'Artificial' Genes Design Simplified, Automated And Speeded Up, By Gene Design P

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'Artificial' Genes Design Simplified, Automated And Speeded Up, By

Gene Design Program From s Hopkins

http://www.medicalnewstoday.com/medicalnews.php?newsid=37882

s Hopkins researchers have announced the development of a Web-

based, automated computer program that they say greatly simplifies

the time-consuming and error-prone process of manually designing

artificial pieces of DNA.

The program, called GeneDesign, guides the design of blueprints for

DNA segments to the exacting specifications required for studying

gene function and genetically engineering cells. The blueprints are

then used by companies or other investigators to synthesize the gene.

A report on the program appears in the April 2006 issue of Genome

Research and online in mid-February. The publicly accessible Web site

can be found at http://slam.bs.jhmi.edu/gd.

GeneDesign automates the process of determining which base pairs --

the building blocks of DNA -- should be linked together in a

particular order to make a gene, according to Jef Boeke, Ph.D.,

professor of molecular biology and genetics and director of the High

Throughput Biology Center at The s Hopkins University School of

Medicine. A gene codes for a specific protein, and the order of the

hundreds or thousands of base pairs making up that gene determines

the order of the amino acid building blocks making up that protein.

Boeke is senior author of the paper.

" GeneDesign not only guides the user in designing the gene, but also

automatically diagnoses design flaws in the sequence of bases making

up the gene, " said Boeke.

Simplifying creation of so-called designer or artificial genes is

important because slight changes in the choice of base pairs making

up specific parts of the gene can have significant effects on how the

gene works and how efficiently it can be inserted into cells. " In the

past, " said Boeke, " researchers had to use many different programs to

address all the requirements of the separate steps of synthetic gene

design. "

The researchers have so far used GeneDesign to make a variety of

synthetic sequences, including a Ty1 element -- a mobile piece of

genetic material found in yeast cells. Ty1 elements can move from one

yeast cell and " jump " into a specific spot in one of a second yeast's

chromosomes. This jumping movement can cause mutations or bring in

additional genetic material to the yeast.

GeneDesign consists of six modules that can be used individually or

in series to automate the tasks required to design and manipulate

synthetic DNA sequences. The program allows the user to start with

either the sequence of the amino acid making up the protein or the

bases making up the gene that codes for that protein. Then the user

moves through a series of steps that guide the design of the gene and

vector that will carry the gene into the cell. Users can follow the

main " Design a Gene " path or use the modules individually as needed.

Vectors are mobile pieces of DNA that are used to carry artificial

genes into cells.

A major advantage to GeneDesign is the ability to choose specific

codons that work especially well in specific organisms, Boeke said. A

codon is a trio of bases in a gene that codes for a specific amino

acid building block. Most amino acids are represented by more than

one codon. For example, the codons GCU, GCC, GCA, GCG can each code

for the amino acid alanine.

Human, bacterial and yeast cells often differ in the codon they

prefer to use for a particular amino acid. " GeneDesign automatically

chooses the best codon to use depending on whether the gene is

supposed to work in a human cell, a bacterium, or a yeast cell, "

Boeke said. " When you're working with hundreds of codons, that's a

significant help. "

The program also simplifies the design of genes that will make

proteins with desired, specific modifications -- for example, changes

that make them work more efficiently.

Another advantage of the GeneDesign is ease of creating restriction

sites -- places along the DNA where the gene can be cut, said

M. , a Ph.D. candidate in the Department of Genetic

Medicine at Hopkins and first author of the paper. Scientists use

molecular scissors called restriction enzymes to make these cuts,

which allow them to do the cutting and pasting needed to put

artificial genes into vectors.

" GeneDesign guides the choice of the series of base pairs where the

restriction enzymes cut the DNA, " said. " That lets

investigators use different restriction enzymes to make cuts exactly

where they want to. "

If the same restriction site sequence occurred throughout the gene,

the specific restriction enzyme that recognizes that site would make

multiple cuts, according to . " That would make it

impossible to do the precise cutting and pasting needed to make and

use artificial genes, " she said.

However, even a successfully designed gene would not benefit

researchers if there were only one copy of it. " To make use of

artificial genes we need to make millions of copies of them for

experiments using a process called polymerase chain reaction, " said

Boeke. " By putting restriction sites into specific spots along the

gene, we can cut it into bite-sized pieces that are easily duplicated

millions of times. So the ability to cut and paste genes back

together again is critical for designing genes to the right

specifications, rapidly replicating them and putting them into

vectors to genetically engineer cells. "

The other authors of the paper include J. Wheelan and M.

Yarrington of The s Hopkins University School of Medicine High

Throughput Biology Center.

This work was supported by National Institutes of Health grants,

including a Research Roadmap grant.