Powerful New Tool for Decoding Gene Functions in Mammals and Man

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A Powerful New Tool for Decoding Gene Functions in Mammals and Man

http://www.medicalnewstoday.com/medicalnews.php?newsid=29058

14 Aug 2005

A collaborative project between American and Chinese researchers

developed a way to study the function of genes in mice and man by

using a moveable genetic element from moths, according to a report in

the journal Cell. " We know how many genes are in the mammalian

genome, but that does not tell us how they carry out their jobs, "

said senior author Tian Xu, Professor and Vice Chair of Genetics at

Yale University School of Medicine and a Medical

Institute Investigator. " We have found a way to systematically

inactivate genes in the mouse genome so we can understand the

functions of these genes. "

After sequencing the human and mouse genomes, many scientists have

shifted their attention to determining the function of all of those

genes. The strategy is to mutate each gene, to observe the

consequences, and investigate the molecular mechanisms. In the past

two decades, only a small percentage of the genes shared by mice and

humans have been analyzed in detail.

Genetic elements, called transposons, move from place to place in the

DNA and allow material to be inserted or relocated. Bacteria swap

antibiotic-resistance genes with transposons. Scientists have

tailored this natural gene shuffling technique to insert genes and to

mutate genes in fruit flies and simple organisms to learn the

function of individual genes.

Transposons have proved to be valuable genetic tools for many

organisms, but not for vertebrates and mammals. General application

in mouse genetics was limited as they travel at low frequencies to

limited locations, and had little capacity to carry DNA fragments. It

took Xu's team six years to develop an efficient tool for genetic

manipulations in vertebrates and mammals. Xu and his colleagues at

Fudan University in Shanghai, China finally chose a transposon called

piggyBac that was originally identified in the cabbage looper moth.

They discovered that it was stable and versatile in mouse and human

cell lines, providing a new way to genetically manipulate mammalian

cells. It also worked in mice even when it carried a couple of extra

genes.

Xu's team made it easier to see the genes piggyBac associates with by

adding a red fluorescent protein and an enzyme that changes the coat

color of a white mouse to grey or black. The genes carried by the

transposons have been stably inherited and expressed through five

generations.

" The transposon acts as a genetic beacon, so researchers can easily

track its location without having to sequence the entire genome, "

said Xu. In their experiments, piggyBac incorporated into many

chromosomes in human and mouse cells. PiggyBac can be removed from a

mouse lineage by breeding with another mouse that has the enzyme to

excise the transposon.

This technique is a powerful new tool for generating transgenic

animals for vertebrates and mammals, and a potential new vehicle for

human gene therapy. Although piggyBac inserts itself randomly into

the DNA, it most often locates in genes, making it useful for

mutating genes and thus, revealing gene functions.

" This work represents another major step forward from Tian's

laboratory. It teaches us how transposons work in mammalian systems,

while providing a tool for the systematic study of gene function

throughout the human and mouse genomes. "

In three months, the two graduate students who worked on the project

generated mice mutating 75 different genes. Xu, Min Han, an HHMI

investigator at the University of Colorado, Boulder, and Yuan Zhuang

of Duke University, and their colleagues at Fudan University are in

the process of scaling up piggyBac for the Mouse Functional Genome

Project, which is aiming to mutate the majority of mouse genes at a

state-of-the-art research facility in China to systematically

understand the functions of the mammalian genes.

Xu expects the technique to be particularly useful for identifying

genes and drug targets for diseases such as cancers and diabetes.

Citation: Cell: (12 August 2005)

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