Major histocompatibility complex heterozygosity enhances reproductive success

We investigated how heterozygosity at the major histocompatibility complex (MHC) affects fitness in wild-derived (F2) house mice (Mus musculus musculus). To compare and control for potential confounding effects from close inbreeding and genome-wide heterozygosity, we used mice that were systematically outbred. We assessed how heterozygosity at MHC and background loci (using 15 microsatellite markers on 11 different chromosomes) affects individual survival and reproductive success (RS) in large, semi-natural population enclosures. We found that overall heterozygosity significantly increased RS, and this correlation was entirely explained by heterozygosity at two MHC loci. Moreover, we found that the effects of MHC heterozygosity depend on the level of background heterozygosity, and the benefits of maximal MHC heterozygosity show a curvilinear effect with increasing background heterozygosity. The enhanced RS from MHC heterozygosity was not because of increased survival, and although MHC heterozygosity was correlated with body mass, body mass did not correlate with RS when heterozygosity is controlled. Breeders were more MHC heterozygous than nonbreeders for both sexes, indicating that MHC heterozygosity enhanced fecundity, mating success or both. Our results show that (i) MHC heterozygosity enhances fitness among wild, outbred as well as congenic laboratory mice; (ii) heterozygosity-fitness correlations can potentially be explained by a few loci, such as MHC; (iii) MHC heterozygosity can increase fitness, even without affecting survival, by increasing mating and RS; and (iv) MHC effects depend on background genes, and maximal MHC heterozygosity is most beneficial at intermediate or optimal levels of background heterozygosity.     

Use of the MHC for mate choice in wild house mice (Mus domesticus)

The mechanisms maintaining natural diversity at the major histocompatibility complex (MHC) are not well understood. To increase knowledge of one potential mechanism, I examined the use of MHC genes for mate choice by wild house mice in a controlled laboratory setting. Three rearing groups of wild test mice were produced: non‐fostered control mice, mice fostered into families of an inbred laboratory mouse strain, and mice fostered into families of a second, MHC‐congenic mouse strain. Mature test mice were given a choice of two opposite‐sex stimulus mice from the two MHC‐congenic strains used for fostering, and were scored for several measures of preference. The results were non‐significant in general, but females of two rearing groups spent significantly more time with mice of one MHC‐type, and in most rearing groups, mice tended to spend more time with this same MHC‐type. Other results showed that male test mice ejaculated indiscriminantly and that female wild mice mated to ejaculation more often in longer length trials, but showed no significant preferences. In this study, fostering seemed to have little or no effect on MHC‐based mate preferences of wild house mice, and wild mice did not appear to be using the MHC to avoid inbreeding. However, some wild female mice used the MHC to choose potential mates. This revised version was published online in July 2006 with corrections to the Cover Date.     

Resistance to HSV-1 in the mouse is governed by two major,independently segregating,non-H-2 loci

Earlier studies showed that genetic resistance of adult, inbred strains of mice to Herpes Simplex Virus-type 1 (HSV-1) is a dominant genetic trait. The present studies were undertaken to determine the number of genetic loci involved and whether they were found within the major histocompatibility complex,H-2, of the mouse. Challenge with HSV-1 of progeny of mice backcrossed to moderately susceptible BALB/c mice, of progeny of mice backcrossed to very susceptible A/J strain mice, and of progeny of the F-2 cross using (C57BL/6 × A/J)F₁ mice indicated that two major loci were responsible for resistance. The backcrosses to BALB/c mice suggested that additional genes on this background enhanced resistance, while further backcrosses with the A/J mice indicated that other genes on the A/J background (or the lack thereof) reduced resistance. Studies with congenic mice showed that genes within theH-2 did not influence resistance or susceptibility.     

Nucleotide variation in wild and inbred mice

The house mouse is a well-established model organism, particularly for studying the genetics of complex traits. However, most studies of mice use classical inbred strains, whose genomes derive from multiple species. Relatively little is known about the distribution of genetic variation among these species or how variation among strains relates to variation in the wild. We sequenced intronic regions of five X-linked loci in large samples of wild Mus domesticus and M. musculus, and we found low levels of nucleotide diversity in both species. We compared these data to published data from short portions of six X-linked and 18 autosomal loci in wild mice. We estimate that M. domesticus and M. musculus diverged <500,000 years ago. Consistent with this recent divergence, some gene genealogies were reciprocally monophyletic between these species, while others were paraphyletic or polyphyletic. In general, the X chromosome was more differentiated than the autosomes. We resequenced classical inbred strains for all 29 loci and found that inbred strains contain only a small amount of the genetic variation seen in wild mice. Notably, the X chromosome contains proportionately less variation among inbred strains than do the autosomes. Moreover, variation among inbred strains derives from differences between species as well as from differences within species, and these proportions differ in different genomic regions. Wild mice thus provide a reservoir of additional genetic variation that may be useful for mapping studies. Together these results suggest that wild mice will be a valuable complement to laboratory strains for studying the genetics of complex traits.     

