exclusive to males. In fact, supertypical heterozygosity was decreased in females. This was suggested by Wright’s FIS values which were −0.0719 showing heterozygote excess for ancestral lineages in males and +0.0661 showing heterozygote deficit in females. At the DRB1 locus, deviations from 0 were negligible (less than or equal to|0.0172|).

The same group of newborns were also typed at the HLA-B locus for Bw4/Bw6 epitopes, and at the class III loci HSP70-2, TNFB and Factor B with no sex-specific change in genotype frequencies.28

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Discussion

This study provided evidence for MHC-mediated prenatal selection in the relatively homogeneous Welsh population. The main finding was different sex-specific frequencies of supertypical HLA-DRB genotypes in newborns. The direction of changes suggested that in utero selection may be more focused on males and may exert pressure for heterozygosity in males. In addition to MHC-mediated mate choice reported previously, these results implied that MHC-mediated selection might also occur after mating in humans. Recent studies suggested that genetic benefits drive not only pre-copulatory but also post-copulatory female choice in animals.11,33,34 Genetic compatibility is more easily detected post-copulation via signals on sperm, and sperm-soma or egg-sperm interactions.34

No other study has sought evidence for MHC-mediated prenatal selection in newborns despite that this is an expected consequence of various observations regarding the influence of the MHC on reproductive physiology. Lineages and gender effect are not usually taken into account in other human studies. As happened in our previous leukaemia association study,27 we have been able to unravel this finding simply by focusing on evolutionarily most distinctive supertypical lineages rather than a large number of high-resolution alleles. A similar approach also helped Ditchkoff et al35 to demonstrate the correlation between MHC class II and sexually selected traits in male deer. Positive selection of heterozygosity for the members of highly dissimilar lineages has been described in mice and called divergent allele advantage.36 The asymmetrical selection for heterozygosity in males contrasts with the promiscuous heterozygote advantage model described by Flaherty37 in which all heterozygotes would be favoured over all homozygotes. Our analysis showed that heterozygosity for the DRB1 alleles belonging to the same lineage is not selected in males.

It has been pointed out that by attempting to examine homozygosity through high-resolution typing, we may be misclassifying functional homozygotes as heterozygotes.10,38 This would have happened if there were groups of alleles closely related to each other. One such grouping is the supertypical families of HLA-DRB1 alleles.17,18,39,40 HLA-DRB1 alleles are not equidistant and degree of heterozygosity depends on the family relationships.40 It appears that heterozygosity for the members of different (class II) supertypic families may be better markers for ‘functional’ heterozygosity at the HLA-DRB1 locus. This suggests that selection does not favour genotypes consisting of HLA-DRB1 alleles from the same supertypic group even if it is heterozygosity for classical HLA-DR alleles such as HLA-DRB1*04 and *07 (both in the HLA-DR53 family), or HLA-DRB1*03 and *13 (both in the HLA-DR52 family). Heterozygosity for supertypical haplotypes secures heterozygosity at most MHC loci due to the distinct evolutionary histories of ‘haplotypes’. Similar to the animal studies,41,42,43,44,45,46,47 prenatal selection to increase genetic diversity in progeny concerned mainly males in the present study.

The results showed the level of selection as the supertypic lineages but further analysis revealed that only the evolutionarily most divergent ones were involved. The phylogenetic studies of HLA-DRB1 alleles showed that all present day alleles coalesce into two groups about 25–30 million years ago.31,32 One group consists of all HLA-DRB1 alleles of the HLA-DRB3 (DR52) family and the other one includes the HLA-DRB4 (DR53) and DRB5 (DR51) families. This is in agreement with an earlier study which identified the HLA-DR52 and -DR53 families as evolutionarily most distinct.40 The lack of increased heterozygosity for DRB4 and DRB5 families in males was consistent with the evolutionary history of HLA-DRB1 alleles from these lineages.

