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Public Consortium Celera Genomics

Sequence Genetic Mapping,


Genomes
Find Genes Mutation Detection

Establish
Function and Diagnostics/
Disease Mechanism Prognostics

Drug
Candidates Cure Gene Therapy
“Sequence the 3 billion (+) base pairs of human DNA
and identify all genes contained in the human genome”

DNA Sequence
‘Reads’ -
Need
60,000,000
of them!!
Time Line of the Human Genome Project
BCM-HGSC: Sequencing Throughput
2,000,000

1,800,000 Today 1.9 M reads


1,600,000

1,400,000

1,200,000

1,000,000

800,000

600,000

400,000

200,000

0
Jan-00 May-00 Sep-00 Jan-01 May-01 Sep-01 Jan-02 May-02
Standard Molecular Biology techniques – running agarose gels.
CS-Packard DNA Production Robotic Systems (x 3)
Multiplexed (104) Capillary Array for Electrophoresis
State of the Art - ABI 3700 “Prism” DNA Sequencer
US $300,000 Each!

A room full of 3700 Sequencers – total price tag of US $22.5 Million


“State of the Art”: Assembly
Whole Genome
BAC by BAC
Shotgun (WGS)
Versus

-Front end loaded,


- Tractable Assembly -Efficient front end,
Problem - Huge Assembly Problem
BCM-
HGSC
Linux Farm
Very small changes in technology
have had a huge impact on the HGP…..

Imagine what a large change


in technology would do…
The Future: More Genomes!!
Rat, Mouse, Rabbit, Dog, Chimp, Rhesus, Zebrafish,
Fugu, Hamster, Cow, Sheep, Pig, Chicken, Honey Bee,
Silk Worm, Shark, Dolphin, Whale, Frog, Sea Urchin,
Sea Squirt, Sea Turtle, Salmon, Hydra, Wallaby,
Platypus, Rice, Wheat, Maize, Sorgum, Soy,
Banana, Poplar, Potato, Corn, Sea Turtle, Wheat,
Pine ……….
COMPLETE (HETEROZYGOUS)
MUTATION DETECTION

ABI 370:
Universal
Primer
Tag PCR

exon
13,000
OMIM - 10,000 Entries

BCM-
HGSC
Dextrocardia and Situs Inversus

Disorders of laterality
occur in
2 – 3 per 10,000 live births
Pulmonary valve
stenosis mutations

BCM-
HGSC
SCREENING 160 SPORADIC PATIENTS IN
NODAL SIGNALING PATHWAY
RECEPTORS NODAL + LEFTYA competing for receptor
TYPE 1 (ALK2 “ACVR1”
ALK4 “ACVR1B”; ALK7
components
(mouse)
TYPE 2 (ActRIIA “ACVR2”;
ActRIIB “ACVR2b”) EGF-CFC
Co-Factor Proteins
Cripto and Cryptic
Interacts with ALK4 receptor

INTRACELLULAR MEDIATORS, SMAD2, SMAD3, SMAD4

SMADS INTERACTS w/ SMADS INTERACTS w/


TGIF to repress pathway FAST1 to activate gene

Human mutations in
Target Genes: PITX2 + NODAL +
all loci marked in read LEFTYB
Epigenetics/Methylation

Epigenix web site

Genomic DNA can be different in


Different cells of the same person…..
BCM-HGSC ~ 230 Personnel

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