Genetic differences in BCG-induced resistance to Schistosoma mansoni are not controlled by genes within the major histocompatibility complex of the mouse.

Induction of nonspecific resistance to Schistosoma mansoni infection after the i.v. injection of viable BCG was investigated in outbred mice and a panel of inbred and H-2 congenic strains. Significant protection was induced in CF1, A/J, C57BL/6, C57BL/10, DBA/2, C57BR, and SJL mice. BALB/c mice were not protected whereas CBA and C3H mice expressed intermediate degrees of protection. Expression of the protective phenomenon is not controlled by genes within the MHC as shown by the marked differences in response between BALB/c and DBA/2 (H-2d) as well as between C57BR and C3H (H-2k) mice. H-2 congenic strains with C57BL/10 background (B10.A and B10.D2) were high responders. BALB.B10 mice carrying the high responder (B10) MHC on the nonresponder (BALB/c) background were not protected. The degree of splenic hypertrophy did not correlate with the expression of nonspecific resistance. These results demonstrate that, in addition to controlling specific immune responses, genetic differences influence the nonspecific protective phenomena related to BCG administration as well.     

The Scent of Genetic Compatibility: Sexual Selection and the Major Histocompatibility Complex

Individuals in some species prefer mates carrying dissimilar genes at the major histocompatibility complex (MHC), which may function to increase the MHC or overall heterozygosity of progeny. Here I review the evidence for MHC-dependent mating preferences from recent studies, including studies on the underlying olfactory mechanisms and evolutionary functions. Many studies indicate that MHC genes influence odour, and some work is beginning to examine the potential role of MHC-linked olfactory receptor genes in mating preferences. MHC-dependent mating preference increases the MHC-heterozygosity of progeny, which is suspected to confer resistance to infectious diseases. In humans, heterozygosity at MHC loci is associated with increased resistance to hepatitis and HIV infections, but experimental evidence for the heterozygote advantage hypothesis has been lacking. Here I re-analyse data from previously published experimental infection studies with mice. I show that although overdominance is rare, resistance is often dominant, suggesting that heterozygotes are often protected. A second (nonmutually exclusive) possibility is that MHC-disassortative mating preferences promotes inbreeding avoidance. This hypothesis is supported by recent evidence that MHC genes play a role in kin recognition, and that mating with close kin has rather deleterious fitness consequences. In conclusion, I discuss other ways that MHC genes might influence sexual selection. The research on MHC-mediated mating preferences is integrating the study of animal behaviour with other seemingly disparate fields, including sensory biology and immunogenetics.     

Allelic Genealogy under Overdominant and Frequency-Dependent Selection and Polymorphism of Major Histocompatibility Complex Loci

To explain the long-term persistence of polymorphic alleles (trans-specific polymorphism) at the major histocompatibility complex (MHC) loci in rodents and primates, a computer simulation study was conducted about the coalescence time of different alleles sampled under various forms of selection. At the same time, average heterozygosity, the number of alleles in a sample, and the rate of codon substitution were examined to explain the mechanism of maintenance of polymorphism at the MHC loci. The results obtained are as follows. (1) The coalescence time for neutral alleles is too short to explain the trans-specific polymorphism at the MHC loci. (2) Under overdominant selection, the coalescence time can be tens of millions of years, depending on the parameter values used. The average heterozygosity and the number of alleles observed are also high enough to explain MHC polymorphism. (3) The pathogen adaptation model proposed by Snell is incapable of explaining MHC polymorphism, since the coalescence time for this model is too short and the expected heterozygosity and the expected number of alleles are too small. (4) From the mathematical point of view, the minority advantage model of frequency-dependent selection is capable of explaining a high degree of polymorphism and trans-specific polymorphism. (5) The molecular mimicry hypothesis also gives a sufficiently long coalescence time when the mutation rate is low in the host but very high in the parasite. However, the expected heterozygosity and the expected number of alleles tend to be too small. (6) Consideration of the molecular mechanism of the function of MHC molecules and other biological observations suggest that the most important factor for the maintenance of MHC polymorphism is overdominant selection. However, some experiments are necessary to distinguish between the overdominance and frequency-dependent selection hypotheses.     

