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The Role of Infectious Disease, Inbreeding and Mating Preferences in Maintaining MHC Genetic Diversity: An Experimental Test [and Discussion]
Philosophical Transactions B
Abstract
In house mice, and probably most mammals, major histocompatibility complex (MHC) gene products influence both immune recognition and individual odours in an allele-specific fashion. Although it is generally assumed that some form of pathogen-driven balancing selection is responsible for the unprecedented genetic diversity of MHC genes, the MHC-based mating preferences observed in house mice are sufficient to account for the genetic diversity of MHC genes found in this and other vertebrates. These MHC disassortative mating preferences are completely consistent with the conventional view that pathogen-driven MHC heterozygote advantage operates on MHC genes. This is because such matings preferentially produce MHC-heterozygours progeny, which could enjoy enhanced disease resistance. However, such matings could also function to avoid genome-wide inbreeding. To discriminate between these two hypotheses we measured the fitness consequences of both experimentally manipulated levels of inbreeding and MHC homozygosity and heterozygosity in semi-natural populations of wild-derived house mice. We were able to measure a fitness decline associated with inbreeding, but were unable to detect fitness declines associated with MHC homozygosity. These data suggest that inbreeding avoidance may be the most important function of MHC-based mating preferences and therefore the fundamental selective force diversifying MHC genes in species with such mating patterns. Although controversial, this conclusion is consistent with the majority of the data from the inbreeding and immunological literature.
... A high inbreeding coefficient leads to an increase in mortality and a decrease in the fertility and the growth rate (Crnokrak and Roff, 1999;DeRose and Roff, 1999;Liberg et al., 2005;Leroy, 2014). The immunity of inbred individuals is also usually reduced (Potts et al., 1994;Radwan et al., 2010). At the genetic level, as a result of inbreeding, homozygosity increases and genetic diversity decreases (Charlesworth, D. and Charlesworth, B., 1987;Crnokrak and Roff 1999). ...
... At the genetic level, as a result of inbreeding, homozygosity increases and genetic diversity decreases (Charlesworth, D. and Charlesworth, B., 1987;Crnokrak and Roff 1999). In particular, there is a decrease in the gene diversity of the major histocompatibility complex (MHC) and the transition of gene alleles to the homozygous state, which leads to a decrease in immunity (Potts and Wakeland, 1993;Potts et al., 1994;Sommer, 2005;Radwan et al., 2010). At the same time, the probability of homozygotization of alleles that carry deleterious or lethal recessive mutations and are found with low frequency in the gene pool of populations increases (Kaidanov, 1996;Charlesworth and Willis, 2009). ...
Archive data were analyzed concerning the reproduction of yellow steppe lemmings (Eolagurus
luteus) in the Moscow Zoo. We used information referring to E. luteus pairs that existed during two periods:
2008–2013 (first colony) and 2017–2020 (second colony). All breeding partners in the first colony had at least
one common ancestor (they originated from two females and one male) and thus were closely related to each
other. The degree of relatedness of partners in the second colony was much lower. The founders of that colony
were five females and five males that had originated from four pairs of unrelated individuals live-trapped in
the Zaisan Basin. We conducted a comparative assessment of the life expectancy and reproductive parameters
of adult yellow steppe lemmings and the survival of their offspring in two colonies, that is, we observed the
effect of different degrees of inbreeding on such parameters. We also assessed the effect of female age on those
values. We assigned the females to two age categories: younger (age of 15–59 days by the time of pair establishment)
and older (age of 60–701 days) category. The results of statistical analysis confirmed the significant
influence of the degree of relatedness of partners on the proportion of reproducing females, the number of
litters per pair, the number of survived pups per pair, the mean number of pups per litter, the inter-birth interval,
the female life expectancy, and the period of pair existence. The influence of female age on these parameters
was insignificant. Our data provide evidence for a pronounced inbreeding depression in the first captive
colony of the yellow steppe lemming.
... Consanguineous reproduction increases offspring homozygosity and promotes the expression of deleterious recessive alleles, which determines the negative consequences of inbreeding depression (Charlesworth and Charlesworth, 1987). Homozygosity, combined with a reduction in major histocompatibility complex (MHC) gene diversity, results in impaired immunity (Potts et al., 1994). ...
