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Lecture 4 January 30, 2006

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Lecture 4 January 30, 2006 End of Chapter 3: codominance through complementation HLA (MHC) genes are codominant and have multiple alleles HLA s are cell-surface ... – PowerPoint PPT presentation

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Title: Lecture 4 January 30, 2006


1
Lecture 4 January 30, 2006
  • End of Chapter 3 codominance through
    complementation

2
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

3
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.

4
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

5
  • 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
6
  • 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
7
HLA genes are codominant A protein from each
parental gene is expresed on cell-surfaces
8
MHC molecules expressed on APCs in a
heterozygous mouse. Both maternal and paternal
genes are expressed.
9
(No Transcript)
10
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

11
Complementation
  • A method to determine if two mutants are due to a
    defect within single gene, i.e. within a single
    genetic locus

12
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)

13
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.
14
A genetic complementation grid showing results
for 6 mutations in all pair wise combinations
15
Representation of the results of complementation
tests by a line diagram
16
Molecular explanation of genetic complementation
17
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
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