Strikingly high levels of heterozygosity despite 20 years of inbreeding in a clonal honey bee

Inbreeding (the mating between closely related individuals) often has detrimental effects that are associated with loss of heterozygosity at overdominant loci, and the expression of deleterious recessive alleles. However, determining which loci are detrimental when homozygous, and the extent of their phenotypic effects, remains poorly understood. Here, we utilize a unique inbred population of clonal (thelytokous) honey bees, Apis mellifera capensis, to determine which loci reduce individual fitness when homozygous. This asexual population arose from a single worker ancestor approximately 20 years ago and has persisted for at least 100 generations. Thelytokous parthenogenesis results in a 1/3 of loss of heterozygosity with each generation. Yet, this population retains heterozygosity throughout its genome due to selection against homozygotes. Deep sequencing of one bee from each of the three known sub‐lineages of the population revealed that 3,766 of 10,884 genes (34%) have retained heterozygosity across all sub‐lineages, suggesting that these genes have heterozygote advantage. The maintenance of heterozygosity in the same genes and genomic regions in all three sub‐lineages suggests that nearly every chromosome carries genes that show sufficient heterozygote advantage to be selectively detrimental when homozygous.     

An investigation of genetic variation within a series of congenic strains of mice

2 congenic strains of mice, B6N.AKN-Ahk and D2N.B6N-Ahb, imported from the USA, were found to be either segregating or fixed for an incorrect allele at a number of biochemical loci. B6N.AKN-Ahk, supposedly congenic with C57BL/6N, had the wrong genotype at 6 out of 12 biochemical loci; D2N.B6N-Ahb, supposedly congenic with DBA/2N, was segregating at 3 out of 9 loci. There was genetic variation in mandible shape within the 2 strains but no abnormal coat colours were found and no hybrid vigour in breeding performance was detected. Analyses in the USA confirmed these results and showed that 2 other congenic strains, C3N.D2N-Ahd and AKN.B6J-Ahb, were also segregating at a number of loci. Some of the alleles found in the C3N.D2N-Ahd mice must be the result of a genetic contamination. The simplest explanation for this breakdown in the backcrossing programme is genetic contamination with other congenic strains or recombinant inbred lines under development in the same laboratory. These findings emphasize the importance of continual genetic monitoring of all genetic stocks at regular intervals and in particular during the development of congenic and recombinant lines.     

Genetic studies of flavivirus resistance in inbred strains derived from wild mice: evidence for a new resistance allele at the flavivirus resistance locus (Flv).

Studies of genetic resistance to flavivirus infection in laboratory mice have led to the development of a single model in which resistance is conferred by an autosomal dominant gene designated Flvr. Because of evidence suggesting that wild mice carry virus resistance genes which are not present in laboratory mice, we compared flavivirus resistance in the inbred strains CASA/Rk, CAST/Ei, and MOLD/Rk, which are derived directly from wild mice, and the congenic strains C3H/RV (Flvr/Flvr) and C3H/HeJ (Flvs/Flvs). Resistance to the Murray Valley encephalitis virus strain OR2 and the 17D vaccine strain of yellow fever virus was assessed by determining the lethality of intracerebral infection and by measuring virus replication in the brain. The resistance of the CASA/Rk and CAST/Ei strains resembled the resistance of C3H/RV mice, whereas the resistance of the MOLD/Rk strain was intermediate between those of C3H/RV and C3H/HeJ mice. Genetic analyses showed that resistance in both the CASA/Rk and MOLD/Rk strains is conferred by single autosomal dominant alleles at the Flv locus. Our data indicate that flavivirus resistance in the CASA/Rk strain is due to a gene which is similar or identical to Flvr, whereas resistance in the MOLD/Rk strain is due to a previously undescribed gene which we designate Flvmr to indicate minor resistance to flavivirus infection. Since genetic resistance to flaviviruses is rare in laboratory mice, the CASA/Rk and MOLD/Rk strains will be valuable for further investigation of this phenomenon.     