The adaptive effects of inbreeding are understudied, but accumulating evidence suggests that it plays a major adaptive role
in speciation, as populations with a history of inbreeding are more prone to it. Differences in inbreeding tolerance in two populations
of Microtus hartingi voles were studied through a series of experiments on reproductive behaviour and partner choice. Modelling
an artificial polygyny via the formation of trios composed of a brother, sister, and an unrelated female has shown an uneven attitude
towards inbreeding, which was closely linked to the reproduction strategy: voles of the Rhodopean population (RP) would reproduce
communally with only a moderate decrease in reproduction success, while in monogamous M. hartingi ankaraensis voles from Central
Anatolia (CAP), the reproductive success dropped almost to zero due to severe social stress resulting in heavily antagonistic behaviour
between females; aggression levels rose with maturation. Studies of reproduction in pairs of relatives revealed the absence of inbreeding
avoidance in the polygynous population (RP) and a sharp decrease in reproduction probability in the monogamous subspecies (CAP).
Olfactory three-choice behavioural tests have proven that voles do not choose the smell randomly, juveniles do not have partner
preferences, and adults choose the unrelated individual’s odour. RP voles prefer to mate with kin first, whereas CAP voles mate with
non-kin first. The differences in reproductive strategy might have evolved due to habitat fragmentation and restriction of natal dispersal
in the RP which has been isolated from the ancient Anatolian Microtus hartingi population since the Pleistocene. The adaptation to
communal reproduction via kin selection resulted in increased inbreeding tolerance.
... Consanguineous reproduction increases offspring homozygosity and promotes the expression of deleterious recessive alleles, which determines the negative consequences of inbreeding depression (Charlesworth and Charlesworth, 1987). Homozygosity, combined with a reduction in major histocompatibility complex (MHC) gene diversity, results in impaired immunity (Potts et al., 1994). ...
The adaptive effects of inbreeding are understudied, but accumulating evidence suggests that it plays a major adaptive role in speciation, as populations with a history of inbreeding are more prone to it. Differences in inbreeding tolerance in two populations of Microtus hartingi voles were studied through a series of experiments on reproductive behaviour and partner choice. Modelling an artificial polygyny via the formation of trios composed of a brother, sister, and an unrelated female has shown an uneven attitude towards inbreeding, which was closely linked to the reproduction strategy: voles of the Rhodopean population (RP) would reproduce communally with only a moderate decrease in reproduction success, while in monogamous M. hartingi ankaraensis voles from Central Anatolia (CAP), the reproductive success dropped almost to zero due to severe social stress resulting in heavily antagonistic behaviour between females; aggression levels rose with maturation. Studies of reproduction in pairs of relatives revealed the absence of inbreeding avoidance in the polygynous population (RP) and a sharp decrease in reproduction probability in the monogamous subspecies (CAP).
Olfactory three-choice behavioural tests have proven that voles do not choose the smell randomly, juveniles do not have partner
preferences, and adults choose the unrelated individual’s odour. RP voles prefer to mate with kin first, whereas CAP voles mate with non-kin first. The differences in reproductive strategy might have evolved due to habitat fragmentation and restriction of natal dispersal in the RP which has been isolated from the ancient Anatolian Microtus hartingi population since the Pleistocene. The adaptation to communal reproduction via kin selection resulted in increased inbreeding tolerance.
... In song sparrows, song complexity was found to advertise optimal MHC diversity, thus, by choosing mates with complex song, females may enhance the immunocompetence and disease resistance of their offspring (Slade, Watson and MacDougall-Shackleton, 2017). MHC-mediated sexual selection can facilitate inbreeding avoidance (Potts, Manning and Wakeland, 1994), enrich genome-wide diversity, and thus, can allow small populations to mitigate the loss of genetic diversity over time. ...
How the underlying forces of sexual selection impact reproductive tactics including elaborate acoustic displays in cetaceans remains poorly understood. Here, I combined 26 years (1995-2020) of photo-identification, behavioural, (epi)genetic, and endocrine data from an endangered population of humpback whales (New Caledonia), to explore male reproductive success, age, physiology, and population dynamics over almost a third of the lifespan of a humpback whale. First, I conducted a paternity analysis on 177 known mother-offspring pairs and confirmed previous findings of low variation in reproductive success in male humpback whales. Second, epigenetic age estimates of 485 males revealed a left-skewed population age structure in the first half of the study period that became more balanced in the second half. Further, older males (> 23 years) more often engaged in certain reproductive tactics (singing and escorting) and were more successful in siring offspring once the population age structure stabilised, suggesting reproductive tactics and reproductive success in male humpback whales may be age-dependent. Third, using enzyme immunoassays on 457 blubber samples, I observed a seasonal decline in male testosterone in the population over the breeding season. Testosterone levels appeared highest during puberty, then decreased and levelled off at the onset of maturity, yet were highly variable at any point during the breeding season and across males of all ages. Lastly, I investigated the influence of genetic diversity at the major histocompatibility complex (MHC) class I and class IIa (DQB and DRB-a) on patterns of male reproductive success in humpback whales. Mating pairs shared fewer alleles than expected under random mating at MHC class I and IIa, thus, providing evidence of an MHC-mediated female mate choice in humpback whales. This thesis provides novel, critical insights into the evolutionary consequences of commercial whaling on the demography, patterns of reproduction and sexual selection of exploited populations of baleen whales.
