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?