Hlavn

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Hlavní histokompatibilní komplex (major
histocompatibility complex, MHC)
Význam imunogenetiky pri studiu evolucní ekologie
volne žijících populací obratlovcu

• Josef Bryja
• Oddelení populacní biologie
• Ústav biologie obratlovcu AV CR, Studenec

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Molecular Ecology
ATGCCGATTACCACACAGCTAATGCCGATTACCACACAGCTAATGCCGAT
TACCACACAGCTAATGCCGATTACCACACAGCTACTGATGGAAAGTCCTG
CATC
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Question zoology, taxonomy ecology, evolution
etc.
New dimension of knowledge
Example paternity analysis in birds
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Genetic markers

• Coding DNA (genes)
• transcribed sequences
• genetic code
• phenotype
• natural selection

• Non-coding DNA
• not functional (not known function)
• neutral to natural selection
• majority of DNA in eukaryotes
• pseudogenes
• repetitive DNA

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Expressed DNA segments - genes

• strict nucleotide structure
• exons and introns, START and STOP codons etc.
• transcription translation ? phenotype
• fuctional importance (f.e. homeotic genes, Wnt
  ligands)

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Why genes in molecular ecology?

• functional importance genetically determined
  variation
• gene products are not visible by standard
  ecological methods, but play a significant role
  in ecology, evolution and behaviour of animals
• it is necessary to use molecular methods to
  identify their variation
• expressed genes are selected by natural selection
• increasing importance in zoological and
  ecological studies (vs. neutral variation
  mtDNA, microsatellites etc.)

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Major histocompatibility complex (MHC)

1. MHC structure and function
2. MHC and natural selection
3. MHC and sexual selection
4. MHC and conservation genetics

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MHC structure and function
MHC history of description
Transplantations
Analyses of inbred mice
Major histocompatibility complex (MHC)
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MHC structure and function
Principle of graft rejection
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MHC structure Class I and II
MHC structure and function
Class I all nucleated cells
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MHC function presenting of antigen
MHC structure and function
MHC Class I
All nucleated somatic cells - intracellular
pathogens
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MHC function
MHC structure and function
Class I
Adaptive immune response
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MHC structure and function
Human MHC (HLA) (Nature 1999)
 gold standard 
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Genetic structure of MHC
MHC structure and function
224 gene loci (128 predicted to be expressed) 3.6
megabase
chromosom 6
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Functional categories of genes within MHC
MHC structure and function

1. Antigen processing and presentation (Class I and
   Class II genes, TAP etc.)
2. Innate immunity, inflammation, regulation of
   immunity (Class III genes, such as C4, C2,
   cytokines, TNF, etc.)
3. Intercellular interactions via MHC receptors and
   ligands (notch, tenascin, class I and II)
4. Functions unrelated to immunity

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Comparative genomics
MHC structure and function
Human (HLA) chr. 6 (completely sequenced in
1999) Mouse (H2) chr. 17 (first description of
MHC) Rat (RT1) chr. 20 (completely sequenced in
2004)
Homology DQA H2-Aa RT1.Ba a subunit of MHC
II
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MHC in other species
MHC structure and function
BoLA - Cattle DLA - Domestic Dogs, Wolves and
Coyotes FLA - Domestic Cats IMGT/NHP Apes, Old
World Monkeys, New World Monkeys SLA - Pigs ELA
Horses Chicken MHC (B-complex Rfp-Y) only
19 genes (1/20 of the human one)  minimal
essential  MHC Nature 1999 http//www.ebi.ac.uk
/ipd/mhc/index.html
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MHC in birds
MHC structure and function
 minimal essential  is not typical for all birds
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MHC in all vertebrates?
MHC structure and function
The class I or class II prototype genes have not
yet been found in the lamprey, amphioxus and the
sea urchin
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Antigen binding site (ABS)
MHC structure and function
antigen recognition site (ARS) peptide
binding region (PBR)
Class I
Class II
crystal structure
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ABS vetšina variability
MHC structure and function
MHC Class II, exon 2 encoding ABS
Bryja et al., Immunogenetics 2005
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MHC structure and function
Intensity of positive selection
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MHC structure and function

• trans-species polymorphism
• neutral polymorphism is not expected to be
  maintained for a long time across speciation
  events (based on coalescent theory)
• polymorphism can persist much longer under
  balancing selection
• the same or similar alleles are found in related
  species

Microtus Arvicola Clethrionomys
Mus
Rattus 5 spp.
MHC Class II, DQA gene, Exon 2 Bryja et al.,
Immunogenetics 2005
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MHC polymorphism
MHC structure and function