... The reduced analgesia displayed by the H. polygyrusinfected males could be interpreted in terms of odor familiarity and responses to group odor templates (e.g., Barnard, Hurst, & Aldhous, 1991). Substantial evidence exists that mice and rats can distinguish between urinary odors on the basis of differences in the major histocompatibil-ity complex (MHC), and use MHC-mediated or related odors for both kin recognition and mating preferences (Eklund, Egid, & Brown, 1991;Potts, Manning, & Wakeland, 1994;Yamazaki et al., 1976). The MHC activity is part of the immune system with infection activating the release of MHC antigens (R. E. Brown, 1995). ...
The present study shows that parasites influence both the responses of males to infected females and the responses of male hosts to females. Male mice exposed for 30 min to the odors of females infected with the nematode parasite Heligmosomoides polygyrus displayed a naloxone-sensitive, opioid-mediated analgesia, whereas males exposed for 1 min showed a shorter duration and lower amplitude naloxone-insensitive “nonopioid” analgesia that involved serotoninergic (5-HT) and excitatory amino acid (N -methyl- d -aspartate [NMDA] receptor) systems. The male mice distinguished between the odors of infected and physically stressed females, displaying greater analgesia after exposure to the odors of infected than stressed females. The analgesic responses to the odors of infected females were also affected by the males' prior sexual experience; sexually experienced males exhibited significantly greater analgesia than sexually naive males. In contrast, male mice infected with H. polygyrus failed to show a nonopioid analgesia after exposure to the odors of infected females and displayed a markedly lower level of opioid analgesia than uninfected mice. These results show that male mice can discriminate between the odors of parasitized and nonparasitized females and find the odors of parasitized estrous females aversive.
... In gray mouse lemurs (Microcebus murinus), researchers failed to find precopulatory MHC mate choice but identified a paternity advantage of fathers with more MHC 'supertypes' (Schwensow et al., 2008). (Potts et al., 1994;Potts & Wakeland, 1993), was shown to use the major urinary protein (MUP) gene cluster for kin discrimination when genome-wide similarity was controlled for (Sherborne et al., 2007). Thus, the complexity of multiple odor molecules also makes it harder to differentiate between straight-forward inbreeding avoidance and choice, for e.g., MHC complementarity. ...
Abstract The harmful effects of close inbreeding have been recognized for centuries and, with the rise of Mendelian genetics, was realized to be an effect of homozygosis. This historical background led to great interest in ways to quantify inbreeding, its depression effects on the phenotype and flow‐on effects on mate choice and other aspects of behavioral ecology. The mechanisms and cues used to avoid inbreeding are varied and include major histocompatibility complex (MHC) molecules and the peptides they transport as predictors of the degree of genetic relatedness. Here, we revisit and complement data from a Swedish population of sand lizards (Lacerta agilis) showing signs of inbreeding depression to assess the effects of genetic relatedness on pair formation in the wild. Parental pairs were less similar at the MHC than expected under random mating but mated at random with respect to microsatellite relatedness. MHC clustered in groups of RFLP bands but no partner preference was observed with respect to partner MHC cluster genotype. Male MHC band patterns were unrelated to their fertilization success in clutches selected for analysis on the basis of showing mixed paternity. Thus, our data suggest that MHC plays a role in pre‐copulatory, but not post‐copulatory partner association, suggesting that MHC is not the driver of fertilization bias and gamete recognition in sand lizards.
... LIST OF TABLES (Potts et al., 1994). Ticks are food for many species of birds and reptiles. ...