Nucleoside phosphorylase 2 (Np-2) of mice

Isozyme patterns of nucleoside phosphorylase (NP) in 16 inbred strains, two recombinant inbred, one congenic, and three species of wild mice were studied. Evidence is provided for a genetic locus, Np-2, encoding an electrophoretic variant which is expressed exclusively in erythrocytes of certain inbred strains. This finding establishes the occurrence of genetic polymorphism of NP among inbred strains of mice. In addition, the Npla allele previously reported only in inbred strains has been observed in one of the species of wild mice (Mus musculus castaneus) studied.     

Wild mouse open field behavior is embedded within the multidimensional data space spanned by laboratory inbred strains

The vast majority of studies on mouse behavior are performed on laboratory mouse strains (Mus laboratorius), while studies of wild-mouse behavior are relatively rare. An interesting question is the relationship between the phenotypes of M. laboratorius and the phenotypes of their wild ancestors. It is commonly believed, often in the absence of hard evidence, that the behavior of wild mice exceeds by far, in terms of repertoire richness, magnitude of variables and variability of behavioral measures, the behavior of the classical inbred strains. Having phenotyped the open field behavior (OF) of eight of the commonly used laboratory inbred strains, two wild-derived strains and a group of first-generation-in-captivity local wild mice (Mus musculus domesticus), we show that contrary to common belief, wild-mouse OF behavior is moderate, both in terms of end-point values and in terms of their variability, being embedded within the multidimensional data space spanned by laboratory inbred strains. The implication could be that whereas natural selection favors moderate locomotor behavior in wild mice, the inbreeding process tends to generate in mice, in some of the features, extreme and more variable behavior.     

Mind the gap: analysis of marker-assisted breeding strategies for inbred mouse strains

The development of congenic mouse strains is the principal approach for confirming and fine mapping quantitative trait loci, as well as for comparing the phenotypic effect of a transgene or gene-targeted disruption between different inbred mouse strains. The traditional breeding scheme calls for at least nine consecutive backcrosses before establishing a congenic mouse strain. Recent availability of genome sequence and high-throughput genotyping now permit the use of polymorphic DNA markers to reduce this number of backcrosses, and empirical data suggest that marker-assisted breeding may require as few as four backcrosses. We used simulation studies to investigate the efficiency of different marker-assisted breeding schemes by examining the trade-off between the number of backcrosses, the number of mice produced per generation, and the number of genotypes per mouse required to achieve a quality congenic mouse strain. An established model of crossover interference was also incorporated into these simulations. The quality of the strain produced was assessed by the probability of an undetected region of heterozygosity (i.e., “gaps”) in the recipient genetic background, while maintaining the desired donor-derived interval. Somewhat surprisingly, we found that there is a relatively high probability for undetected gaps in potential breeders for establishing a congenic mouse strain. Marker-assisted breeding may decrease the number of backcross generations required to generate a congenic strain, but only additional backcrossing will guarantee a reduction in the number and length of undetected gaps harboring contaminating donor alleles. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users.     

The Ig light chain restricted B6.kappa(-)lambda(SEG) mouse strain suggests that the IGL locus genomic organization is subject to constant evolution

In laboratory mice, the different Ig lambda light chain subtypes (lambda 1, lambda 2, lambda x and lambda 3) are expressed on 60, 16, 16 and 8%, respectively, of the lambda-positive peripheral B cells. Eighteen years ago, our laboratory characterized a lambda 1(-) wild mouse strain: SPE ( Mus spretus). In this report, we describe the characterization of another wild-derived Mus spretus inbred strain, SEG, that presents the same characteristic, namely the absence of lambda 1 expression. An almost congenic strain, B6.lambda(SEG), was detected in a series of recombinant congenic strains carrying 2% of SEG/Pas genome in a C57BL/6J background. This B6.lambda(SEG) strain was crossed to Igh (a) C kappa (-) mice in order to derive two different additional congenic strains: B6.kappa(-)lambda(SEG) Igh (a) and B6.kappa(-)lambda(SEG) Igh (b). In this paper, we characterize the genomic organization and the expression of the SEG IGL locus. Altogether, our data show that the SEG IGL locus is constituted by a single functional IGLJ2SEG-IGLC2SEG, two pseudo IGLJ4SEG1/2-IGLC4SEG1/2 gene clusters and two V gene segments: IGLV2SEG and IGLVXSEG. In particular, we show the absence of IGLV1 and IGLVSD26 gene segments. IGLVSD26 was reported to be present in some Mus m. musculus mice and absent in BALB/c. Here, we confirm its presence not only in other Mus m. musculus mice but also in Mus spretus mice. Consequently, we propose that IGLVSD26-related gene segments define a new family that we name V lambda 4. The study of the organization of different IGL loci, in addition to the V lambda 4(+) reported here, could elucidate questions concerning the evolution of the lambda locus.     

