The role of infectious disease, inbreeding and mating preferences in maintaining MHC genetic diversity: an experimental test

1994 ◽  
Vol 346 (1317) ◽  
pp. 369-378 ◽  
Keyword(s):  
Genetic Diversity ◽  
Balancing Selection ◽  
Natural Populations ◽  
House Mice ◽  
Heterozygote Advantage ◽  
Immune Recognition ◽  
Mating Preferences ◽  
Conventional View ◽  
Mhc Genes ◽  
Allele Specific

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.

scholarly journals Transition from background selection to associative overdominance promotes diversity in regions of low recombination

2019 ◽  
Author(s):  
Kimberly J. Gilbert ◽  
Fanny Pouyet ◽  
Laurent Excoffier ◽  
Stephan Peischl
Keyword(s):  
Genetic Diversity ◽  
Balancing Selection ◽  
Purifying Selection ◽  
Heterozygote Advantage ◽  
Background Selection ◽  
Deleterious Mutations ◽  
Recombination Rates ◽  
Locus Model ◽  
Genome Wide ◽  
Linked Selection

SummaryLinked selection is a major driver of genetic diversity. Selection against deleterious mutations removes linked neutral diversity (background selection, BGS, Charlesworth et al. 1993), creating a positive correlation between recombination rates and genetic diversity. Purifying selection against recessive variants, however, can also lead to associative overdominance (AOD, Ohta 1971, Zhao & Charlesworth, 2016), due to an apparent heterozygote advantage at linked neutral loci that opposes the loss of neutral diversity by BGS. Zhao & Charlesworth (2016) identified the conditions when AOD should dominate over BGS in a single-locus model and suggested that the effect of AOD could become stronger if multiple linked deleterious variants co-segregate. We present a model describing how and under which conditions multi-locus dynamics can amplify the effects of AOD. We derive the conditions for a transition from BGS to AOD due to pseudo-overdominance (Ohta & Kimura 1970), i.e. a form of balancing selection that maintains complementary deleterious haplotypes that mask the effect of recessive deleterious mutations. Simulations confirm these findings and show that multi-locus AOD can increase diversity in low recombination regions much more strongly than previously appreciated. While BGS is known to drive genome-wide diversity in humans (Pouyet et al. 2018), the observation of a resurgence of genetic diversity in regions of very low recombination is indicative of AOD. We identify 21 such regions in the human genome showing clear signals of multi-locus AOD. Our results demonstrate that AOD may play an important role in the evolution of low recombination regions of many species.

scholarly journals How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings

2010 ◽  
Vol 277 (1684) ◽  
pp. 979-988 ◽  
Author(s):  
Lewis G. Spurgin ◽  
David S. Richardson
Keyword(s):  
Genetic Diversity ◽  
Rare Allele ◽  
Heterozygote Advantage ◽  
Relative Importance ◽  
Wild Populations ◽  
Fluctuating Selection ◽  
Mhc Genes ◽  
Histocompatibility Complex ◽  
Mhc Diversity ◽  
Rare Allele Advantage

Major histocompatibility complex (MHC) genes have been put forward as a model for studying how genetic diversity is maintained in wild populations. Pathogen-mediated selection (PMS) is believed to generate the extraordinary levels of MHC diversity observed. However, establishing the relative importance of the three proposed mechanisms of PMS (heterozygote advantage, rare-allele advantage and fluctuating selection) has proved extremely difficult. Studies have attempted to differentiate between mechanisms of PMS using two approaches: (i) comparing MHC diversity with that expected under neutrality and (ii) relating MHC diversity to pathogen regime. Here, we show that in many cases the same predictions arise from the different mechanisms under these approaches, and that most studies that have inferred one mechanism of selection have not fully considered the alternative explanations. We argue that, while it may be possible to demonstrate that particular mechanisms of PMS are occurring, resolving their relative importance within a system is probably impossible. A more realistic target is to continue to demonstrate when and where the different mechanisms of PMS occur, with the aim of determining their relative importance across systems. We put forward what we believe to be the most promising approaches that will allow us to progress towards achieving this.

scholarly journals Supergene formation is associated with a major shift in genome-wide patterns of diversity in a butterfly

2021 ◽  
Author(s):  
María Ángeles Rodríguez de Cara ◽  
Paul Jay ◽  
Mathieu Chouteau ◽  
Annabel Whibley ◽  
Barbara Huber ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Balancing Selection ◽  
Mate Preferences ◽  
Heterozygote Advantage ◽  
Effective Population ◽  
Adaptive Introgression ◽  
Continental Scale ◽  
Geographic Structure ◽  
Genome Wide ◽  
Genetic Diversity And Structure