The deficit for homozygous genotypes in males found in this study is in agreement with predictions and results of experimental studies. This deficit suggests that mechanisms are in place to prevent the birth of MHC homozygous males. The unknown mechanisms may be selective fertilization, selective implantation, or losses during embryonic development and foetal growth.48 The high primary sex ratio at fertilization (160 males to 100 females) that gets closer to unity towards birth49,50,51,52 and the fact that up to 80% of conceptions are lost53,54,55 imply a disproportionately high loss of males in utero. One study even located the male-specific prenatal deaths to the embryonic organogenesis period.51 This may be why studying partners with recognized miscarriages has not been as informative as hoped. It is believed that detectable miscarriages constitute only a minority of postzygotic losses due to an MHC effect. Our findings imply that MHC-mediated selection is one of possibly several mechanisms involved in prenatal selection of males. Involvement of the MHC in sperm-ovum interactions, selective fertilization, implantation and abortion was first proposed a long time ago,56,57,58 and is not without molecular basis59 or supporting evidence.48 Our results may help to better investigate these issues in human studies.

Mate choice mechanisms have also evolved to assure diversity at the MHC and operate in a variety of species10,11,22,60,61 including humans62,63 but not in all populations.64 Our data do not directly allow to exclude disassortative mate choice as a possible cause of the observed deficiencies. In the light of the gender effect noted, however, it is unlikely that this could be the sole explanation.

No human study has examined the deficit for MHC homozygosity in newborns, but there are studies in rats41,42,43,65 and mice.44 In one of the earliest studies and its continuation, Palm found that depending on the MHC type, newborn rats may have deficits for homozygosity that appears as increased heterozygosity. The remarkable feature of this finding was that it occurs in newborn males only.41,42,43 Also in mice, it has been noted that when deficit for homozygosity for an MHC type occurs, this concerns males.44 Another mouse study found excess heterozygosity at a different histocompatibility locus, H-3, in males only for certain combinations.45 Most convincingly, some combinations of MHC-linked semi-lethal embryonic t-lethals allow prenatal survival, and sex affects lethality. Two different studies showed a male deficit among live births with the t6/tw5 genotype46,47 suggesting higher sensitivity of male concepti to deleterious genotypes. Whatever the reason for this, there is consistency in the observations that MHC homozygosity preferentially affects males in the intrauterine period. The male-specificity of the deficit for ‘supertypical homozygosity’ for the most divergent lineages found in the present study is not unprecedented but still not conclusively strong either. A replication of our findings is required in a second study with sufficient statistical power in an ethnically homogeneous population.

In animals, importance of MHC heterozygosity in males has been shown in different contexts. First of all, since females do the mate and sperm choices, it is advantageous for males to be genetically diverse. Brown reviewed the importance of heterozygosity at somatic allozyme loci in male fitness and mating success.66,67 By offering genetically diverse rather than uniform sperms, heterozygote males would increase their chances in sperm selection (selective fertilization), in selective implantation and embryonic growth. If the pre-copulatory mate choice concerns the MHC and aims for heterozygosity as several studies suggested,61,63,68 heterozygote males will have advantage over homozygotes. In male pheasants, there is a correlation between their MHC types and spur length which is a sexually selected trait. In males, decreased homozygosity at the MHC loci has been reported.69 In white-tailed deer,there is also a correlation between the MHC and sexually selected traits in males.35 Ditchkoff et al35 collapsed the MHC-DRB alleles into two ancestral lineages—similar to what we did in the present study—and found that male deer who possessed alleles from different lineages had greater antlers, body mass and skull length than deer with two alleles from the same lineage. In macaques, the contribution of MHC class II heterozygosity to reproductive success of males but not females has been reported.70 These examples suggest a biological basis for selection of heterozygote males beginning in utero.

Although it is plausible that MHC may directly govern the selection process, it is equally possible that diversity in highly polymorphic loci such as MHC may simply be an indicator of the degree of genetic relatedness.58 MHC specifically appears to be a marker for genome-wide diversity in mammals.71 This could cause seemingly MHC-mediated selection while in fact selection is governed by another locus or a complex interaction of multiple loci.

