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Parasite/pathogen
The Major Histocompatibility Complex (MHC)
| Question | Answer |
|---|---|
| What is the MHC? | Suite of genes coding for cell surface gycoprotein molecules in all vertebrates • Refered to as human leukocyte antigen (HLA) complex in humans |
| What is the MHC? | • First identified in conjunction with organ transplants ... hence the name • Role in distinguishing self from non-self |
| What does it do? | • Encodes molecules that bind and present antigens on the cell surface • Allow identification of non-self peptides (antigens) • Major role in determining acquired immune response |
| 3 main classes of MHC genes… and thus molecules | Class l • Present antigenic peptides to Tc cells • Endogenously derived peptides • intracellular pathogens e.g. viruses |
| 3 main classes of MHC genes… and thus molecules | Class ll • Present antigenic peptides to TH cells • Process exogenous antigens • Extracellular pathogens e.g. Gut parasites |
| 3 main classes of MHC genes… and thus molecules | Class III • Secrete proteins that have an immune function • Involved in inflammation etc |
| MHC genes | • set of replicated genes (mutliple gene duplications) • Genes linked together in a haplotype (a set of alleles across loci) • Inherited as a haplotype - little recombination |
| MHC genes | • Alleles – codominantly expressed (?) • Individuals – heterozygous or homozygous at each locus • Results in lots of MHC molecules - with slightly different structure - on each cell |
| Peptide binding region (PBR) | • PBR = Key area of MHC loci • Different amino acids at the PBR – result in different peptide binding properties • Bind different bits of different pathogens! |
| Peptide binding region (PBR) | • Promiscuous binding (?) • We expect MHC alleles to be directly associated with pathogen resistance |
| Pathogen resistance: MHC allele - pathogen associations | • In Humans (called HLA) – Malaria (Hill et al 1991: Hill 1998, 1999) – HIV progression (Trachtenberg et al 2003) |
| Pathogen resistance: MHC allele - pathogen associations | • In other animals – Sheep and nematodes (Paterson et al 1998) – Chickens & Marek’s disease (Briles et al 1977) – Chickens and avian flu (Boonyanuwat et al 2006a,b) |
| Maintenance of MHC variation (polymorphism) | - much variation in MHC • To do with selection from pathogens? • How is variation maintained in populations in the face of strong selection? • Why don’t all individuals contain the same ‘BEST’ MHC genes????? |
| Balancing selection | – forms of natural selection which work to maintain genetic polymorphism (multiple alleles at a locus) within a population – any kind of natural selection in which no single allele is absolutely most fit |
| Evidence for historical balancing selection | 1. Patterns of nucleotide substitution – Ratio of nonsynonymous (amino acid altering) to synonymous (silent) substitutions in the DNA - high in PBR regions |
| 2. Trans-species persistence of MHC alleles | At both MHC loci, each chimp allele (C) is more closely related to a human allele (H) than to other chimp alleles (Nei & Hughes 1991) |
| Evidence for balancing selection | dn/ds ratios and trans-species persistence -Tell us that balancing selection has operated some time in the past -But nothing about how balancing selection maintains variation |
| Evidence for balancing selection | -Three main models of balancing selection proposed - Heterozygote advantage - Rare allele advantage - Fluctuating selection -To find evidence we need to look for selection in contemporary populations |
| Heterozygote advantage | - better than homozygote at the MHC – 2 different alleles at a locus identify broader range of antigens • Detect more pathogen strains • Better detection of any single pathogen strain |
| Heterozygote advantage | Dominance Hz = better because they are more likely to contain the ‘best’ allele Overdominance the combination of alleles in Hz is better than both alleles alone (Synergy) - more resistant |
| Rare allele advantage – new alleles | Relative fitness of an allele declines when the frequency of that allele is high To begin with the frequency of ‘green’ MHC molecule is high because it detects the common ‘green' antigen (from the pathogen) |
| Rare allele advantage – new alleles | Individuals with new/rare MHC alleles are better able to detect pathogen variants that have evolved to evade common MHC alleles |
| Rare allele advantage – old alleles | 1000 generations for unselected allele to decrease from freq 1 to 0.1% (Borghans et al 2004) |
| Rare allele advantage | Theoretical support • Mechanistic models – good support Empirical evidence - very hard to show as changes occur over evolutionary time |
| Rare allele advantage | But its effect is inferred from: • spatial variation in relationship between resistance to a specific pathogen and MHC alleles in a host (i.e. different alleles confer resistance to same pathogen in different populations) |
| Rare allele advantage | - from changes in allele frequency over time in a single population - correlation between frequency of MHC allele and resistance |
| Fluctuating selection (Environmental heterogeneity) | Spatio-temporal fluctuations in pathogens infecting the host ......and thus selection Selects for different MHC alleles at different places and at different times Host gene flow and temporal fluctuations – maintains MHC variation in metapopulation |
| Fluctuating selection (Environmental heterogeneity) | Not single pathogen, due to different pathogens at different times and places in host population Evidence - greater among subpopulation variation at MHC than at neutral markers - shows different selection acting in different places at different times |
| Interacting mechanisms cause balancing selection | Mechanisms may positively reinforce each other Heterozygote advantage Rare allele advantage Fluctuating selection |
| Sexual selection and MHC variation? | • An individual’s MHC characteristics – May influence quantitative traits (e.g. size, secondary sexual characteristics) of an individual – linked to individual fitness and behaviour in natural populations • Importance of the MHC in sexual selection |
| MHC-based mate choice for ’good genes’ | Individual survival & condition is (at least partially) determined by the MHC genes they carry – Diversity of MHC alleles – Specific alleles |
| MHC-based mate choice for ’good genes’ | • Mate choice based on condition dependent cues – Good genes passed onto offspring • MHC diversity/specific alleles important |
| MHC-based mate choice for ’genetic compatibility’ | • Females prefer males with compatible MHC genes to their own – Most different set of MHC alleles - maximise offspring MHC diversity • Choice based on direct cues, e.g. smell – MHC dissimilarity important |
| MHC-dependent mate choice - evidence | • MHC-dependent mate choice • Humans Evidence = for both MHC dissimilarity and male MHC diversity • Fitness consequences? |
| Fitness consequences in the Seychelles warbler | Positive association between MHC diversity and juvenile survival mean life span of individuals with - less than 4 alleles = 1 year more than 4 alleles = 2.5 years |
| What drives MHC-dependent fertilisation patterns | • Pre-copulatory – MHC based mate choice – MHC dependent male-male competition • Post-copulatory – MHC related selective fertilisation – MHC dependent selective abortion – MHC dependent mortality of eggs/embryos |
| Interacting mechanisms cause balancing selection | • Mechanism may positively reinforce each other Heterozygote advantage Rare allele advantage Fluctuating selection |
| Conversation and the MHC | Individuals with greater MHC variation can identify and process and larger number of antigens – combat a wider range of pathogens |
| Conversation and the MHC | Populations with greater MHC variation can identify and process and larger number of antigens – combat a wider range of pathogens |
Created by:
rose.coo
Popular Ecology sets