Murine scent mark microbial communities are genetically determined

Scent marking in mice allows males to communicate information such as territory ownership, male competitive ability and current reproductive, nutritional, social and health status. It has been suggested that female mice eavesdrop on these olfactory cues, using them as a means of selecting mates with dissimilar major histocompatibility complex (MHC) genes, known as H2 in mice. The mechanisms underpinning MHC-dependent olfactory communication remain unresolved. Using congenic mouse strains and molecular methods we explore the involvement of the microbial communities, a known source of odourants, in scent marks to test the hypothesis that the microbial communities and hence the olfactory signals are genetically determined. Here we show that the indigenous microbial community of murine scent marks is genetically determined. Both background genotype and H2 haplotype influence the community structure of the scent mark flora, removing the possibility that community composition is solely orchestrated by the MHC. Qualitative and quantitative components of the bacterial community associated with MHC haplotype and background genotype were identified. The analyses confirm that the four groups of congenic mice tested are distinguishable on basis of the microbiology of their scent marks alone, strengthening the role of microorganisms in the development of MHC-dependent odours.     

Recessive T cell response to poly (Glu50Tyr50) possibly caused by self tolerance

The proliferative T cell response of inbred mouse strains to the random copolymer poly(Glu50Tyr50) (GT) was found to fall into two categories. Some strains responded only marginally (delta cpm values less than 10,000 and stimulation indices less than 3), whereas other strains mounted a substantial response (delta cpm 10,000 to 80,000, SI 3 to 30). The response is controlled by the A alpha and A beta loci of the major histocompatibility complex (MHC), as well as by genes not linked to the MHC. Because the response is selectively inhibited by monoclonal antibodies specific for the A alpha A beta molecule, we assume that its control by A loci is manifested as an A-restriction of the participating T (Ly-1high, Ly-2-) cells. It is of interest that the responsiveness is recessive in F1 hybrids of responder and nonresponder strains that are H-2-identical, but differ at their genetic background. Nonresponsiveness of these F1 mice is caused neither by a defect of antigen presentation, nor the result of immune suppression on priming or at the effector phase of the response. It is most likely the consequence of clonal deletion during the establishment of self-tolerance.     

Quantitative analysis of mouse urine volatiles: in search of MHC-dependent differences

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, influence mating preference and other social behaviors in mice. Training experiments using urine scent from mice differing only in the MHC complex, from MHC class I mutants or from knock-out mice lacking functional MHC class I molecules (beta2m-deficient), suggest that these behavioral effects are mediated by differences in MHC-dependent volatile components. In search for the physical basis of these behavioral studies, we have conducted a comparison of urinary volatiles in three sub-strains of C57BL/6 mice, a beta2m-deficient mutant lacking functional MHC class I expression and two unrelated inbred strains, using the technique of sorptive extraction with polydimethylsiloxan and subsequent analysis by gas chromatography/mass spectrometry. We show (i) that qualitative differences occur between different inbred strains but not in mice with the C57BL/6 background, (ii) that the individual variability in abundance in the same mouse strain is strongly component-dependent, (iii) that C57BL/6 sub-strains obtained from different provenance show a higher fraction of quantitative differences than a sub-strain and its beta2m-mutant obtained from the same source and (iv) that comparison of the spectra of beta2m mice and the corresponding wild type reveals no qualitative differences in close to 200 major and minor components and only minimal differences in a few substances from an ensemble of 69 selected for quantitative analysis. Our data suggest that odor is shaped by ontogenetic, environmental and genetic factors, and the gestalt of this scent may identify a mouse on the individual and population level; but, within the limits of the ensemble of components analysed, the results do not support the notion that functional MHC class I molecules influence the urinary volatile composition.     

Analysis of wild-derived mice for Fv-1 and Fv-2 murine leukemia virus restriction loci: a novel wild mouse Fv-1 allele responsible for lack of host range restriction.

