Why synthsize genes and genomes?

103 106105104

-minimal life-genome rewrite-genetic circuits

-metabolic pathways

-vaccines-gene therapy-individual genes

-assembly scaffolds

DNA length(base pairs)

Error Correction with Flawed Components

A C G G

T C T G

A C T A

A C T GWinograd and Cowan (1967) “Reliable Computation in the Presence of Noise”

A circuit containing N (error-free) gates can be simulated with probability of error at most , using N log(N/) faulty gates, which fail with probability p, so long as p<pth.

von Neumann (1956)

DNA “consensus vote”

x

Mismatch Recognition

+ Nuclease Activity

M

N

x

x

M

N

M

N

M

N

Repair Operation

Complete error correction when no strand is error-free

xMN

Exchange RepairCopies 1 and 2

Repair Operation

Complete error correction when no strand is error-free

xMN

Exchange RepairCopies 1 and 2

Repair Operation

Complete error correction when no strand is error-free

Exchange RepairCopies 2 and 3

Repair Operation

Complete error correction when no strand is error-free

Exchange RepairCopies 2 and 3

Current milestone: 1 error per 20,000 bpNext milestone: 1 error per 100,000 bp

Repair Operation

Complete error correction when no strand is error-free

Why Synthetic Genomes?

• Drug biosynthesis of new proteins– Nonnatural Amino Acids

• Optimal codons

• Genome stability Safer Bio-isolation

Nonnatural amino acids Genome Engineering

Cellular ChassisVirus-resistant strains

E. coli rE.coli

Recoding E.coli: rE.coli

E. ColiMG16554.6 MB

Remove tRNAs, tRNA synthetases- three codons “free”- Viral resistance?

2. AGR (R) > CGR (R)

Remove RF1- one codon available for unnatural amino acids- Viral resistance?

1. UAG stop > UAA stop

1. Codons: AGY Ser > UCX Ser2. tRNAs: AGY Ser > AGY Leu3. Codons: UUR/CUX Leu > AGY Ser4. tRNAs: UUR Leu > UUR Ser5. Codons: UCX Ser > UUR Ser (Leu & Ser now switched)

tRNAs: AGY (S) > AGY (L)

3. AGY (S) > UCX (S)

tRNAs: UUR (L) > UUR (S)

3. UUR/CUX (L) > AGY (S)