Probing the Mouse Genome

Rick Woychik of the Biology Division can tell you almost anything you want to know about mouse genes. So, what does this have to do with sequencing the human genome? Well, as it turns out, there are a number of similarities (perhaps more than we'd like to admit) between mouse genes and human genes. And, as a practical matter, it's a lot easier to conduct a controlled study of a mouse in a lab than a man on the street.

Woychik looks at efforts to sequence the human genome as the first step in understanding how the genetic code actually works. "Once we've sequenced and analyzed all the DNA bases of the human genome," he says, "we will know where all the genes are, but we won't know what they do." Studying the mouse genome could provide some of the missing pieces of the genomic puzzle.

"If we determine the function of a particular mouse gene whose location we know," Woychik says, "we can often look at the corresponding area on a human chromosome and locate the functionally equivalent human gene."

One of the techniques Woychik uses to probe the mouse genome is known as insertional mutagenesis. In this technique, hundreds of identical pieces of DNA are injected into mouse zygotes (fertilized eggs) in the hope of creating mutations in the resulting offspring. The DNA fragments, or "transgenes," are then incorporated, seemingly at random, into the zygote's genetic code. More often than not, this process results in normal laboratory mice, but every so often an unusual variation in the appearance or physical structure of one of the offspring, such as malformed limbs or internal organs, suggests that a mutation has occurred. "When we see an abnormality in the appearance of the offspring," Woychik says, "we test to determine whether the gene that was interrupted by a transgene is responsible for the change in appearance."

Another technique used to investigate the function of various mouse genes is known as targeted mutagenesis. In contrast to the random mutations introduced by insertional mutagenesis, targeted mutagenesis allows researchers to determine the effect of introducing a mutation at a specific site on a selected gene.

This degree of accuracy is achieved by introducing changes in the chromosomal DNA of cultured embryonic cells using a process called homologous recombination. In this approach, altered genetic material is inserted back into the context of a living mouse by microinjecting the manipulated cells into a host blastocyst (a 4-day-old mouse embryo).

Uncovering all the functional parallels between the genes of mice and humans could easily occupy several research lifetimes, but Woychik and his group have a more modest goal. Says Woychik: "We hope we can begin to establish molecular connections between individual genes on the genome and specific developmental processes in both mice and men.

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