Wild-derived mice originally obtained from Asia, Africa, North America, and Europe were typed for in vitro sensitivity to ecotropic murine leukemia viruses and for susceptibility to Friend virus-induced disease. Cell cultures established from some wild mouse populations were generally less sensitive to exogenous virus than were cell cultures from laboratory mice. Wild mice also differed from inbred strains in their in vitro sensitivity to the host range subgroups defined by restriction at the Fv-1 locus. None of the wild mice showed the Fv-1n or Fv-1b restriction patterns characteristic of most inbred strains, several mice resembled the few inbred strains carrying Fv-1nr, and most differed from laboratory mice in that they did not restrict either N- or B-tropic murine leukemia viruses. Analysis of genetic crosses of Mus spretus and Mus musculus praetextus demonstrated that the nonrestrictive phenotype is controlled by a novel allele at the Fv-1 locus, designated Fv-10. The wild mice were also tested for sensitivity to Friend virus complex-induced erythroblastosis to type for Fv-2. Only M. spretus was resistant to virus-induced splenomegaly and did not restrict replication of Friend virus helper murine leukemia virus. Genetic studies confirmed that this mouse carries the resistance allele at Fv-2.     

Major histocompatibility complex-conferred resistance to Theiler's virus-induced demyelinating disease is inherited as a dominant trait in B10 congenic mice.

Intracerebral inoculation of Theiler's murine encephalomyelitis virus into susceptible strains of mice produces chronic demyelinating disease in the central nervous system characterized by persistent viral infection. Immunogenetic data suggest that genes from both major histocompatibility complex (MHC) and non-MHC loci are important in determining susceptibility or resistance to demyelination. The role of the MHC in determining resistance or susceptibility to disease can be interpreted either as the presence of antigen-presenting molecules that confer resistance to viral infection or as the ability of MHC products to contribute to pathogenesis by acting as viral receptors or by mediating immune attack against virally infected cells. These alternatives can be distinguished by determining whether the contribution of the MHC to resistance is inherited as a recessive or dominant trait. Congenic mice with different MHC haplotypes on identical B10 backgrounds were crossed and quantitatively analyzed for demyelination, infectious virus, and local virus antigen production. F1 hybrid progeny derived from resistant B10 (H-2b), B10.D2 (H-2d), or B10.K (H-2k) and susceptible B10.R111 (H-2r), B10.M (H-2f), or B10.BR (H-2k) parental mice exhibited no or minimal demyelination, indicating that on a B10 background, resistance is inherited as a dominant trait. Although infectious virus, as measured by viral plaque assay, was cleared inefficiently from the central nervous systems of resistant F1 hybrid progeny mice, we found a direct correlation between local viral antigen production and demyelination. These data are consistent with our hypothesis that the immunological basis for resistance is determined by efficient presentation of the viral antigen to the immune system, resulting in local virus clearance and absence of subsequent demyelination.     

The major histocompatibility complex and mating preferences in wild house mice (mus domesticus)

This study examined the relationship between the major histocompatibilitycomplex (MHC) genes and mate choice by wild house mice in acontrolled laboratory setting in an attempt to understand themechanisms maintaining natural MHC diversity. Three rearinggroups of wild test mice were produced: nonfostered controlmice, mice fostered into families of an inbred laboratory mousestrain, and mice fostered into families of a second mouse straindiffering genetically from the first only within the MHC region.At maturity, test mice were given a choice of two opposite-sexstimulus mice of the two MHC-congenic strains used for fostering.Test mice were scored for several measures of preference includingamount of time spent with either stimulus mouse, and ejaculationwith a stimulus mouse. Females in two of three rearing groupsspent more time with one MHC type regardless of rearing environment,suggesting that females did not prefer mates dissimilar fromfamily MHC type. Time preferences tended to be stronger in femalesthan in males. Male test mice ejaculated indiscriminantly. Femalewild mice mated to ejaculation more often in longer trials,but these matings were still too infrequent to assess preferences.Fostering had little or no effect on MHC-based mate preferencesof wild house mice, and no evidence suggested that MHC was usedto avoid inbreeding. Wild female mice may still choose matesbased on MHC haplotypes (but do not necessarily prefer MHC-dissimilarmates); other cues are probably also used. Based on these results,inbreeding avoidance does not seem a strong mechanism for maintainingnatural MHC diversity