Abnormal Gene Function
DNA
mRNA
Transcription
Translation
Protein
DNA -> RNA -> Protein
Synthesis of Abnormal ProteinsMutations Often Result in the
X
X
X
Future-Shaping Techologies
• Genetic Screening - Marfan Case• Gene Replacement - Bubble Babies• Stem Cells• Cloning - Dolly the Sheep• Agriculture - Crop Modification
mf/mf = 1/4 offspring = Marfan
+/+ = 1/4 offspring = Normalor+/mf mf/+ = 1/2 offspring = Normal
+ +
mfmf
mf
+
+
mf
One quarter of the offspring from two Marfan carrier parents will have Marfan Syndrome
+ mf
Two types of mother’s eggs
+
mf
Two types of father’s sperm
+/mf
+/+ mf/+
mf/mf
Genes, Chromosomes, and Genomes
Gene = Basic Unit of Inheritance
Gene 1 Gene 2 Gene 5Gene 3 Gene 4
Genome = 30,000-50,000 Genes
Chromosome = 1,000-5,000 Genes
≈ 5,000 Genes Cause Disease When Mutant
Mutations Carried in Father’s Genome
+
Mass Scale IVF
Mutations Carried in Mother’s Genome
Normal red blood cells
Sickle cell red blood cells
+ + +
scsc
+ sc
sc
sc
+
+
sc
Two types of mother’s eggs
Two types of father’s sperm
One half of the offspring from two Sickle Cell carrier parents will be protected from Malaria
+/+ = 1/4 offspring = Normal/ Malaria Sensitive
sc/sc = 1/4 offspring = Sickle Cell
+/sc
+/+ sc/+
sc/sc
+/sc or sc/+ = 1/2 offspring = Normal/Malaria Resistant
Resistance to Malaria
Low Blood Pressure
Longevity
Musical Ability
Resistance to Flu
Low Cancer Risk
Reduced Risk for Alzheimer Disease
Desirable Traits Can be Linked to Disease Genes
Immunity to Plague
SCID “Bubble” Baby
Dolly and Kid
Cloned Sheep
A/P Axis
AbdomenHead
Tail
A possible picture of the most recent commonancestor of vertebrate and invertebrates
Mouth
Anus/Genitals
Nervous System
Non-neural Ectoderm
D/V Axis
Photosensitiveorgans
SensoryAppendages?
Eyespot?
Gills?
Protrusions orappendages
http://homophila.sdsc.edu
Fly Genes similar to Human Angelman Gene
Alignment of Human and Fly Angelman Genes
Human Protein: LRLKVRRDHIIDDALVRLEMIAMENPADLKKQLFly Protein: LKLTVRRDQLINDALIGLEMVAMSNPKDLKKQLMatch/Similar: L+L*VRRD*+I+DAL+*LEM+AM*NP*DLKKQL
Human Disease Genes in Flies
• >2,400 of 5,000 Human disease genes identified
• Many disease genes have fly counterparts
– 75% disease genes related to a fly gene – 30% disease genes highly similar to a fly gene
• Disease genes with counterparts in flies fall into all major categories of disorders
Appropriate Disease Genes to Study in Flies
• Human Disease Gene Function Poorly Understood• Fly Counterpart Highly Related to Human Gene• Facility of Genetic Analysis in Fly• Identified Loci Subject to Explicit Test in Humans:
“Closing-the-Loop”
Closing-the-Loop in Humans
• Identify New Candidate Disease Genes– Alzheimer Disease (FAD)
• Identify Human Modifier Loci– Primary Congenital Glaucoma (PCG)
• Dissect Complex Polygenic Trait– Cardiac Defects in Down syndrome (DS)
• Identify Candidate Protein Targets– Angelman Syndrome (AS)
• Study host-pathogen interactions– Bacterial toxin function
• Place Disease Gene in a Pathway– Dyggve-Melchoir-Clausen syndrome (DMC)
Placing DMC in a genetic pathway
Goal:
Identify genetic pathway in which DMC functions
Method:
1) Mis-express human and Drosophila DMC genes in Drosophila.
2) Mutate single Drosophila dmc orthologue
3) Determine if the pathway identified in Drosophila is also affected
in human DMC or SMC patients.
DMC: a gene in search of a function
• DMC Phenotype– Short trunk dwarfism– Psychomotor retardation– Radiologically Identical to Smith-McCort Dysplasia– Encodes multispan transmembrane protein: Dymeclin– Unknown function in regulating bone growth
Normal DMC patient
DMC: a gene in search of a function
• DMC Phenotype– Short trunk dwarfism– Psychomotor retardation– Radiologically Identical to Smith-McCort Dysplasia– Encodes multispan transmembrane protein: Dymeclin– Unknown function in regulating bone growth
Normal Growth Plate DMC patient
Nakamura et al., Am J Med Genet 72:11-17, 1997
The fly wing as genetic assay system
BMP Pathway Mutant
L4L4
L5
L2
L3
Hh Pathway Mutant
L2
L3
L4
L5
L3
Normal Wing
L2
L4
L5
BMP
BMP
Hh
M Notch & Wg
Notch Pathway Mutant
L2
L3
L4
L5
ptc, dpp
L2
L3
L4
L5
sal
Veins form at Gene Expression Boundaries
AP En
En -> Hh -> Diffuses -> dpp in A/P Organizer
L3
L4
OrganizerA/P
pct
L2
L3
L4
L5
hh
Dpp
Dpp -> Diffuses -> sal -> L2 vein
APdpp
sal
sal
brk
L2
omb
brk L5
L3
L4
Reduced hh functionL2
L3L4
L5
WTL2
L3
L4
L5
Hh Determines Positions of L3 and L4 Veins
Reduced hh function
dppAP
L3L4
hh dppEn
En -> Hh -> Diffuses ->dpp in A/P Organizer
ptc, dppAP En
L3
L4hh dpp
Ectopic dmc reduces the response to Hh
ptcGAL4>dmc
L3L4
L2
L5
enGAL4>dmc
L3L4
L2
L5
ubiGAL4>dmc
L3L4
L2
L5wt
L3
L4
L2
L5
New CovenantJesse Bier
Nobody tells the flowers what to do,they grow the way they please.They don't take orders from me and you—nor do the grasses or trees.
But that was long ago,before the age of science.Now that we know what we know,we splice them to compliance.
Soon trees must do what they are told,according to special genes. Nothing the same as of old—and grasses, flowers know what that means.
Next to come are you and meafter the flowers, trees and grasses.But: Who will decide and overseenewfounded families, permanent classes?