Human Diseases and Biomarkers
Immune Response and Antibodies
Viruses and Vaccines
October 17, 2005
10:20 to 11:10 am
• Marker: Something used as a mark or
indication, as a bookmark or tombstone.
• Biomarker: A characteristic or factor by
which a cell or molecule can be recognized
Examples of Biomarkers
• Hemoglobin expression is a marker of red
• Chiasma is a marker of chromosome
recombination during meiosis
• CD4 is a marker of helper T cells
• Antibody that recognnizes HIV is a marker
of HIV infection
• CD69 expression is a marker of T cell
Without biomarkers, the study of
biology and medicine would be
General Introduction of the
Human Genome: ~30,000 genes
Homozygosity and Heterozygosity
• Homozygosity: The state of having identical
genes at one or more paired loci in
• Heterozygosity: The state of having
different allelic genes at one or more paired
loci in homologous chromosomes.
Genetics and Human Diseases
• Dominant Inheritance (顯性遺傳). Every
affected individual has at least one affected
parent. Heterozygoes are affected.
• Recessive Inheritance (隱性遺傳). When
both parents are homozygoes
(asymptomatic carriers), one fourth of their
offspring will be affected.
• Hardy-Weinberg Law
– For A and a alleles, there are 3 possible
combinations: AA, Aa, aa.
– p (proportion of A genes) + q (proportion of a
genes) = 1.
– Binomial distribution of genotypes: p2 (AA),
2pq (Aa), q2 (aa).
• Two parts: Innate and adaptive immune
• Cells of the immune system.
• How does immune response get started?
• Two general types of effector systems:
humoral (antibody-mediated) and cell-
• A term for a group of microorganisms that
are capable of passing through fine filters
that retain most bacteria, and are incapable
of growth and reproduction apart from
• Types of viruses.
• Any preparation intended for active
immunological prophylaxis preparations of
killed microbes or virulent strains or living
microbes of attenuated (variant or mutant)
strains; or microbial, fungal, plant,
protozoal, or metazoan derivatives or
ENU Mutant Mice As a Tool to
Study Immunology and Human
October 17, 2005
11:20 am – 12:10 pm
Major Genome-Wide Mouse
• Australia: Australian National
• USA: Baylor; Jackson Lab; ORNL; U
• Germany: GSF
• UK: Medical Research Council, Harwell
• Japan: RIKEN
• Canada: University of Toronto
• Large-scale creation of randomly
induced mutant mice.
• Screen for phenotypes outside the
• Inheritance test.
• Map mutated gene.
• Mouse model established!
BREEDING SCHEME FOR ENU-MUTAGENIZED MICE
day100 donor of mutant sperms
Unique aspects of MMPCF
• Extensive renovation required
before scientific projects can
• “Live” experimental subjects.
• Upstream rather than
downstream: Discovery tool.
• Less bias than pure hypothesis-driven
• Any given G3 mice can harbor ~10 mutated
genes. 3,000 mice ~ one genome coverage.
• Hypermorph, hypomorph, and null mutations
can all be identified.
• Embryonic lethals and fertility mutants will be
• Phenotypes caused by 2 or more affected
genes are not identified.
Oracle-based “Mos-Track” mouse
MosTrack Routine Check
Breeding Termination Spouse
Breeder View Breeder G2
Registration of Death
Mouse Update Mouse Unknown
Generate New Pedigree
ENU Mutant Log
Mouse Card Print by Mouse
Print Print by Cage
Search Breeding History
Family Tree Panel –
Family tree show how family members that are related for a selected pedigree/breeder. We
can easily check the breeding status by reviewing this chart.
Number count of selected family
G2 Spouse without litters
G2 Spouse with litters
Evolution of mouse cards
2002 - 2003 2003 Mar – 2004 Mar 2004 Mar - Present
Screening results generated by
WT F2 progeny
Pedigree 154: Dilute coat color
G3 B6J 154-f 007 and littermates
G3 B6J 171-q 015 WT
Polydactyl extra toe & extra footpad
WT G3 B6J 165-l 057
Syndactyl of the 2nd and 3rd digits at right forelimb
also, missing a digit and a footpad
WT G3 B6J 162-c 159
Pedigree 137: Abnormal Limb
Affected animals have short digits and mini-paws,
showing great difficulty in forelimb grip.
WT G3 B6J 137-c 062
1 Day of Age
G3 B6J 189-d 001 WT
Short tail newborns:
High neonatal mortality rate
G3 B6J 131-c 067 WT
G3 B6J 174-j 027 WT
Pedigree 244: Circler
G1 male displays erratic circling behavior
G1 Phenodeviant and littermate
Huge Right Eye
G3 B6J 202-m 033 WT
Short Snout (some with upturned end)
G3 B6J 200-g 119 WT WT G3 B6J 200-g 119
Sex: Female Sex: Female
Pedigree 215: Nervous
Pedigree 248: Hopping
Proof of concept established
• Marker set up
• Rough mapping (Beier’s approach)
– Use of 40 STR makers comprising 21
chromosomal intervals in 19 autosomes
– The score of non-recombinant haplotype
– Interval χ2 analysis
• Semi-Fine mapping to a 1-2 cM region
What Does All This Mean?
• Opportunity to perform basic, applied, and
clinical studies using the same mutant
models, a solid foundation for integration
• In-depth gene function in the context of
mouse model system advances fundamental
knowledge, enables drug discovery, and may
result in disease prevention/treatment,
better health/quality of life for people.