AbstractSelection shapes genetic diversity around target mutations, yet little is known about how selection on specific loci affects the genetic trajectories of populations, including their genome-wide patterns of diversity and demographic responses. Adaptive introgression provides a way to assess how adaptive evolution at one locus impacts whole-genome biology. Here we study the patterns of genetic variation and geographic structure in a neotropical butterfly, Heliconius numata, and its closely related allies in the so-called melpomene-silvaniform subclade. H. numata is known to have evolved a supergene via the introgression of an adaptive inversion about 2.2 million years ago, triggering a polymorphism maintained by balancing selection. This locus controls variation in wing patterns involved in mimicry associations with distinct groups of co-mimics, and butterflies show disassortative mate preferences and heterozygote advantage at this locus. We contrasted patterns of genetic diversity and structure 1) among extant polymorphic and monomorphic populations of H. numata, 2) between H. numata and its close relatives, and 3) between ancestral lineages in a phylogenetic framework. We show that H. numata populations which carry the introgressed inversions in a balanced polymorphism show markedly distinct patterns of diversity compared to all other taxa. They show the highest diversity and demographic estimates in the entire clade, as well as a remarkably low level of geographic structure and isolation by distance across the entire Amazon basin. By contrast, monomorphic populations of H. numata as well as its sister species and their ancestral lineages all show the lowest effective population sizes and genetic diversity in the clade, and higher levels of geographical structure across the continent. This suggests that the large effective population size of polymorphic populations could be a property associated with harbouring the supergene. Our results are consistent with the hypothesis that the adaptive introgression of the inversion triggered a shift from directional to balancing selection and a change in gene flow due to disassortative mating, causing a general increase in genetic diversity and the homogenisation of genomes at the continental scale.

scholarly journals A rare MHC haplotype confers selective advantage in a free-living ruminant

2020 ◽  
Author(s):  
Wei Huang ◽  
Kara L Dicks ◽  
Jarrod D Hadfield ◽  
Susan E Johnston ◽  
Keith T Ballingall ◽  
...  
Keyword(s):  
Life Span ◽  
Mhc Class Ii ◽  
Balancing Selection ◽  
Natural Populations ◽  
Class Ii ◽  
Ovis Aries ◽  
Fluctuating Selection ◽  
Soay Sheep ◽  
Mhc Genes ◽  
Mhc Class Ii Genes

AbstractThe major histocompatibility complex (MHC) is the most variable gene family known in vertebrates. Parasite-mediated selection (PMS) is believed to be the main force maintaining diversity at MHC genes, but it has proven hard to demonstrate the exact PMS regime that is acting in natural populations. Demonstrating contemporary selection on MHC alleles is not trivial, and previous work has been constrained by limited genetic tools, low sample sizes, short time scales and anticonservative statistical approaches. Here, we use a conservative statistical approach to examine associations between MHC genes and fitness components, using haplotypes of expressed MHC class II genes in a large sample of Soay sheep (Ovis aries) monitored over their lifetimes between 1989 and 2012. Of the eight MHC haplotypes (A-H) identified, we found that haplotype C was associated with decreased male breeding success, haplotype D was associated with increased female life span, and haplotype F was associated with decreased female life span. Consistent with the increased lifespan in females, haplotype D has increased in frequency throughout the study period. Our results suggest the existence of contemporary balancing selection on MHC class II genes in Soay sheep as might be expected under the hypotheses of rare allele advantage or fluctuating selection and do not support an effect of heterozygous advantage.

scholarly journals Polymorphism and balancing selection at major histocompatibility complex loci.

Genetics ◽  
1992 ◽  
Vol 130 (4) ◽  
pp. 925-938 ◽  
Author(s):  
N Takahata ◽  
Y Satta ◽  
J Klein
Keyword(s):  
Major Histocompatibility Complex ◽  
Dna Sequences ◽  
Balancing Selection ◽  
Heterozygote Advantage ◽  
Nucleotide Substitution Rate ◽  
Major Histocompatibility ◽  
Effective Population ◽  
Nucleotide Substitutions ◽  
Mhc Genes ◽  
Histocompatibility Complex

