Transcript Lecture 4: codominance and complementation

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 proteins involved in the
recognition of self and non-self by the immune system
– important in determining histocompatibility for
transplantation
 HLA’s present foreign antigens to the immune system –
figure in the resistance to viral and bacterial pathogens
 HLA’s 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
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.
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

 Class II MHC genes: encode glycoproteins expressed primarily on APC’s
(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
• 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
HLA genes are codominant: A protein from
each parental gene is expresed on cellsurfaces
MHC molecules expressed on APC’s in a heterozygous mouse.
Both maternal and paternal genes are expressed.
TC cell
CD8
TCR
TH cell
TCR
CD4
Class I MHC
Class II MHC
Most
nucleated
cells
“Target cell”
Professional
APC’s:
•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
Complementation
 A method to determine if two mutants are
due to a defect within single gene, i.e.
within a single genetic locus
Mutant
screen:
A 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)
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.
A genetic complementation grid showing results
for 6 mutations in all pair wise combinations
Representation of the results of
complementation tests by a line diagram
Molecular explanation of genetic complementation
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