The present study showed that in a sample of Welsh population, MHC-mediated prenatal selection might be governed at the level of evolutionarily distinct haplotypes and negative selection of homozygotes may be restricted to male offspring only. It remains to be seen whether this is unique to the population examined or a more general phenomenon. Our results are consistent with those of the animal studies, and support the conclusions reached in previous studies. Further studies will examine the possible role of human MHC as a genetic compatibility system in selective fertilization, and as a determinant of male-specific prenatal selection that dramatically changes the primary sex ratio from fertilization to birth. Our results may or may not be replicated in other populations but in any case they provide testable working hypotheses for further research.

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Subjects and methods

Newborns

Random, anonymous umbilical cord blood samples were obtained from full-term babies born in the University Hospital of Wales and Llandough Hospital in Cardiff, UK over a period of 12 months. This practice was in compliance with the regulations of the local institutional ethics committee. It was not practically possible to obtain samples from every newborn over this period but no newborn was intentionally excluded on the basis of any selection criteria. The samples were collected until the number in both sex groups exceeded 200. In the final group of 415 newborns, there were 201 boys and 214 girls. This gives a male-to-female (M:F) ratio of 0.939 that is slightly lower than the expected M:F ratio (1.056) in newborns (non-significant (NS)).

Typing method

The HLA-DRB1/3/4/5 loci were typed at the DNA level using the Biotest DRB-ELPHA typing kit which is based on a solid phase sequence-specific oligonucleotide probe technique. The HLA-DRB1 alleles identified were HLA-DRB1*01, 15/16, 03, 04, 11, 12, 13, 14, 07, 08, 09, and 10. This level of resolution is the same as that used in identifying heterozygote advantage in hepatitis B infection.24 The test also detects the presence of the supertypical HLA-DRB locus (HLA-DRB3, -DRB4 or -DRB5).

Assignment of HLA class II supertypes

Because some haplotypes lack a supertypical locus,16 the assignment of lineages (ie, the presence of DRB3, DRB4 or DRB5) partly relies on the results of HLA-DRB1 typing. Different supertypical loci cannot occur on the same haplotype, they behave like and can be treated as allelic specificities17 despite not being truly allelic, ie, not encoded by the same locus.40 The DRB3 gene is present on HLA-DRB1*03, *11, *12, *13 and *14 haplotypes; DRB4 on HLA-DRB1*04, *07 and *09 haplotypes, and DRB5 on HLA-DRB1*15 and *16 haplotypes. There is no known exception to these associations. DRB1*01, *08, and *10 haplotypes do not belong to any of these lineages (Figure 1). A sample was assigned as homozygous for HLA-DRB4 (DR53) lineage when no other supertype was detected and the HLA-DRB1 type was any combination of DRB1*04, *07 or *09. This meant having a double dose of the HLA-DRB4 gene, ie, homozygote for the DRB4 family. A sample was assigned as HLA-DR52 homozygote (having double dose of DRB3) if the HLA-DRB1 type consisted of only DRB1*03, *11, *12, *13 or *14. Those typed as having only HLA-DRB1*15 and/or *16 were DRB5 (DR51) homozygote.

Estimation of allele, haplotype and genotype frequencies, and other population genetics parameters

Allele frequencies were estimated by direct counting. This was done for the whole group as well as each sex. Allele frequency was the ratio of the number of chromosomes carrying the allele to the total number of chromosomes. Frequencies of homozygous or heterozygous genotypes were estimated by direct counting. Expected homozygosity rates and genotype frequencies were calculated from the allele frequencies in the same sample of the population assuming Hardy-Weinberg equilibrium. Observed heterozygosity and homozygosity, Wright’s fixation index (FIS72 as a measure of heterozygote deficiency or excess and Nei’s unbiased genetic identity73 were computed on the statistical package PopGene v1.32.74

Statistical analysis

Fisher’s exact test was the method of choice for the analysis of all 2×2 tables concerning observed frequencies. For the comparisons between an observed and a corresponding expected frequency, the one-sample Z-test was used. The significance of the distribution of genotype frequencies in two sexes was tested by the χ2-test using the appropriate degrees of freedom.75 All P values are two-tailed.

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Acknowledgements

We are grateful to Drs Mary Carrington and Bill Klitz for a critical review of an earlier version of this report. We thank the staff at Interbranch HLA Laboratory in Halle, Germany for technical assistance.