Abstract Amino acid replacements in the peptide-binding region (PBR) of the functional major histocompatibility complex (Mhc) genes appear to be driven by balancing selection. Of the various types of balancing selection, we have examined a model equivalent to overdominance that confers heterozygote advantage. As discussed by A. Robertson, overdominance selection tends to maintain alleles that have more or less the same degree of heterozygote advantage. Because of this symmetry, the model makes various testable predictions about the genealogical relationships among different alleles and provides ways of analyzing DNA sequences of Mhc alleles. In this paper, we analyze DNA sequences of 85 alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci with respect to the number of alleles and extent of nucleotide differences at the PBR, as well as at the synonymous (presumably neutral) sites. Theory suggests that the number of alleles that differ at the sites targeted by selection (presumably the nonsynonymous sites in the PBR) should be equal to the mean number of nucleotide substitutions among pairs of alleles. We also demonstrate that the nucleotide substitution rate at the targeted sites relative to that of neutral sites may be much larger than 1. The predictions of the presented model are in surprisingly good agreement with the actual data and thus provide means for inferring certain population parameters. For overdominance selection in a finite population at equilibrium, the product of selection intensity (s) against homozygotes and the effective population size (N) is estimated to be 350-3000, being largest at the B locus and smallest at the C locus. We argue that N is of the order of 10(5) and s is several percent at most, if the mutation rate per site per generation is 10(-8).

scholarly journals Negative frequency-dependent selection is frequently confounding

2017 ◽  
Author(s):  
Dustin Brisson
Keyword(s):  
Genetic Diversity ◽  
Evolutionary Biology ◽  
Balancing Selection ◽  
Natural Populations ◽  
Research Progress ◽  
Selective Force ◽  
Frequency Dependent ◽  
Frequency Dependent Selection ◽  
Negative Frequency Dependent Selection ◽  
Peer Community

AbstractThis preprint has been reviewed and recommended by Peer Community in Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100024).The existence of persistent genetic variation within natural populations presents an evolutionary problem as natural selection and genetic drift tend to erode genetic diversity. Models of balancing selection were developed to account for the high and sometimes extreme levels of polymorphism found in many natural populations. Negative frequency-dependent selection may be the most powerful selective force maintaining balanced natural polymorphisms but it is also commonly misinterpreted. The aim of this review is to clarify the processes underlying negative frequency-dependent selection, describe classes of natural polymorphisms that can and cannot result from these processes, and discuss observational and experimental data that can aid in accurately identifying the processes that generated or are maintain diversity in nature. Finally, I consider the importance of accurately describing the processes affecting genetic diversity within populations as it relates to research progress.

A Chromosomal Region Promoting Outcrossing in a Conifer

Genetics ◽  
2001 ◽  
Vol 159 (3) ◽  
pp. 1283-1289
Author(s):  
Claire G Williams ◽  
Yi Zhou ◽  
Sarah E Hall
Keyword(s):  
Linkage Group ◽  
Chromosomal Region ◽  
Expressed Sequence Tag ◽  
Balancing Selection ◽  
Lethal Factor ◽  
Genetic Mechanism ◽  
Heterozygote Advantage ◽  
Experimental Profile ◽  
Gametic Selection ◽  
Pinus Taeda L

Abstract Prefertilization mechanisms influencing selfing rates are thought to be absent in conifers. Outcrossing in conifers is promoted via an embryo-lethal system, but the genetic mechanism is poorly understood. This study is the first experimental profile of the genetic mechanism promoting outcrossing in conifers. Molecular dissection of a Pinus taeda L. selfed pedigree detected a chromosomal region identified as PtTX3020-RPtest9. Within this region, a semilethal factor was tightly linked (r = 0.0076) to a polymorphic expressed sequence tag (EST). The linkage group flanking the lethal factor showed strong heterozygote advantage. Using genotypic frequencies for the linkage group, three hypotheses about the semilethal factor could be tested: (1) the presence of a balanced lethal system, i.e., a lethal factor present in each of the two marker intervals; (2) gametic selection operative prior to fertilization; and (3) a stage-specific lethal factor. Selection acted via the embryo-lethal system. No support for a genetic mechanism operating prior to fertilization was found. The semilethal factor exerted no effect after embryo maturity. The genetic mechanism promoting outcrossing in P. taeda L. appears to have a balancing selection system due to either pseudo-overdominance or true overdominance.

scholarly journals In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
O. Ajibola ◽  
M. F. Diop ◽  
A. Ghansah ◽  
L. Amenga-Etego ◽  
L. Golassa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Transmembrane Domain ◽  
Vaccine Development ◽  
Balancing Selection ◽  
Immune Recognition ◽  
African Countries ◽  
Vaccine Candidates ◽  
D Values ◽  
Tajima’S D

AbstractGenetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima’s D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima’s D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

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