The study aimed to identify and characterise ticks collected from selected wildlife species from selected areas in South Africa using morphological traits and DNA barcoding. The ticks were collected during necropsy and stored at the South African National Biodiversity Institution-National Zoological Gardens (SANBI/NZG) Biobank. A total of 48 individual tick specimens (adult, engorged and nymphs) from 13 hosts of captive wildlife were morphologically identified using appropriate morphological keys. DNA was extracted from whole ticks, followed by amplification of the COI and 16S rRNA genes. Amplification was confirmed by gel electrophoresis, and the amplicons were sequenced. The following tick species were morphologically identified from different species of wild animals: Amblyomma marmoreum, Haemaphysalis elliptica, Amblyomma hebraeum, Amblyomma nuttalli, Ixodes spp., Hyalomma truncatum, Hyalomma rufipes, Otobius megnini, Rhipicentor nuttalli, Rhipicephalus simus, Rhipicephalus evertsi evertsi, Amblyomma (Aponomma) exornatum, Rhipicephalus evertsi mimeticus and Rhipicephalus spp cf. sp nr pravus. Amblyomma spp. were the most common species, and represented 22.9% of the identified ticks. Sequencing results confirmed the morphologically results, and indicated that the new sequences were 95 – 100% similar to published sequences of ticks from wild and domestic animals, and vegetation in different parts of southern Africa. However, sequences of three tick species that were morphologically identified as Rhipicephalus evertsi evertsi, Hyalomma truncatum and Rhipicephalus simus, were closely similar to published sequences of Rhiphicephalus mimeticus, Hyalomma glabrum and Rhipicephalus gertrudae, respectively. The findings of this study confirm previous reports that wildlife in South Africa harbour a wide diversity of ticks of veterinary and public health importance, and that COI and 16S rRNA genes are suitable markers for characterisation of ticks. This study also highlights the risk of transmission of ticks and tick-borne diseases to new areas and hosts during translocation of wild animals. Future work should assess the risk of these ticks as vectors of tick-borne infections of human and livestock in order to inform management of tick-borne diseases, including tick-borne zoonoses, in captive facilities in South Africa.
The first volume in the new Cambridge Handbooks in Behavioral Genetics series, Behavioral Genetics of the Mouse provides baseline information on normal behaviors, essential in both the design of experiments using genetically modified or pharmacologically treated animals and in the interpretation and analyses of the results obtained. The book offers a comprehensive overview of the genetics of naturally occurring variation in mouse behavior, from perception and spontaneous behaviors such as exploration, aggression, social interactions and motor behaviors, to reinforced behaviors such as the different types of learning. Also included are numerous examples of potential experimental problems, which will aid and guide researchers trying to troubleshoot their own studies. A lasting reference, the thorough and comprehensive reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The first volume in the new Cambridge Handbooks in Behavioral Genetics series, Behavioral Genetics of the Mouse provides baseline information on normal behaviors, essential in both the design of experiments using genetically modified or pharmacologically treated animals and in the interpretation and analyses of the results obtained. The book offers a comprehensive overview of the genetics of naturally occurring variation in mouse behavior, from perception and spontaneous behaviors such as exploration, aggression, social interactions and motor behaviors, to reinforced behaviors such as the different types of learning. Also included are numerous examples of potential experimental problems, which will aid and guide researchers trying to troubleshoot their own studies. A lasting reference, the thorough and comprehensive reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The first volume in the new Cambridge Handbooks in Behavioral Genetics series, Behavioral Genetics of the Mouse provides baseline information on normal behaviors, essential in both the design of experiments using genetically modified or pharmacologically treated animals and in the interpretation and analyses of the results obtained. The book offers a comprehensive overview of the genetics of naturally occurring variation in mouse behavior, from perception and spontaneous behaviors such as exploration, aggression, social interactions and motor behaviors, to reinforced behaviors such as the different types of learning. Also included are numerous examples of potential experimental problems, which will aid and guide researchers trying to troubleshoot their own studies. A lasting reference, the thorough and comprehensive reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The HLA region is a model system for the study of multilocus interactions. There are several well-defined, tightly linked, highly polymorphic loci. The physiology of the gene products is relatively well understood, information is available on the history of past generations, including disease and migration patterns, and comparative studies (e.g., H-2 in mice) supply useful background data. With the Ninth Workshop we have the additional asset of pedigree data which permits the accurate scoring of haplotypes and the testing of selection components. Three separate approaches have been taken in the analysis of the population data from the Ninth Workshop: the level of homozygosity at each locus, an overall population measure of two-locus disequilibrium, and haplotype pattern analysis, which evaluates disequilibrium patterns to determine which haplotypes have been subject to selection.