• High allelic variability more than 200
  described alleles in some human loci
• Gene duplication - species specific Class I up
  to 17 loci in cichlids vs. max. 3 loci in
  salmonids
• Recombination both within and among loci

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Complex MHC polymorphism
MHC structure and function
DQB
DRB 1-11
Rhesus macaque
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Maintenance of allelic polymorphism
contemporary natural selection?
Selection on MHC

• Disease based mechanisms (host-parasite
  interactions)
• overdominance hypothesis (heterozygote
  advantage) heterozygotes resist a broader array
  of pathogens than homozygotes
• negative frequency dependent selection hypothesis
  (rare allele advantage) cycling of fitness
  values of different genotypes in both hosts and
  pathogens
• Reproductive mechanisms (sexual selection)

(Bernatchez Landry, JEB 2003 Garrigan
Hedrick, Evolution 2003 Piertney Oliver,
Heredity 2006)
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Overdominance hypothesis
Selection on MHC
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Negative frequency-dependent selection hypothesis
Selection on MHC

• rare alleles advantage ? dynamic host-parasite
  coevolution
• association between MHC alleles and helmints load
  (mice, gerbils, lemurs - 2005) or survival to
  bacteria (Atlantic salmon)
• seems more probable than overdominance hypothesis

black infected white not infected
Gerbillurus paeba (Harf Sommer 2005)
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Comparison of neutral and MHC variation- another
way to detect contemporary selection
Selection on MHC

• MHC variation
• random genetic drift
• migration (gene flow)
• selection

• neutral variation (microsatellites)
• random genetic drift
• migration (gene flow)

Fst measure of population differentiation
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MHC vs. neutral markers example of local
adaptation in fish
Selection on MHC

• Salmo salar (Landry Bernatchez 2001)
  Microsatellites vs. MHC class IIB gene
• no correllation of FST estimated from
  microsatellites and MHC ( different population
  genetic structure on both marker types)
• higher differenciation (FST) on MHC
• similar results in other salmonids
• local adaptation for microhabitats in the river
• no evidence of selection in other vertebrate
  groups

(Landry Bernatchez 2001)
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MHC vs. neutral markers local adaptation during
population cycle in voles
Selection on MHC

• large-scale population dynamics (4-5 years
  periods)
• neutral genetic structure (17 microsatellite
  loci)
• two MHC Class II genes (DQA, DRB)

• Arvicola terrestris
• in the Jura Mts., Franche Comté

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MHC vs. neutral markers local adaptation during
population cycle in voles
DRB
17 MS

• 3 years of increasing phase

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Density dependent changes in selection pattern
Selection on MHC
High density - balancing selection
Low density - local diversifying selection
(Bryja et al., submitted to Evolution)
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MHC and mate choice

• Potts et al. 1991 Mating patterns in seminatural
  populations of mice influenced by MHC genotype.
  Nature, 352. 619-621.
• mechanism not well understood (? MHC fragments
  volatiles ? olfactory sensory neurons VNO
  nonvolatile stimuli)
• odours are used in mate choice and kin
  recognition

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Sexual selection hypotheses
MHC and mate choice

• A) mating preferences to enhance parasite
  resistance disease based models of sexual
  selection
• MHC good genes
• B) inbreeding avoidance hypothesis genetic
  incompatibility system (avoidance of the
  expression of recessive deleterious mutations)
• MHC complementary genes

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MHC and mate choice in fish
MHC and mate choice
? increased offspring heterozygosity
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Gasterosteus aculeatusMilinski et al.

• Recently duplicated MHC class IIB genes
• Majority of individuals have medium number of
  alleles
• Medium number of alleles minimum of parasites
• ?? calculate their own alleles and choose ??
  to the intent of optimizing the number in the
  offspring
• choice is affected by MHC peptid ligands

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MHC and mate choice in birds
MHC and mate choice
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MHC and mate choice in mammals
MHC and mate choice
..... much controversy still exists
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Conservation genetics
MHC and conservation

• adaptive variation - outbreeding depression

Fundamental question in conservation
genetics How much MHC diversity is required to
ensure long-term population viability ?
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How much MHC diversity is required to ensure
long-term population viability ?
MHC and conservation

• Bottleneck ? low genetic variation (including
  adaptive variation) due to genetic drift ?
  vulnerability to infectious disease
• Balancing selection retain variation at
  selected loci (MHC)

vs.
s lt 1/2Ne
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Future prospects in MHC research

• increase number of well-designed studies in wild
  populations (parasites, neutral variation,
  measures of conditions etc.)
• experiments using individuals with known MHC
  genotypes (survival and reproduction)
• genomics, transcriptomics, proteomics
  description of real MHC variation