Lecture 4 January 30, 2006

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Lecture 4 January 30, 2006

• End of Chapter 3 codominance through
  complementation

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HLA (MHC) genes are codominant and have multiple
alleles

• HLAs are cell-surface proteins involved in the
  recognition of self and non-self by the immune
  system important in determining
  histocompatibility for transplantation
• HLAs present foreign antigens to the immune
  system figure in the resistance to viral and
  bacterial pathogens
• HLAs are codominantly expressed
• Multiple alleles of HLA in a population increases
  the likelihood that the population will survive a
  pathogen threat, also cause histoincompatibility
  in organ and tissue transplants

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Polymorphism and polygeny

• MHC genes are polymorphic that is, there are
  large numbers of alleles for each gene
• MHC genes are polygenic that is, there are a
  number of different MHC genes.

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Mouse and Human genomic map of MHC genes

• Class II MHC genes pairs of class II a and b
  chains are DR, DP, DQ
• with extra DR-b chain, up to four types of
  class II MHC
• Class III MHC genes complement proteins C2, C4,
  factor B,
• cytokine TNF-a, lymphotoxin TNF-b
• Class I MHC genes
• three types of class I MHC a-chains are called
  HLA-A, HLA-B and HLA-C
• Non-classical genes labeled in black DM
  catalyzes peptide binding to MHC class II
  molecules, DN and DO regulate DM, TAP and LMP are
  components of the proteasome

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• Class II MHC genes encode glycoproteins
  expressed primarily on APCs (macrophages,
  dendritic cells and B cells) where they present
  processed antigenic peptides to TH cells
• Class III MHC genes encode secreted proteins
  that have immune functions e.g. components of the
  complement system and molecules involved in
  inflammation, and other proteins
• Class I MHC genes encode glycoproteins expressed
  on the surface of nearly all nucleated cells
  present peptide antigens to TC cells
• b2-microglobulin, which forms a complex with the
  MHC class I a-chains is encoded on a separate
  chromosome

Chromosome 17
Simplified comparison of MHC genes in mouse and
human
Chromosome 6
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• Haplotype the particular combination of MHC
  alleles found on one parental chromosome
• Expression of MHC alleles is codominant, with
  protein products expressed from both haplotypes
  in an individual

The many combinations of possible haplotypes
contributes to the difficulty of finding
compatible donors for tissue transplantion
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HLA genes are codominant A protein from each
parental gene is expresed on cell-surfaces
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MHC molecules expressed on APCs in a
heterozygous mouse. Both maternal and paternal
genes are expressed.
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TC cell
TH cell
TCR
TCR
CD8
CD4
Class I MHC
Class II MHC
Most nucleated cells Target cell

• Professional
• APCs
• B cell
• macrophage
• dendritic cell

• Class I MHC presents processed endogenous antigen
  to CD8 (cytotoxic) T cells CD8 cells are Class I
  restricted
• Class II MHC presents processed exogenous antigen
  to CD4 (helper) T cells CD4 cells are Class II
  restricted

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Complementation

• A method to determine if two mutants are due to a
  defect within single gene, i.e. within a single
  genetic locus

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Mutant screenA group of organisms are purposely
mutagenized with radiation or chemical mutagens

• A great example the Heidelberg mutagenesis
  screen performed by Christiane Nusslein-Volhard
  and Eric Wieschaus, which won the Nobel Prize for
  Medicine in 1995
• They established and tested 27,000 fly lines
  (saturation screen of 5000 expected genes in
  Drosophila)
• They found 18,000 lethal mutations
• 4332 mutations causing embryonic lethality
• 580 mutations causing embryonic phenotypes
• 139 complementation groups (genes)

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Genetic Complementation
A genetic complementation test allows one to
determine if two mutations with the same
phenotype are in the same gene or in 2 different
genes.
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A genetic complementation grid showing results
for 6 mutations in all pair wise combinations
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Representation of the results of complementation
tests by a line diagram
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Molecular explanation of genetic complementation
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Next time Chapter 4 Chromosomes
At right A newt lung cell in culture at an
intermediate stage of mitotic spindle formation,
when most of the chromosomes (blue) have already
connected to spindle microtubules emanating from
the centrosomes but have not yet congressed to
the spindle equator. Immunofluorescence
highlights alpha-tubulin (green) gamma-tubulin
(magenta) keratin (red) Image A. Khodjakov