A biological perspective on morals may not solve personal dilemmas, but it may clarify their roots. In this overview, I shall survey some parallels between social cells and social organisms with respect to the genetic and behavioral basis of cooperation and conflict. No lessons are preached here about how individuals or cells should behave. In particular, I do not connect any moral stance with genetics. On the contrary, I would like to suggest that moral dilemmas are more frequently caused by genetic factors than solved by them.
Previous studies of mating preference signified that mice can sense one another's major histocompatibility complex (MHC) types, probably by olfaction. This conclusion has now been substantiated by the use of a Y-maze whose two arms were differentially scented with currents of air conducted through boxes occupied by B6 (H-2b) males and by B6-H-2k congenic males. Four B6 mice, two males and two females, were successfully trained, by water deprivation and reward, to enter the arm scented by B6 or B6-H-2k males. One of the males and one of the females were trained to select the B6-scented arm; the other male and female were trained to select the B6-H-2k-scented arm. Untrained mice showed no MHC discrimination in the maze. The performance of the trained mice in distinguishing between MHC congenic homozygous F2 segregants derived from a cross of B6-H-2k with B6 was as good as their performance in distinguishing the respective inbred strains, thus essentially eliminating alternative and significant additional explanations of MHC-associated sensory discrimination. The data further indicate that chemosensory discrimination of MHC types can be entirely dissociated from sex differences and from the circumstances of mating.
When a male mouse is presented with two H-2 congenic two female in estrus, his choice of a mate is influenced by their H-2 types. The term "strain preference" is used to describe the general tendency of the male population of one inbred strain to prefer two female of one H-2 type rather than another. The term "consistency of choice" is used to describe the added tendency of particular two males of one inbred strain, in sequential mating trials, to prefer two females of the H-2 type they chose in previous trials. Statistical analysis showed trends in the data that support the following conclusions: (a) The choice is made by the male, not the female. (b) The strain preference of two males may favor two females of dissimilar H-2 type (four of six comparisons), or of similar H-2 type (one of six comparisons). (c) Consistency of choice does not always correspond with strain preference. In one of six comparisons of H-2 genotypes there was no strain preference but pronounced consistency of choice by individual two male.This suggests memory, but fortuitous bias is not excluded. (d) Strain preference of the same male population may favor two male of the same or a different H-2 type, depending on which different H-2 type is offered as the choice alternative to self.These findings conform to a provisional model in which olfactory mating preference is governed by two linked genes in the region of H-2, one for the female signal and one for the male receptor. These mating preferences could in natural populations serve the purpose of increasing the representation of particular H-2 haplotypes or of maintaining heterozygosity of genes in the region of H-2.
Transgenic mice homozygous for a beta 2-microglobulin (beta 2-m) gene disruption and normal mice that had been treated with a CD8-specific mAb were infected intranasally with an H3N2 influenza A virus. Both groups of CD8T cell-deficient mice eliminated the virus from the infected respiratory tract. Potent CTL activity was detected in lung lavage populations taken from mice with intact CD8+ T cell function, with minimal levels of cytotoxicity being found for inflammatory cells obtained from the antibody-treated and beta 2-m mutant mice. We therefore conclude that cells infected with an influenza A virus can be cleared from the respiratory tract of mice lacking both functional class I major histocompatibility complex (MHC) glycoproteins and class I MHC-restricted, CD8+ effector T cells.
The major histocompatibility complex (MHC) has been theorized to play a critical role in kin recognition in two contexts, mating and cooperation. Recent work has greatly strengthened this view. The MHC is uniquely important for understanding the evolution of kin recognition because so much is known about its genetics, cell biology, and molecular evolutionary history. Our review integrates recent advances in these fields around the central theme of kin recognition. The chemical cues involved in mammals are controversial and appear to involve microorganisms in some cases. The genes that code MHC glycoproteins, although highly diverse within many species, are similar across generic boundaries in primates and rodents. The potential mechanisms of selection for the incredible allelic diversity at MHC loci are as controversial as ever, but they now also include behavioral mechanisms of disassortative mating and inbreeding avoidance. These studies show how behavior, disease, and molecular genetics can be integrated in a context of evolution and natural selection.
Genes of the highly polymorphic H-2 major histocompatibility complex impart to each mouse a scent that is characteristic of its H-2 haplotype. Recognition of these individual odors affects mate choice and other aspects of reproduction. Other parts of the genome also contribute to genetically determined individuality of body scent.